Lai Suzhiwang's new adjuvant strategy is effective in shrinking tumors and improving prognosis: patients with locally advanced thyroid cancer usher in opportunities for surgery

*Only for medical professionals to read and reference, this material is supported by Hutchison Medicine
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The neoadjuvant treatment strategy of sofatinib combined with teriprizumab may provide surgical treatment opportunities for patients with locally advanced thyroid cancer
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Thyroid cancer is the most common malignant tumor of the head and neck
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In 2020, there were 586,202 new cases of thyroid cancer in the world, and 48,646 deaths due to thyroid cancer.
The incidence rate has become a clear upward trend [1]
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Most patients with thyroid cancer have a good prognosis and can survive long-term after surgery and follow-up 131I treatment
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However, for some patients with locally advanced thyroid cancer at the time of initial diagnosis, the prognosis of the patients is seriously affected due to the loss of surgical opportunities or the inability to completely remove them
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Unable to complete surgical resection has become one of the main causes of death in patients with thyroid cancer
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In recent years, neoadjuvant therapy has been widely used in the treatment of a variety of malignant tumors, as a kind of neoadjuvant therapy, as a kind of application before surgical treatment, trying to reduce the stage of patients' tumors, so as to achieve organ preservation and R0 resection
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In the field of thyroid cancer, whether neoadjuvant therapy can also benefit patients with locally advanced inoperable thyroid cancer has attracted the attention of experts and scholars
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The medical profession specially invited Professor Ji Qinghai and Professor Chen Jiaying from the Cancer Institute of Fudan University to analyze the exploration and development of neoadjuvant therapy for thyroid cancer
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Can it be surgically removed? Thyroid cancer is the most common endocrine tumor, which determines the prognosis of patients with locally advanced thyroid cancer.
The incidence rate has also been increasing year by year in recent years.

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Among the main types of thyroid cancer, differentiated thyroid cancer (DTC) is the most common, accounting for more than 95% of all new-onset thyroid cancer patients [2]
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The prognosis of patients depends largely on the progress of the tumor and the ability to achieve complete surgical resection
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Professor Ji Qinghai said: “Traditionally, we believe that compared with other malignant tumors, thyroid cancer has a relatively good prognosis and that patients have a chance of long-term survival after systemic treatment
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However, this “good” prognosis must depend on complete surgical resection
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For patients In terms of whether surgery can be performed and the tumor can be completely removed during the operation, it is the most critical factor in determining the prognosis
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"Professor Ji Qinghai said that many patients with thyroid cancer in the clinic are already locally advanced when they are diagnosed and cannot be completely operated on.
The opportunity for surgery has been lost
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According to the eighth edition of the American Cancer Council (AJCC) staging standards, locally advanced thyroid cancer is usually defined as a tumor that significantly invades surrounding important structures, such as the recurrent laryngeal nerve, trachea, esophagus, larynx, large blood vessels in the neck, upper mediastinum, or extensive skin Muscles and so on
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Because the tumor is adjacent to important nerves and blood vessels, these patients may have progressive dyspnea and dysphagia as the tumor progresses
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Asphyxiation caused by tumor ulceration and bleeding may even become an important cause of death in patients with locally advanced thyroid cancer
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The treatment of locally advanced patients is also the most difficult, and inability to operate has become the biggest threat to the survival of patients with locally advanced thyroid cancer
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Sofantinib+Treplimumab-a neoadjuvant strategy research hypothesis "Based on the important role of surgery in the treatment of thyroid cancer, for patients with locally advanced thyroid cancer, can we regain the opportunity for surgery
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Become the key to fundamentally improve the prognosis of patients and obtain long-term survival
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"Professor Ji Qinghai said: "In recent years, with the rapid development of molecular targeting technology and immunotherapy, many patients with malignant tumors have benefited from this, and have achieved a fundamental improvement in survival time and quality of life
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For thyroid cancer, a malignant tumor that is not sensitive to traditional radiotherapy and chemotherapy, whether targeted and immunotherapy can be used to achieve translational therapy for locally advanced patients has become the field that we most want to study in depth
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"In recent years, there have been occasional reports that seem to confirm the feasibility of neoadjuvant treatment strategies for patients with locally advanced thyroid cancer
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Professor Chen Jiaying said that in these medical reports, we can see that some patients with locally advanced inoperable thyroid cancer After 3-9 months of neoadjuvant therapy with targeted drugs, the patient achieved significant tumor regression and finally successfully underwent surgery
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“Based on the excellent tumor shrinkage effects of neoadjuvant therapy in these case reports, and the target The synergistic model of immunotherapy and immunotherapy drugs reminds us whether we can choose a targeted + immune combined neoadjuvant therapy strategy to apply to patients with locally advanced thyroid cancer, so that they can regain the chance of surgery and improve the prognosis
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"Professor Chen Jiaying said, "Based on this idea, we chose a small molecule tyrosinase inhibitor (TKI) independently developed by our country, sofantinib, in combination with teriprizumab to carry out a treatment for the difficulty of locally advanced surgery.
The clinical study of neoadjuvant therapy in patients with differentiated thyroid cancer [3] aims to observe and evaluate the effectiveness and safety of sofatinib combined with teriprizumab in patients with locally advanced thyroid cancer
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"In terms of research design, patients with locally advanced differentiated thyroid cancers, including papillary thyroid carcinoma and follicular carcinoma, who are older than 21 years old and confirmed histopathologically can be enrolled in the group to receive neoadjuvant treatment
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Patients in the enrolled group will be given neoadjuvant therapy .
Sofatinib 250mg oral qd combined with 240mg teriprizumab intravenous drip once a week
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Since the start of treatment, imaging examinations will be performed every 2 cycles to evaluate the efficacy, until surgery is possible, disease progresses, voluntary withdrawal is informed, toxicity is intolerable, or the researcher thinks that it is necessary to withdraw from the study
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The primary endpoint of the study is the objective response rate (ORR), and the secondary endpoints are R0/1 resection rate, disease control rate (DCR), time to remission (TTR), progression-free survival (PFS), overall survival (OS) ), and other adverse events
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Figure 1 Neoadjuvant treatment study design for patients with locally advanced operatively difficult differentiated thyroid cancer.
Regarding the criteria for patient enrollment, Professor Chen Jiaying said: "We have strictly limited the patients enrolled in neoadjuvant therapy
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Patients must be confirmed histopathologically.
Locally advanced differentiated thyroid cancer
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At the same time, we also have an accurate definition of locally advanced thyroid cancer , including unresectable, difficult R0/R1 resection due to surgical difficulties, or T4 stage thyroid cancer defined by AJCC
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"Successfully enrolled in the group.
After the completion of the baseline assessment, the patients were given neoadjuvant therapy with sofatinib + teriprizumab and evaluated the efficacy of imaging until the patients could undergo surgical treatment, disease progression, or drug toxicity was not tolerated and left the group
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Professor Ji Qinghai said: “Strictly and accurately defining the enrolled population and rationally formulating research implementation plans are the prerequisites for clinical research to ultimately obtain effective results and provide true and reliable evidence for disease diagnosis and treatment
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At the same time, strict enrollment standards can also become the future The basis for guiding patients with locally advanced thyroid cancer to receive neoadjuvant treatment "At present, many patients have been enrolled in the group for treatment, and some patients have achieved good tumor control during the treatment process and have entered the stage of surgical treatment
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Locally advanced thyroid cancer-neoadjuvant treatment of shrinking tumors creates surgical opportunities (the following cases are only brief case descriptions of relevant researchers in the clinical research process, for scientific communication and reference by medical professionals
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Individual cases are usually different, and the specific treatment plan and medication should be combined with the individual situation and strictly follow the doctor's advice
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) Case 1 Short-term progression of thyroid cancer after surgery, sofantinib + teriprizumab brings opportunities for R0 resection.
Basic information: The patient, 69 years old, was admitted to the hospital for further treatment for "more than 1 year after thyroid cancer" After: On November 30, 2018, the patient underwent thyroid cancer resection in an outside hospital.
Postoperative pathology revealed: right lobe thyroid papillary carcinoma; tumor invaded surrounding intramuscular tissue
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Immunohistochemistry: P53(+), Ki-67 about 60%, CgA(-), SYN(-), PgP(+++), ToPoII negative
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Postoperative laryngoscopy revealed paralysis of the right vocal cords
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In January and April 2019, both "abscess incision and drainage" and "neck infection lesion debridement exploration + fistula repair" were performed due to "surgical incision infection" in January and April 2019.
Postoperative pathology: see infiltration in the fibrous connective tissue near the right side of the trachea Papillary thyroid carcinoma tissue
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On April 30, 2020, the patient underwent "bilateral residual thyroidectomy" due to "right thyroid lobe occupation"
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Postoperative pathology revealed that papillary thyroid carcinoma was seen in the right lobe of the thyroid
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On July 11, 2020, oral I-131 treatment was performed for the first time
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It is suggested that a reexamination of the neck and chest CT after the treatment of the right neck space-occupying showed: space-occupying lesions were seen on the right side of the neck, the lesion and the trachea were unclear, and the trachea was compressed and narrowed to the left
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There are multiple lymph nodes in the submandibular and deep neck
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Enrollment status: Diagnosis: Papillary thyroid carcinoma, tumor stage: T4N1M0, IVA stage, tumor invaded important structures such as trachea and esophagus, and R0/R1 cannot be resected into the group
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Enrollment treatment: CT examination of the neck before neoadjuvant treatment on May 21, 2021: The tumor was located next to the right trachea with a long diameter of 15.
6 mm, and the tumor significantly invaded the esophagus
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Figure 2 Cervical CT examination on May 21, 2021.
Sofantinib 250 mg orally and teriprizumab 240 mg intravenously were given twice on May 25 and June 17, 2021
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The medication was suspended on July 5, 2021 due to immune-related hepatitis
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Efficacy evaluation: First evaluation after neoadjuvant medication on July 5, 2021, re-examination of neck CT showed that the tumor was similar to the treatment, and the longest diameter was 13.
8mm
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Efficacy assessment SD
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Figure 3 The first evaluation of CT results after neoadjuvant therapy on July 5, 2021.
The second evaluation after neoadjuvant medication on August 24, 2021.
Re-examination of neck CT showed that the tumor was smaller than before, and the longest diameter 11.
1mm and the esophagus were obvious.
Interval, esophageal invasion has been reduced, and the therapeutic effect is evaluated SD
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Figure 4 The second evaluation of CT results after neoadjuvant treatment on August 24, 2021.
Surgical treatment: After neoadjuvant treatment, the patient underwent radical resection of the right paratracheal tumor on September 1, 2021, and the right paratracheal tumor was completely removed during the operation During the operation, the tumor invasion of the esophagus was significantly reduced compared with that before neoadjuvant treatment.
The esophageal muscle layer was removed and the mucosal layer was preserved
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(R0 resection) Case 2 was newly diagnosed with locally advanced thyroid cancer.
Sofantinib + Teriprizumab brought opportunities for R0 resection.
Basic information: The patient was female, 76 years old, and was admitted to the hospital for further treatment due to “neck mass found for 2 months” Diagnosis and treatment process: On June 29, 2021, the patient underwent a puncture of the neck mass and was sent to our hospital for a case consultation prompt: papillary thyroid carcinoma
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Immunohistochemistry: PAX8 (+), TTF-1 (+), P40 (-), PD-L1 22C3 (TPS<1%)
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CT examination of the neck on June 28, 2021 showed that: the left supraclavicular mass is not clearly demarcated from the left thyroid gland, and there are multiple nodules on both sides of the thyroid gland
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The ultrasound examination on June 29, 2021 showed that the parenchymal nodules on the left lower neck and left supraclavicular may be malignant
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The examination on July 13, 2021 (PET-CE) revealed that there were multiple nodules in the two lobes of the thyroid, and no increase in FDG metabolism was seen
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Metastasis of the left supraclavicular lymph node
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Enrollment status: Diagnosis: Papillary thyroid carcinoma, tumor stage: T4N1M0, stage IVA, tumor invaded the common carotid artery, and could not be admitted into the group by surgery
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Enrollment treatment: CT examination of the neck before neoadjuvant treatment on June 25, 2021 showed that the left cervical lymph node had a lateral diameter of 6.
1 cm, infringing on the left common carotid artery
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Figure 5 Cervical CT examination on June 25, 2021.
Patients were given Sofatinib 250 mg oral treatment on July 27, 2021
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On August 18, September 8, and September 27, 2021, the patient was given sofatinib 250 mg orally + 240 mg teriprizumab intravenously for three times
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Efficacy evaluation: The first evaluation after neoadjuvant medication on September 2, 2021, re-examination of neck CT showed that the tumor shrinkage effect was obvious, the tumor's transverse diameter was reduced to 3.
75mm, and the tumor was separated from the common carotid artery
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Efficacy evaluation PR
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Figure 6 The first evaluation of CT results after neoadjuvant treatment on September 2, 2021.
The first evaluation after neoadjuvant medication on October 11, 2021.
Re-examination of neck CT showed that the tumor shrinkage effect was obvious, and the effect of PR was evaluated
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Figure 7 The second evaluation of CT results after neoadjuvant treatment on October 11, 2021.
Surgical treatment: After neoadjuvant treatment, the patient underwent modified radical resection of left thyroid lobe + right thyroid cancer on November 3, 2021, and the operation was complete The entire nail and the enlarged lymph nodes of the right neck were removed, and the common carotid artery was preserved intact
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Achieve R0 resection
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Although the tumor diagnosis and treatment process of the above two patients were different, they were all included in the group to receive neoadjuvant therapy because the tumor progressed to invade important tissue structures such as the esophagus and carotid artery and could not achieve R0 resection
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After the completion of the baseline imaging examination and evaluation, we all gave the patients 250mg of oral sofatinib + 240mg of teriprizumab intravenously
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Although the first patient suspended medication early due to immune hepatitis, in the evaluation of the efficacy after neoadjuvant therapy, the obvious tumor shrinkage effect of sofatinib + teriprizumab can be seen
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This allows the above-mentioned patients to finally obtain the opportunity of surgery and achieve R0 resection, which is of great significance for patients with locally advanced thyroid cancer
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Professor Chen Jiaying emphasized: “At present, according to the AJCC staging method of thyroid cancer, it is still controversial whether the definition of T4 patients can be operated
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In clinical practice, according to the actual situation, the tumor invades the esophagus, recurrent laryngeal nerve, and important large blood vessels in the neck.
The diaphragm and other important tissues can still achieve R0 resection through detailed preparations and careful surgical operations, and neoadjuvant therapy can reduce the difficulty of surgery due to its tumor shrinking effect
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At the same time, relying on its tumor retreat effect, we are intraoperative It is possible to preserve the patient’s organs as completely as possible, reduce the possibility of damage to important tissue structures, thereby reducing the impact of surgery on the patient’s quality of life
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This is of great significance for patients with thyroid cancer who generally have a longer survival period after R0 resection
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"T4 stage thyroid cancer under the AJCC staging standard-neoadjuvant brings new hope.
" Once patients with locally advanced thyroid cancer cannot undergo surgery, we are helpless
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"When talking about the reasons for the application of neoadjuvant therapy for patients with thyroid cancer, Professor Ji Qinghai said: "We are very clear that for patients with thyroid cancer, surgery is very important
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Under the premise of ensuring safety, complete R0 resection as much as possible can significantly extend the survival period
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Even if only R1 resection can be achieved, a good local control rate can still be obtained through subsequent I-131 treatment or local external radiation
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Once the opportunity for surgery is lost, neither radiotherapy nor chemotherapy can achieve satisfactory therapeutic effects
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At the same time, phase II clinical studies have confirmed that Sofatinib has a certain effect on advanced thyroid cancer, while showing good tumor shrinkage effects
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We believe that if the medication window is moved to before surgery for locally advanced patients, it will win surgery for patients with locally advanced inoperable thyroid cancer, or it may change the current treatment situation for locally advanced patients
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"As for how to determine the benefit population of neoadjuvant therapy, Professor Ji Qinghai said that thyroid cancer is different from other head and neck tumors
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The
determination of neoadjuvant therapy population for head and neck squamous cell carcinoma mainly depends on the tumor stage
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For thyroid According to the AJCC staging scheme of cancer, it is difficult to judge the people who will benefit from neoadjuvant treatment
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At present, with the update of surgical treatment technology and equipment, many patients with T4 stage thyroid cancer based on the AJCC definition can already achieve complete surgical resection
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At the same time, relying on the good tumor shrinking effect of neoadjuvant therapy, in addition to increasing the chance of surgery for patients, it is of great significance for preserving the organ function of surgical patients and improving the quality of life of patients.

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Professor Ji Qinghai emphasized that the enrollment criteria formulated for this clinical study of neoadjuvant therapy hope to become the screening criteria for the adapted population of neoadjuvant therapy for patients with thyroid cancer in the future
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So as to realize the support based on clinical research data and guide clinical practice to bring the gospel to more patients with thyroid cancer
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Finally, the prospects and expectations of neoadjuvant therapy for thyroid cancer
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Professor Ji Qinghai said that in addition to the significance of neoadjuvant therapy affecting the treatment of locally advanced patients, we also hope to further explore the mechanism of tumor heterogeneity in translational research, including how to predict the effect of tumors on targeted and immunotherapy in advance.
Efficacy, etc.
, for patients with medullary thyroid cancer, undifferentiated cancer, and other thyroid cancers with poor prognosis and a heavier disease burden, bring opportunities for surgery, and cooperate with targeted and immunotherapy to achieve survival benefits for patients
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Expert profileProfessor Ji Qinghai Chief Expert of the Head and Neck Tumor Comprehensive Treatment Group, Fudan University Tumor Hospital, Deputy Chairman of the Thyroid Cancer Professional Committee of the Chinese Anti-Cancer Association Committee Member Dr.
Chen Jiaying, Deputy Chief Physician of Head and Neck Surgery, Fudan University Cancer Hospital, has rich clinical experience in diagnosis and treatment, mainly researching the treatment of locally advanced thyroid cancer at the doctoral stage, and has published nearly 30 papers in related fields, including the first or co-first author Reference materials for 7 SCI papers: [1] World Health Organization.
International Agency for Research on Cancer.
32-Thyroid-fact-sheet.
Available at https://gco.
iarc.
fr/today/data/factsheets/cancers/32 -Thyroid-fact-sheet.
pdf[2] Chinese Medical Doctor Association Surgeons Branch, Thyroid Surgeons Committee.
Chinese Expert Consensus on Postoperative Management of Differentiated Thyroid Cancer (2020 Edition)[J].
Chinese Journal of Practical Surgery.
2020.
40(9) :1021-1028.
[3] Toripalimab Combined With Surufatinib for Locally Advanced Thyroid Cancer: a Phase II Study.
https://clinicaltrials.
gov/ct2/show/NCT04524884?term=surufatinib&cntry=CN&draw=3&rank=12 "This information is intended It is promoting the communication and exchange of medical information
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