Reconstruction of Cervical Lymphatic System During Head and Neck Squamous Cell Carcinoma Surgery

Official title

An Exploratory Study of Reconstruction of Cervical Lymphatic System by Vascularized Lymphoid Tissue Transplantation During Head and Neck Squamous Cell Carcinoma Surgery

Overview

Head and neck squamous cell carcinoma is one of the most common malignant tumors. At present, the standard treatment of head and neck squamous cell carcinoma recommended by the National Comprehensive Cancer Network(NCCN) treatment guideline in the United States and the Chinese Society of Clinical Oncology(CSCO) treatment guideline in China is a comprehensive treatment model based on surgery, supplemented by radiotherapy, chemotherapy, immunization and targeted therapy. Neck lymph dissection is one of the most important surgical procedures for the treatment of head and neck squamous cell carcinoma. The injury of surgery and postoperative adjuvant radiotherapy leads to inadequate drainage of lymphatic system, leading to head and neck lymphedema. Vascularized lymph node transplantation is successfully used in the treatment of upper and lower limb lymphedema, but has not been reported in the treatment of head and neck lymphedema. At present, neck lymph dissection is the standard surgical protocol for head and neck squamous cell carcinoma, and there is no clear evidence that neck lymph dissection can be avoided. The dorsal thoracic artery flap can be used to make the flap of chimeric axillary lymph node, and can also be used as one of the vascularized lymph transplantation donor areas for the treatment of lymphedema without increasing the risk of upper limb lymphedema in the donor area. Therefore, the investigators propose: Can the function of the head and neck lymphatic system be reconstructed by transplanting normal lymph nodes from other parts of the body into the neck to form new lymphatic pathways at the same time of operation for head and neck squamous cell carcinoma? In our previous operation for head and neck squamous cell carcinoma, thoracic dorsal artery flap with partial axillary lymphoid tissue transplantation was used to repair head and neck defects. Retrospective analysis showed that the lymph node transplantation in the previous cases survived. Therefore, this project designed a prospective exploratory clinical study to clarify the activity and donor safety of cervical vascularized lymphatic transplantation, and further explore the effect of vascularized lymphatic tissue transplantation to rebuild the cervical lymphatic system in reducing the incidence of postoperative head and neck lymphedema, alleviating cervical fibrosis after radiotherapy and even improving the prognosis of patients.

Detailed description

Head and neck squamous cell carcinoma is one of the most common malignant tumors. At present, the standard treatment of head and neck squamous cell carcinoma recommended by the NCCN treatment guideline in the United States and the CSCO treatment guideline in China is a comprehensive treatment model based on surgery, supplemented by radiotherapy, chemotherapy, immunization and targeted therapy. Neck lymph dissection is one of the most important surgical procedures for the treatment of head and neck squamous cell carcinoma. The injury of surgery and postoperative adjuvant radiotherapy leads to inadequate drainage of lymphatic system, leading to head and neck lymphedema. Lymphedema is a progressive process that includes features such as lymphatic stasis, lymphatic vessel remodeling and dysfunction, inflammation, fatty tissue deposition, and eventually fibrosis. Therefore, in addition to edema, complications such as cervical fibrosis may occur, which seriously affects the quality of life of patients with head and neck squamous cell carcinoma. In addition, the absence of lymphatic tissue in the neck after cervical lymph dissection may damage the local lymphatic immune monitoring function of the head and neck, and affect the postoperative therapeutic effect and prognosis of patients.

Surgical treatment of head and neck lymphedema includes lymphatic venous shunt and vascularized lymph node transplantation, which involves the transfer of healthy lymph nodes from unaffected parts of the body to the site of lymphedema. Vascularized lymph node transplantation is successfully used in the treatment of upper and lower limb lymphedema, but has not been reported in the treatment of head and neck lymphedema.

At present, neck lymph dissection is the standard surgical protocol for head and neck squamous cell carcinoma, and there is no clear evidence that neck lymph dissection can be avoided. Therefore, head and neck lymphedema after head and neck squamous cell carcinoma is a common surgical complication. In our previous study, the investigators collected the data of 71 patients with head and neck squamous cell carcinoma undergoing surgical treatment, and found that the greater the scope of cervical lymph dissection, the more serious the degree of lymphedema after surgery. In addition, our research group has successfully implemented thoracic dorsal artery flap to repair oral cancer defects in more than 100 cases in the early stage, which proved that the success rate of thoracic dorsal artery flap is high and the functional injury of the donor area is small. The dorsal thoracic artery flap can be used to make the flap of chimeric axillary lymph node, and can also be used as one of the vascularized lymph transplantation donor areas for the treatment of lymphedema without increasing the risk of upper limb lymphedema in the donor area.

There are no effective preventive measures for head and neck lymphedema and neck fibrosis in patients with head and neck squamous cell carcinoma after comprehensive treatment. In order to reduce the pain, cost and possibility of reoperation caused by postoperative treatment, the prevention of head and neck lymphedema after the operation of head and neck squamous cell carcinoma has become an important clinical problem to be solved in this project. Therefore, the investigators propose: Can normal lymph nodes from other parts of the body be transplanted into the neck to form new lymphatic pathways during head and neck squamous cell carcinoma surgery to rebuild the function of the head and neck lymphatic system and avoid postoperative complications such as lymphedema? In our previous study, 6 patients with head and neck squamous cell carcinoma were successfully transplanted with dorsal thoracic artery flap carrying part of armpit lymphoid tissue during operation to reconstruct the neck lymphatic system. Postoperative Magnetic Resonance(MR) And ultrasound showed that the size and structure of the transplanted lymph nodes were normal, no lymph node necrosis was observed, and blood flow was lymphatic portal type. No upper limb lymphedema occurred in the donor area.

In this study, patients with head and neck squamous cell carcinoma with clinical stages of T2-3,N0-3,M0 and T4a,N0-3,M0 requiring surgical treatment and repair by skin flap transplantation were selected, and were enrolled by Simon stage II, and the intervention measures were based on the recommended surgical methods in the guidelines and the vascularization axillary lymphatic transplantation at the same time. The main study endpoints were the survival of transplanted lymph nodes, the incidence and degree of lymphedema in the head and neck, and the incidence and degree of lymphedema in the upper limb of the donor area. Secondary endpoints were 2-year disease-free survival, 2-year overall survival, patient quality of life evaluation, and safety evaluation.

Interventions

• Procedure Vascularized lymphatic transplantation
  Preoperative ultrasonography was performed to check the distribution, quantity and size of axillary lymph nodes. During the operation, methylene blue was injected subcutaneously into the elbow fossa to make the axillary lymph nodes in area B and D chromogenic, and avoid damage to the arm drainage lymph nodes. Adjusting the flap design according to the size of the defect. The perforating branches of lymphoid tissue in areas A and C of grade I were located about 3-5cm above the perforating branch

Primary outcome measures

• Incidence of head and neck lymphedema within 2 years after surgery [Time frame: At least 3 months to 2 years after surgery]
• severity of head and neck lymphedema within 2 years after surgery [Time frame: At least 3 months to 2 years after surgery]

Secondary outcome measures (6)

• The survival of transplanted lymph nodes at 3 months and 6 months after comprehensive treatment [Time frame: 3，6，12，24 months after comprehensive treatment]
• Incidence of upper limb lymphedema in donor area [Time frame: At least 6 months to 2 years after surgery]
• degree of upper limb lymphedema in donor area [Time frame: At least 6 months to 2 years after surgery]
• 2-year disease-free survival [Time frame: within 2 years after surgery]
• 2-year overall survival [Time frame: within 2 years after surgery]
• Postoperative magnetic resonance lymphangiography was performed by injecting contrast agent into the flap to check the number of transplanted lymph nodes [Time frame: 3，6，12，24 months after comprehensive treatment]

Eligibility criteria

Inclusion criteria

• This study selected T2-3,N0-3,M0; Patients with T4a,N0-3,M0 head and neck squamous cell carcinoma (AJCC 8th) can be treated surgically with flap repair and no axillary lymphatic metastasis.
• No history of other malignant tumors 3.18-75 years old

4\. Baseline check is normal:

• In the past 14 days without the use of granulocyte colony-stimulating factor, the absolute value of neutrophil (ANC) ≥1.5x109/L;
• Platelets ≥100×109/L in the past 14 days without blood transfusion;
• Hemoglobin >9g/dL in the last 14 days without blood transfusion or use of erythropoietin;
• Total bilirubin ≤1.5× upper limit of normal (ULN);
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5×ULN (ALT or AST ≤5×ULN in patients with liver metastasis);
• Serum creatinine ≤1.5×ULN and creatinine clearance (calculated by Cockcroft- Gault formula) ≥60 ml/min;
• Good coagulation function, defined as International standardized ratio (INR) or prothrombin time (PT) ≤1.5 times ULN;
• Normal thyroid function, defined as thyroid stimulating hormone (TSH) within the normal range. If baseline TSH is outside the normal range, subjects with total T3 (or FT3) and FT4 within the normal range can also be enrolled;
• The myocardial enzyme profile is within the normal range (if the researchers comprehensively judge that the simple laboratory abnormality is not clinically significant, it is also allowed to be included);
• For female subjects of reproductive age, a urine or serum pregnancy test should be taken and the result is negative within 3 days prior to the first treatment (day

1 of cycle 1). If the urine pregnancy test results cannot be confirmed as negative, a blood pregnancy test is requested. Women of non-reproductive age were defined as at least one year after menopause or having undergone surgical sterilization or hysterectomy;

• If there is a risk of conception, all subjects (male or female) should use contraception with an annual failure rate of less than 1% for the entire duration of treatment up to 120 days after the last treatment (or 180 days after the last chemotherapy drug administration).
• No axillary lymph node metastasis.

Exclusion criteria

• Diagnosis of other malignant tumors, or treatment of HNSCC did not start.
• Prior to treatment, an active autoimmune disease requiring systemic treatment (e.g. use of disease-modifying drugs, glucocorticoids, or immunosuppressants) has occurred within the previous 2 years. Replacement therapies (such as thyroxine, insulin, or physiologic glucocorticoids for adrenal or pituitary insufficiency) are not considered systemic therapy;
• Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
• Known history of human immunodeficiency virus (HIV) infection (i.e. HIV 1/2 antibody positive);
• Untreated active hepatitis B (defined as HBsAg positive and HBV-DNA copy number detected greater than the upper limit of normal value in the laboratory of the research center);

Note: Hepatitis B subjects who meet the following criteria can also be enrolled:

• Pre-treatment HBV viral load <1000 copies /ml (200 IU/ml), subjects should receive anti-HBV therapy throughout study treatment to avoid viral reactivation
• For subjects with anti-HBC (+), HBsAg (-), anti-HBS (-) and HBV viral load (-), prophylactic anti-HBV therapy is not required, but close monitoring of viral reactivation is required
• Active HCV-infected subjects (HCV antibody positive and HCV-RNA levels above the lower limit of detection);
• Pregnant or lactating women;
• The presence of any serious or uncontrolled systemic disease, such as:

• The resting electrocardiogram has major abnormal rhythm, conduction or morphology, such as complete left bundle branch block, heart block above Ⅱ degree, ventricular arrhythmia or atrial fibrillation;
• Unstable angina pectoris, congestive heart failure, New York Heart Association (NYHA) grade ≥ 2 chronic heart failure;
• Any arterial thrombosis, embolism or ischemia occurred within 6 months before treatment, such as myocardial infarction, unstable angina pectoris, cerebrovascular accident or transient ischemic attack;
• Poor blood pressure control (systolic > 140 mmHg, diastolic > 90 mmHg);
• There is a history of non-infectious pneumonia requiring glucocorticoid therapy within 1 year prior to treatment, or there is currently clinically active interstitial lung disease;
• Active pulmonary tuberculosis;
• There is an active or uncontrolled infection that requires systemic treatment;
• Clinically active diverticulitis, abdominal abscess, gastrointestinal obstruction;
• Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
• Poor diabetes control (fasting blood glucose (FBG) > 10mmol/L);
• Urine routine indicated urine protein ≥++, and confirmed 24-hour urine protein quantity > 1.0 g;
• Patients with mental disorders who cannot cooperate with treatment;
• Axillary lymphatic metastasis
• Medical history or evidence of disease that may interfere with the test results, prevent participants from fully participating in the study, abnormal treatment or laboratory test values, or other conditions that the investigator considers unsuitable for enrollment. The Investigator considers other potential risks unsuitable for participation in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun Yat-sen Memorial Hospital, Sun Yat-sen University — Guangzhou

Publications

• Cohen O, Brauer PR, Judson BL, Burtness BA, Earles J, Mehra S. Guideline - Adherence in advanced stage head and neck cancer is associated with improved survival - A National study. Oral Oncol. 2022 Feb;125:105694. doi: 10.1016/j.oraloncology.2021.105694. Epub 2021 Dec 28. PMID 34971883
• Vos JL, Elbers JBW, Krijgsman O, Traets JJH, Qiao X, van der Leun AM, Lubeck Y, Seignette IM, Smit LA, Willems SM, van den Brekel MWM, Dirven R, Baris Karakullukcu M, Karssemakers L, Klop WMC, Lohuis PJFM, Schreuder WH, Smeele LE, van der Velden LA, Bing Tan I, Onderwater S, Jasperse B, Vogel WV, Al-Mamgani A, Keijser A, van der Noort V, Broeks A, Hooijberg E, Peeper DS, Schumacher TN, Blank CU, d PMID 34937871
• Savvides PP. The role of chemotherapy in the management of patients with head and neck cancer. Semin Plast Surg. 2010 May;24(2):137-47. doi: 10.1055/s-0030-1255331. PMID 22550434
• Deng J, Ridner SH, Dietrich MS, Wells N, Wallston KA, Sinard RJ, Cmelak AJ, Murphy BA. Prevalence of secondary lymphedema in patients with head and neck cancer. J Pain Symptom Manage. 2012 Feb;43(2):244-52. doi: 10.1016/j.jpainsymman.2011.03.019. Epub 2011 Jul 30. PMID 21802897
• Stubblefield MD, Weycker D. Under recognition and treatment of lymphedema in head and neck cancer survivors - a database study. Support Care Cancer. 2023 Mar 23;31(4):229. doi: 10.1007/s00520-023-07698-3. PMID 36952136
• Deng J, Lukens JN, Swisher-McClure S, Cohn JC, Spinelli BA, Quinn RJ, Chittams J, McMenamin E, Lin A. Photobiomodulation Therapy in Head and Neck Cancer-Related Lymphedema: A Pilot Feasibility Study. Integr Cancer Ther. 2021 Jan-Dec;20:15347354211037938. doi: 10.1177/15347354211037938. PMID 34387119
• Schaverien MV, Asaad M, Selber JC, Liu J, Chen DN, Hall MS, Butler CE. Outcomes of Vascularized Lymph Node Transplantation for Treatment of Lymphedema. J Am Coll Surg. 2021 Jun;232(6):982-994. doi: 10.1016/j.jamcollsurg.2021.03.002. Epub 2021 Mar 22. PMID 33766726
• Coroneos CJ, Asaad M, Wong FC, Hall MS, Chen DN, Hanasono MM, Schaverien MV. Outcomes and technical modifications of vascularized lymph node transplantation from the lateral thoracic region for treatment of lymphedema. J Surg Oncol. 2022 Mar;125(4):603-614. doi: 10.1002/jso.26783. Epub 2022 Jan 6. PMID 34989418

Identifiers

NCT: NCT06815705 · SYSJS-2024-074-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗