Individualized Primary Clinical Target Volume Based on Margin Expansion for Nasopharyngeal Carcinoma

Individualized Primary Clinical Target Volume Based on Margin Expansion for Nasopharyngeal Carcinoma: A Non-Inferiority, Multicenter, Randomized Phase 3 Trial

This is a non-inferiority, multicenter, randomized phase 3 trial aimed to evaluate whether primary clinical target volume (CTVp) delineation based on margin expansion provides comparable outcomes compared with the consensus CTVp approach based on margin expansion and the stepwise extension pattern in newly diagnosed non-metastatic nasopharyngeal carcinoma.

This multicenter, prospective, randomized phase 3 trial aims to evaluate a margin-expansion-based primary clinical target volume (CTVp) delineation strategy in patients with newly diagnosed non-metastatic nasopharyngeal carcinoma (NPC). The primary objective is to demonstrate non-inferiority of this CTVp approach compared with the consensus CTVp defined by the CSTRO, CACA, CSCO, HNCIG, ESTRO, and ASTRO guidelines (which incorporate both margin expansion and local stepwise extension patterns), with local relapse-free survival as the primary endpoint. Secondary objectives include comparisons of overall survival, failure-free survival, distant metastasis-free survival, locoregional relapse-free survival, and regional relapse-free survival between the two CTVp strategies, as well as assessments of radiotherapy-related complications, quality of life, and their impact on the tumor immune microenvironment, along with exploration of the underlying biological mechanisms.

Eligible patients will be prospectively enrolled from multiple centers across China and randomized in a 1:1 ratio to receive either the margin-based CTVp or the consensus guideline-based CTVp. Comprehensive treatment in both arms will follow current clinical guidelines and be stratified by tumor stage. Prognosis, toxicity, and quality-of-life outcomes will be systematically compared between the two groups.

Inclusion Criteria:

1. Age: 18 Years to 65 Years.

2. Eastern Cooperative Oncology Group performance status ≤1.

3. Patients with newly diagnosed, histologically confirmed nasopharyngeal carcinoma (non-keratinizing subtype).

4. Tumor staged as T1-4N0-3M0 (AJCC 9th).

5. Patients must sign informed consent and be willing and able to comply with the requirements of visits, treatment, laboratory tests and other research requirements stipulated in the research schedule.

6. Women of childbearing potential and male subjects with female partners of childbearing potential must agree to use reliable contraceptive measures from screening to 1 year after treatment.

7. For subjects requiring chemotherapy, the following are additionally required:

   1. normal bone marrow function (white blood cell count > 4 × 10^9/L, hemoglobin > 90 g/L, platelet count > 100 × 10^9/L);
   2. normal liver and kidney function (total bilirubin ≤ 1.5 × upper limit of normal, alanine transaminase and aspartate transaminase ≤ 2.5 × upper limit of normal, alkaline phosphatase ≤ 2.5 × upper limit of normal, creatinine clearance rate ≥ 60 mL/min).

Exclusion Criteria:

1. Active tuberculosis: active tuberculosis within the past 1 year should be excluded regardless of treatment; a history of active tuberculosis > 1 year ago is exclusionary unless prior adequate anti-tuberculosis treatment is documented.

2. Active infection requiring systemic treatment.

3. Previous or concurrent with other malignant tumors, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary cancer.

4. History of radiotherapy, except for non-melanoma skin cancer located outside the target volume of radiotherapy for nasophayngeal carcinoma.

5. Prior or concurrent treatment for local or regional disease other than that specified in the research plan.

6. Pregnant or lactating women (a pregnancy test is required for women of childbearing potential).

7. Contraindications to MRI examination, for example: claustrophobia, allergy to MRI contrast.

8. History of psychiatric disorders, alcoholism or drug abuse, and other situations assessed by the investigators that may compromise the safety or compliance of patients, such as serious disease requiring timely treatment (including mental illness), severe laboratory abnormalities, or family-social risk factors.

9. For participants requiring chemotherapy, the following must also be excluded:

   1. anti-human immunodeficiency virus positive or diagnosed with acquired immune deficiency syndrome;
   2. uncontrolled heart disease (heart failure [NYHA Class ≥ 2], unstable angina, myocardial infarction in past 1 year, supraventricular or ventricular arrhythmia requiring treatment or intervention).

10. For participants requiring immunotherapy, the following must also be excluded:

    1. hepatitis B virus surface antigen positive and Hepatitis B virus DNA > 1000 copies/mL;
    2. anti-hepatitis C virus positive;
    3. active, known or suspected autoimmune disease (including but not limited to uveitis, enteritis, hepatitis, pituitary disease, nephritis, vasculitis, hyperthyroidism, hypothyroidism and asthma requiring bronchodilators, exceptions are type I diabetes mellitus, hypothyroidism not requiring hormone replacement therapy, skin disorders not requiring systemic treatment [such as vitiligo, psoriasis or alopecia]);
    4. previous interstitial lung disease or pneumonia requiring oral or intravenous steroid therapy;
    5. chronic treatment with systemic glucocorticoid (dose equivalent to or over 10 mg prednisone per day, subjects who use inhaled or topical corticosteroids are eligible) or any other form of immunosuppressive therapy;
    6. allergy to macromolecular protein preparations, or any component of PD-1 monoclonal antibody;
    7. receiving live vaccine within 30 days prior to the first dose of PD-1 monoclonal antibody.