Head and neck cancer is more common in China, accounting for about 19.9%~30.2% of all malignant tumors in the body. Since most of them are in progressive or advanced stages when they are diagnosed, and the local recurrence rate is high (40-60%), the 5-year survival rate of head and neck cancer does not exceed 40% even with the application of current conventional classical treatments. In recent years, people have been studying the integrated treatment including surgery, radiotherapy, chemotherapy and biotherapy to improve the efficacy. Previous studies have shown that the adenoviral vector human recombinant P53 gene (rAd-p53) has a good therapeutic response in head and neck squamous carcinoma. From November 2004 to May 2005, we applied rAd-p53 combined with chemotherapy to treat 4 cases of advanced recurrent head and neck squamous carcinoma, and obtained better results as follows: I. Clinical data Case 1: Male 68 years old, 11 months postoperative for left hypopharyngeal carcinoma, recurrent metastasis in left neck lymph node with headache for 1 month. Previous treatment: total laryngectomy + partial hypopharyngectomy in March 2004, postoperative local adjuvant radiotherapy (50 Gy); pain in the left jaw and left face in February 2005, CT examination confirmed the diagnosis of recurrence of left carotid sheath and parapharyngeal space and lymph node metastasis in the left carotid bifurcation, mass size about 3.4×2.9×2.4 cm. Laboratory tests before treatment: liver and kidney function, blood routine: all within normal values. Treatment regimen: rAd-p53 1012 viral units, ultrasound-guided local injection once a week for 8 weeks, paclitaxel 60mg/m2 cisplatin 35mg/m2 intravenous drip once a week for 3 weeks, rest in the 4th week, 4 weeks 1 cycle, two cycles in total, granulocyte colony-stimulating factor was applied in case of bone marrow suppression during treatment. RESULTS: Pain was significantly reduced (pain self-evaluation from 7 to 3), and the local mass was reduced in size about 3.0×2.3×1.4 cm on repeat CT; efficacy was assessed as stable (NC). Laboratory tests: liver and kidney function: normal; blood routine: WBC 2.52~8.73×109/L, P 63.7%, L 16.5%, Plat 136~230×109/L. Adverse effects: after each rAd-p53 gene therapy, fever, body temperature about 38℃, recovered after symptomatic treatment; severe pain at the local injection site, given before injection, prednisolone 100 mg, intramuscular injection, which was tolerated by the patient; gastrointestinal reactions: poor appetite, nausea, affecting feeding, little eating, occasional vomiting; bone marrow suppression, after the 3rd chemotherapy, requiring supportive treatment with granulocyte colony-stimulating factor. After 1 month of rest for economic reasons the patient was switched to other treatment with TTP for 13 weeks. Case 2: Male 68 years old, 8 months postoperative for squamous carcinoma of the right hypopharynx, admitted with 1 month of local recurrence and pulmonary metastasis. Postoperative pathology: moderately differentiated squamous carcinoma of the hypopharynx, 1/11 metastasis in cervical lymph nodes, T2N1M0. Previous treatment: The patient underwent right hypopharyngeal carcinoma resection + right cervical lymphatic dissection + tracheotomy in March 2004. He received local adjuvant radiotherapy (600Gy) after surgery, and was found to have local recurrence and pulmonary metastasis on review 7 months later. CT examination before treatment: right carotid artery and soft tissue shadow behind the thyroid gland with unclear border, size 3.0×2.7×1.8 cm. and laboratory tests: liver and kidney function, blood routine: all within normal values. Treatment regimen: rAd-p53 1012 viral units ultrasound-guided local injection once a week for 8 weeks, paclitaxel 60mg/m2 cisplatin 35mg/m2 intravenous drip once a week for 3 weeks, rest in the 4th week, 4 weeks for 1 cycle, two cycles in total. RESULTS: Repeat CT showed a soft tissue shadow of the right carotid artery and posterior thyroid gland, smaller than before, with a size of 2.2×1.8×1.5 cm,. However, the shrinkage was less than 50%; ultrasound examination: the tumor shrank, and the injection was locally echogenically enhanced and showed fibrotic changes. The therapeutic efficacy was assessed as stable (NC). Laboratory examination: liver and kidney function: normal; blood routine: WBC 1.66~8.93×109/L, P 68.7%, L 16.5%, Plat 196~253×109/L. Adverse effects: fever, temperature about 38℃, recovered by itself after each rAd-p53 gene therapy; digestive tract: poor appetite, nausea, but did not affect eating, occasional vomiting; bone marrow suppression, after the 2nd chemotherapy, supportive treatment with granulocyte colony-stimulating factor was required, and the patient tolerated the treatment. After 2 weeks of rest, the patient continued to receive treatment and was rechecked at the end of the 4th cycle of treatment. Case 3: Female, 52 years old, 1.5 years postoperative for right maxillary squamous carcinoma, with local recurrence and regional lymph node metastasis. In December 03, metastasis to the right cervical lymph nodes was found, so radical cervical lymph node dissection was performed. 30 times (6 weeks) of radiotherapy was administered after surgery, the dose was ominous. extensive infiltration. He came to the hospital for gene therapy, and CT examination was performed before treatment, which showed postoperative changes in the right maxillary sinus and indistinct soft tissue boundaries in the right orbital apex and right pterygoid sinus. Laboratory tests: liver and kidney function and blood routine were within normal values. Treatment protocol: rAd-p53 1012 viral units intravenous injection once a week for 9 weeks, paclitaxel 60mg/m2 cisplatin 35mg/m2 intravenous drip once a week for 3 weeks, rest in the 4th week, 1 cycle in 4 weeks, evaluation after 2 cycles, results: CT examination, the soft tissue at the right orbital apex and right pterygoid sinus was smaller than before. Laboratory examination: SGOT 15.0 ~57.0 U/L , SGPT 15.0~35.0 U/L, Bil 4.6~13.7 umol/L, BUN 2.53~4.88 umol/L, Cr 54.40~87.6 umol/L, WBC 2.53~6.67×109/L, P 85.7%, L 10.5%. Plat 350~403×109/L. Adverse effects: after each gene therapy, there was fever with body temperature around 38℃, which recovered after symptomatic treatment; Gastrointestinal reactions: poor appetite, nausea, but could eat with slightly less amount; occasional vomiting; bone marrow suppression, after the 2nd chemotherapy, supportive treatment with granulocyte colony-stimulating factor was required. Liver function returned to normal with liver preservation therapy and treatment was terminated due to eye surgery. 2 months rechecked for tumor progression; TTP 23 weeks. Case 4: A 75-year-old male with mucinous epidermoid carcinoma of the left submandibular gland 5 years after surgery and recurrent regional lymph node metastasis for 1 year. Postoperative pathology: mucinous epidermis-like carcinoma of the submandibular gland, highly malignant, with 1/9 lymph node metastasis. Previous treatment: Left submandibular gland, partial hyoidectomy + upper cervical lymph node dissection was performed in October 99; after surgery, he received 32 times of local adjuvant radiotherapy at an unknown dose and 3 cycles of chemotherapy at an unknown dose, and in November 03, mediastinal and left cervical lymph node metastasis was found on review. He was treated with Iressa in combination with Capecitabine for 4 months and achieved remission. In March 04, the tumor recurred again and was treated with CetuximAB (C225) in combination with CPT-11 + 5-Fu + levamizole once a week at an unknown dosage for a total of 22 times. The tumor was found to shrink on review, and 1 month after stopping the drug, a new metastasis appeared in the right cervical lymph node, so he came to the hospital for gene therapy. PET and CT examination before treatment: irregular soft tissue shadow in the lower part of the right anterior triangle of the neck, multiple enlarged lymph nodes in the bilateral carotid canal. Laboratory tests of liver and kidney function and blood routine were within normal values. Treatment regimen: rAd-p53 1012 viral units intravenous injection, once a week for 10 weeks, Jianze 700mg/m2 cisplatin 35mg/m2 intravenous drip, once a week for 3 weeks, rest in the 4th week, 4 weeks 1 cycle, total 3 cycles, results: reexamination PET, carotid canal lymph nodes significantly reduced, anterior carotid triangle soft tissue shadow basically disappeared; efficacy assessment was partial remission (PR). Laboratory examination of liver and kidney function: normal, blood routine: WBC 1.92~8.93×109/L, P 81.4%, L 12.5%, Plat 106~264×109/L. Adverse effects: after each gene therapy, fever, body temperature about 38.5℃, recovered after symptomatic treatment; digestive tract: poor appetite, nausea, but not affecting eating, occasional vomiting. Myelosuppression, after the 1st chemotherapy, required treatment with granulocyte colony-stimulating factor and macro and granule support. The patient was able to tolerate the treatment. The patient continued treatment after 4 weeks of rest and 28 weeks of TTP. II. Discussion The treatment of patients with advanced head and neck tumors requires a multidisciplinary and comprehensive treatment combining surgery, radiotherapy and chemotherapy has gained consensus. Although the survival rate of patients with head and neck tumors has improved and survival period has been prolonged in recent years due to the improvement of surgery and radiotherapy, the wide application of platinum and paclitaxel anticancer drugs, and the introduction of new chemotherapy drugs; however, for patients with recurrent local recurrence and distant metastasis, receiving repeated However, for patients with recurrent local recurrence and distant metastases, after receiving repeated radiotherapy and chemotherapy, the sensitivity of tumor to radiotherapy and chemotherapy is obviously reduced, and the toxic side effects of treatment further decrease the tolerance of patients. Therefore, reversing tumor resistance and improving sensitivity to radiotherapy and chemotherapy are particularly important for patients to gain access to further treatment. The p53 tumor suppressor gene is closely related to tumorigenesis, progression and patient prognosis. More than 50% of tumors have abnormalities of p53 gene mutations and deletions; especially in patients with head and neck squamous carcinoma, the incidence of p53 gene variants is as high as 95%. Previous research data showed that wild-type p53 genes are involved in cell cycle regulation and induction of apoptosis. The introduction of wild-type p53 gene can increase the sensitivity of head and neck squamous carcinoma to radiotherapy and chemotherapy. rAd-p53 is a recombinant adenovirus constructed by genetic recombination, and its anti-tumor mechanism: 1. By introducing exogenous p53 gene expression, it can specifically cause apoptosis or put tumor cells in a severe hibernation state without damaging normal cells. 2. Highly expressed p53 protein and recombinant viral particles can effectively stimulate the body’s specific anti-tumor immune response, and local injection can cause 3. p53 protein can also play a “bystander effect” to kill tumor cells through cellular transmission and regulation of the immune system. 4. introduction of wild-type p53 can enhance the killing effect of radiotherapy and chemotherapy on tumor cells. p53 local intratumoral injection was applied to treat 33 patients with recurrent or metastatic head and neck squamous carcinoma, and no dose-limiting toxic side effects or serious adverse reactions were observed. The disease progressed. Among the surgically resectable cases, one case was pathologically confirmed to have pathological CR after surgery. The results showed that systemic or local application of rAd-p53 was safe, tolerated by patients, and had some efficacy. The cytotoxic effect of rAd-p53 in combination with cisplatin on nasopharyngeal carcinoma cell lines was 25% higher than when cisplatin was used alone, and about 50% of cells underwent apoptosis when the combination was used, whereas the apoptosis rate of either drug alone was quite low, and the two drugs interacted in a superimposed manner [9]; when combined with doxorubicin, it increased the transfection of rAd-p53 in head and neck tumor cells and enhanced the expression of rAd-p53 by exogenous p53 expression and promoting p53-mediated apoptosis in tumor cells, producing synergistic antitumor effects [2]. It provides a theoretical basis for the clinical application of paclitaxel or cisplatin combined with p53 gene in the treatment of head and neck tumors. In our group, four patients with recurrent or metastatic head and neck tumors, whose lesions progressed after repeated surgery, radiation or chemotherapy, were treated with a single-week regimen of rAd-p53 gene combined with paclitaxel or Jianzhi plus cisplatin without serious toxic side effects, and the efficacy was evaluated after two courses of treatment: two cases obtained sub-remission, two cases were stable, and the clinical symptoms of the four patients were significantly improved, local pain symptoms were reduced, and the dosage of morphine was reduced. Morphine dosage was reduced, appetite improved, weight increased, and KPS score improved by 10 points on average. Major adverse effects during treatment: all 4 patients developed fever with a temperature of about 38°C after drug administration, which was treated with symptomatic treatment or resolved on its own. All 4 patients had no liver or kidney function or myocardial damage, and all 4 cases had different degrees of myelosuppression, which was related to chemotherapy; there is no data proving that rAd-p53 aggravates chemotherapy drug’s There is no information that rAd-p53 aggravates the myelosuppression of chemotherapeutic agents; the leukocytes of 4 patients were recovered quickly by the adjuvant treatment of granulocyte colony-stimulating factor. Conclusion: The application of rAd-p53 was safe by intravenous infusion or local intratumoral injection and was tolerated by patients; p53 gene combined with chemotherapy is effective for advanced head and neck tumors and deserves further study.