Progress in comprehensive treatment of maxillary sinus cancer Abstract Most of the maxillary sinus cancers are already in advanced stage when they are diagnosed, and they often invade many important surrounding organs extensively, including nasal cavity, sieve sinus, orbit and skull base bone, so their cure rate is very low. Many patients die because of local uncontrolled recurrence. In the last decade, the treatment of maxillary sinus cancer has been improved due to the application of comprehensive treatment, such as surgery, radiotherapy, chemotherapy, etc., and with the continuous improvement of equipment and technology. Keywords maxillary sinus cancer, comprehensive treatment The incidence of maxillary sinus cancer accounts for about 1%-2% of the malignant tumors in the head and neck, due to the lack of specific symptoms and signs in the early stage, most patients are already in the advanced stage when they are diagnosed, and the local anatomical relationship of maxillary sinus is complex, and the tumor expansion often involves many important tissues and organs in the neighboring area. Therefore, it is very important to choose the appropriate treatment method to improve the 5-year survival rate and quality of life of patients. In the past 10 years, scholars at home and abroad have adopted various treatment measures for primary cancer, including surgery, radiotherapy, chemotherapy, immunotherapy, etc., and have gained a lot of clinical practice experience. 1.Surgical treatment of maxillary sinus cancer Surgical treatment has a long history, since Gensoul (1829) and Ferguson (1848) used facial incision to remove the tumor of the upper collar bone, it has been more than a hundred years, the operation has been improved several times, in terms of resection methods, repair and reduction of complications, have made great progress. In the 1960s, the development of surgery has basically reached its peak, and the wide range of resection has been expanded to posterior maxilla, infratemporal recess and even through combined craniofacial resection, including part of the skull base together with resection. Due to the limitation of local anatomy, it is still not easy to perform a complete resection satisfactorily in most advanced patients. The 5-year survival rate of conventional surgical resection is basically about 10%-20% due to incomplete resection or invasive implantation of shed cancer cells, resulting in recurrence after surgery. Zhu Wenhua et al. reported [1] that the 5-year survival rate of radiotherapy alone or surgery alone was 20%-25%, and Niu Guanwei [2] reviewed 63 cases of advanced maxillary sinus cancer, 17 cases were operated alone, and their 3-year survival rate was 23.53% and 5-year survival rate was 17.65% respectively. Although it has been reported in the literature that the 5-year survival rate of a few selected advanced paranasal sinus cancers treated by combined craniofacial resection can reach 50%, the complications are more frequent and the operative mortality rate is 7%-10.7% [3], obviously, this procedure can only be considered for the treatment of a few strictly selected cases. The current view is that as much physiological function as possible should be preserved to improve the quality of survival, because the quality of survival can also directly affect the survival rate. In recent years, surgical oncology tends to be conservative, instead of blindly pursuing enlarged resection, modern radiotherapy techniques are integrated, the scope of surgical operation is reasonably narrow, and surgical techniques are improved to preserve the function of the patient’s body and improve the quality of survival[4] . There are indications that the reduction of surgical trauma is beneficial to the recovery of immune function[5,6] . Based on the above, most people believe that except for early cases, conventional surgical treatment alone is not curative for most patients, and the treatment of maxillary sinus cancer cannot rely on surgery alone, but must be comprehensive. 2.Radiotherapy for maxillary sinus cancer Since the beginning of 20th century, X-rays and radium have been used to treat the cancer, radiotherapy has been used more often for this disease. In the early years, external X-rays or intracavitary radium were mainly used, but the efficacy was very poor, and complications such as soft tissue and bone necrosis often occurred. After sufficient irradiation, most of the tumors can be seen to shrink significantly in appearance, or even disappear completely. However, about 80% of the surgically resected specimens can still be seen to have cancerous tissue remaining after radiotherapy, so the long-term outcome can hardly be improved. Some people have used sensitizers or hyperbaric oxygen chamber to improve the efficacy, but the results were not very effective [7]. In recent years, with the continuous modernization and precision of radiotherapy equipment, the development of three-dimensional radiotherapy technology has provided a new treatment means for radiation therapy of maxillary sinus cancer, so that the shape of the high-dose area is close to that of the target area in the three-dimensional direction, and through intensity-controlled conformal radiotherapy, the tumor control dose can be increased while protecting the surrounding vital organs and normal tissues to the maximum extent. 8] reported that in five patients with maxillary sinus cancer, the treatment plans were made by conventional, conformal and conformal methods, and the results showed that the conformal and conformal plans reduced the average dose to the surrounding vital organs by 65-62% when the tumor was treated with the same dose. David et al.[9] reported that, when comparing the inverse intensity treatment plan with the 3D conformal plan, the dose attainment and shape compliance of the target area were better than that of the 3D conformal plan, and the intensity plan could protect the surrounding vital organs and normal tissues as much as possible. However, due to the complex anatomy of maxillary sinus area, many surrounding bony structures and air cavities, dense sensitive and vital organs, no gap between the target area and sensitive and vital organs, and even encapsulation of vital organs, as well as the limitation of equipment (e.g., larger width of multileaf grating), the dose distribution of conformal and intensity radiation therapy for maxillary sinus cancer is not as satisfactory as theoretically or imagined. The question of whether to irradiate lymph node-negative necks is controversial; Grau et al[10] concluded that lymph node-negative patients have a low risk of neck recurrence and do not need prophylactic irradiation, while Jeremic et al[11] and Le et al[12] concluded that prophylactic irradiation is effective in preventing neck recurrence in lymph node-negative patients. The study data showed that out of 96 patients without lymph node metastasis at the time of initial diagnosis, 15 (19.2%) of 78 patients without prophylactic irradiation had neck recurrence (all patients with stage T3-4, 12 of which were squamous carcinoma), while no neck recurrence was observed in 18 cases with prophylactic irradiation. Wang Tianquan [13] et al. reported that the survival and local control rates of 71 cases of maxillary sinus cancer were compared between conventional external irradiation and full accelerated hyper-segmentation ( 1) 36 cases in the full accelerated hyper-segmentation group ( CAHF); 5d/week, twice a day, 1.5Gy each time, with an interval of 6h or more, total DT66~70Gy/44~46 f/32~34d; ( 2) 35 cases in the conventional segmentation group ( CF), 5 times/day, and no cervical recurrence. The total DT66~80Gy /33~35f/44~46d was 2.0Gy for 5 times/w, 1 time/d. The local control rates at 1, 2, 3, 4 and 5 years were 62.8%, 34.3%, 22.9%, 14.3%, 5.7% and 88.6%, 66.7%, 52.8% for the conventional irradiation group and the full hyper-segmentation group, respectively, The survival rates at 1, 2, 3, 4, and 5 years were 65.7%, 45.7%, 28.6%, 22.8%, 16%, and 94.4%, 72.2%, 58.3%, 57.2%, and 36.1% for the conventional irradiation and full accelerated hyper-segmentation groups, respectively (P < 0.05), with the accelerated hyper-segmentation group being higher than the conventional segmentation group. There was no significant difference in late complications and causes of death between the two groups. Conclusion: Full accelerated hyper-segmentation radiotherapy can significantly improve the local control rate and survival rate for patients with inoperable advanced maxillary sinus cancer. It has also been reported in overseas literature that hyper-segmentation radiotherapy can significantly improve the efficacy of head and neck tumors, and the related research is under further study. With the progress of radiotherapy equipment and technology, its efficacy will be improved even more. 3.Chemotherapy alone, there is no ideal chemotherapeutic drug, and considering the patient's body condition, the resistance or resistance of cancer tumors to drugs and the selectivity of drugs to cancer cells, maxillary sinus cancer rarely uses chemotherapy alone. In clinical practice, many patients are reluctant to undergo surgery for various reasons, such as possible disfigurement after surgery, high recurrence rate of surgery, and the inability of elderly patients to tolerate surgery, and choose chemotherapy instead. Geng Zhongli et al [14] randomly divided 30 cases of advanced maxillary sinus cancer into two groups: 15 cases in the superficial temporal artery perfusion group, using high-dose hydroxycamptothecin + adriamycin + 5-FU for superficial temporal artery cannula perfusion; 15 cases in the intravenous drip group, using the same dose for intravenous drip, and compared the efficacy of the two groups. Results: 6 cases (40.0%) of complete remission (CR) and 7 cases (46.7%) of partial remission (PR) in the superficial temporal artery infusion group, with an overall remission rate of 86.7%; 1 case (6.7%) of CR and 6 cases (40.0%) of PR in the intravenous drip group, with a statistically significant difference in the remission rate between the two groups (P < 0.05). Conclusion: Hydroxycamptothecin + Adriamycin + 5-FU perfusion chemotherapy with superficial temporal artery cannulation is a better treatment for advanced maxillary sinus cancer. Zhao Jinlong et al [15] retrospectively analyzed the results of 20 patients with advanced maxillary sinus cancer treated with intraoperative high-dose cisplatin (200 mg/mg2 ) infusion chemotherapy with intravenous sodium thiosulfate. 20 patients had an efficiency of 100%, 18 patients were effective and 2 patients were ineffective in postoperative evaluation. The tumor shrank significantly after surgery, and no serious complications occurred except for nausea and other gastrointestinal symptoms. Conclusion: Local high-dose perfusion therapy for maxillary sinus cancer is safe and reliable, improves the survival quality of advanced patients, and can be one of the treatment methods chosen for patients with advanced maxillary sinus cancer. Li Jichen et al [16] reported that 11 patients with maxillary sinus cancer who were clinically advanced or could not (unwillingly) be treated surgically due to their systemic conditions were treated with super-selective direct arterial perfusion chemotherapy, and the efficacy of arterial chemotherapy was 100%, as shown by the relief of pain and swelling of the tumor on the day or the second day after chemotherapy, and the appearance of secretions or necrotic tissue in the mouth and nasal cavity. Among the follow-up cases, 5 cases were in complete remission and 6 cases were in partial remission. Conclusion: Two-way arterial chemotherapy is one of the effective means to treat maxillary sinus cancer and can be used as part of the comprehensive sequential treatment. 4. Comprehensive treatment of maxillary sinus cancer The treatment methods of maxillary sinus cancer include surgery, radiotherapy, chemotherapy and immunotherapy. Due to the limitation of adjacent organs and the anoxic state of maxillary sinus itself, radiotherapy alone is difficult to cure, and surgery cannot completely remove the tumor, therefore, it is considered that the best choice for the treatment of maxillary sinus cancer is to adopt a comprehensive treatment plan[17] . Although the advantages of combined treatment for maxillary sinus cancer have been widely recognized, there is no consensus on the specific treatment mode so far[18] . 4.1 Combination of surgery and radiotherapy Surgery + radiotherapy is considered to be a better treatment for mid- to late-stage maxillary sinus cancer. In a retrospective analysis of 432 cases of advanced maxillary sinus cancer by Ren Baoyuan et al [19], the 5-year survival rates were 15.6%, 21.7% and 40.1% for the radiotherapy, surgery and surgery + radiotherapy groups, respectively (40% for preoperative radiotherapy and 43% for postoperative radiotherapy). Hinerman RW et al [20] reported that 54 patients received preoperative radiotherapy, postoperative radiotherapy and radiotherapy alone, with five-year local control rates of 61%, 65% and 37%, respectively. However, different pathological types of maxillary sinus tumors have different radiosensitivities, and therefore their treatment protocols are focused differently. Highly differentiated squamous carcinoma: Radiation therapy + surgery should be the treatment of choice. Most of the early stage patients can be treated satisfactorily with radiotherapy alone, while the late stage patients should still be treated with a combination of radiotherapy and surgery. Adenoid cystic carcinoma is a tumor of epithelial origin in the small salivary gland, which is often invaded by nerve sheath. Radiotherapy options include preoperative radiotherapy, postoperative radiotherapy, and preoperative plus postoperative radiotherapy. There are many debates about whether surgery or radiotherapy should be given first, some think that preoperative radiotherapy has more advantages, some advocate postoperative radiotherapy, and some adopt half course of radiotherapy before and after surgery, thinking that half course of radiotherapy before surgery can not only kill some cancer cells, but also inhibit the vitality of cancer cells and reduce the possibility of distant metastasis and local recurrence, because the radiation dose is small and there is no serious radiotherapy reaction, which is conducive to postoperative wound healing, It has been endorsed by many people. The reasons are: (1) preoperative radiotherapy can control the metastases in the retropharyngeal lymph nodes, which are beyond the capability of surgery; (2) preoperative radiotherapy can shrink the tumor, increase the possibility of surgical resection and reduce the risk of rapid recurrence; (3) preoperative radiotherapy can reduce the spread and implantation of cancer cells. According to Niu Guanwei [2], preoperative radiotherapy can confine and reduce the scope of tumors, so that those tumors that cannot be completely removed can be completely removed and cancer cells can be prevented from spreading. According to Li Junmei et al [22], preoperative plus postoperative radiotherapy for maxillary sinus cancer is better than preoperative radiotherapy in terms of local control of tumor, but there is no significant difference in 5-year survival rate. The preoperative plus postoperative radiotherapy group can take into account that preoperative radiotherapy can make full use of the good blood supply and sensitivity of microscopic lesions, which can reduce the vitality of cancer cells and make it easy to achieve a curative effect after surgery; at the same time, it can take into account the clean surgical margins and target the residual areas with additional radiotherapy, which can be carried out smoothly in a planned manner. Zhang Zhendong [23] reported that the three adjuvant radiotherapy modalities, preoperative, postoperative or preoperative plus postoperative, had no significant effect on survival rate in comprehensive treatment. Zhang Qing [24] et al. concluded that preoperative radiotherapy is a better treatment modality, while postoperative radiotherapy affects the sensitivity of the tumor to radiation due to insufficient local blood supply and low oxygen tension in the tissues due to the tissue scar produced by the surgery, and in addition, it is difficult to design a precise irradiation field for postoperative radiotherapy due to the irregular incisions and cavities left by the surgery, which increases the chance of recurrence. Zhang Yanping [25] reported that complete surgical resection plus postoperative radiotherapy in 14 patients with advanced disease significantly improved the cure rate and reduced the chance of recurrence. Therefore, radical surgery plus radiotherapy is the main treatment for adenoid cystic carcinoma of the maxillary sinus. Malignant fibrous histiocytoma of the maxillary sinus (MFH) is less common, its pathological type is specific and insensitive to radiation, and the effect of monotherapy is poor, prone to metastasis and recurrence. Hua Xiaoyang et al. reported [26] that extensive and complete surgical resection is the main treatment for MFH. Postoperative supplementation with radiotherapy and chemotherapy can significantly improve the local control rate and reduce metastasis. At present, radical surgery plus radiotherapy is the main treatment for MFH. 4.2 Combination of surgery and chemotherapy Currently, the combination of radiotherapy and surgery is recognized as a better treatment for maxillary sinus cancer, but radiotherapy has its limitations and is not suitable for repeated treatment. However, radiotherapy has its limitations and is not suitable for repeated treatment. In contrast, screening chemotherapy can be applied for a short period of time before surgery and can also be used periodically after surgery, which can effectively inhibit the development of tumor and further improve the efficacy of surgery. Since this method is not limited by conditions and equipment, it can be widely used in clinical practice. Pre-operative chemotherapy often uses three or more anticancer drugs to deliver effective concentrations of anticancer drugs to the tumor area before the vascular bed in the maxillary sinus area is destroyed, so as to inhibit or kill biologically active cancer cells, shrink the tumor body in the sinus area, and eliminate metastatic cancer in the lymph nodes of the posterior pharynx, so as to facilitate complete surgical resection. Chemotherapy with anti-cancer drugs is effective in killing cancer cells directly or through metabolic effects, especially for occult metastases in the parapharyngeal or lymphatic regions, which can be eradicated by chemotherapy. The primary cancer cells degenerate and their activity decreases, reducing the ability of surgical wound implantation and local recurrence or metastasis elsewhere. Chemotherapy is less damaging to the skin in the surgical area, and the flap heals easily after surgery, which facilitates rapid postoperative recovery [27]. Li Tianxin et al [28] reported that the 3-year and 5-year survival rates of 60 patients with advanced maxillary sinus cancer were 35% and 30%, respectively, after chemotherapy plus surgery, which were statistically not significantly different from those of radiotherapy plus surgery. 4.3 Combination of chemotherapy, radiotherapy and surgery This regimen is also called triple therapy, mainly using arterial chemotherapy. It was first introduced in Japan, and since 1965, it has become a popular treatment in Japan [29]. Preoperative planned radiotherapy and chemotherapy can make use of the vascular bed of the maxillary sinus and the tumor area to reduce the tumor size before the blood supply is destroyed, so that the tumor can be removed locally without damaging the surrounding vital organs as much as possible. Postoperatively, radiation and chemotherapy can be used to kill the subclinical lesions around the surgical field. In this way, the survival rate and local control rate of tumor patients are not affected, and the quality of survival is improved, which is the development direction of comprehensive treatment of maxillary sinus cancer nowadays and is also welcomed by patients. The future development of this treatment is highly anticipated. The method has been used since 1965 by Yasuo Sato et al [30-32], in which 60 cobalt radiotherapy was administered at 2000 radx2 in the anterior and lateral fields, followed by superficial facial artery cannulation under general anesthesia and 5-FU 250 mg infusion (finished in 10 minutes), followed by superior collar sinus opening and drainage and tumor scraping, with all the tumor tissue scraped as much as possible, but not more than the border of the tumor tissue. The tumor was then filled with 5-FU ointment and gauze (after daily change, necrotic tissues were aspirated out and the residual tumor tissues were scraped out and then 5-FU ointment and gauze were put in), and the next day, 5-FU 250mg and BUdR 500mg were injected (after the drip lasted for about 1 hour), and radiotherapy was administered. The above treatment was repeated 5-6 times, and the whole course of treatment was completed. The total amount of 5-FU was 1250-1500mg, and 800-1600rad of radiotherapy. In the future, if residual cancer or recurrent cancer is found, intracavitary radiotherapy or surgical resection will be added. The 5-year survival rate was reported to be 58%. In addition, according to the pathological observation of the scraped tumor, if only a small amount of tumor tissue remains after the tumor reduction surgery, the cancer cells can be significantly degenerated by 1000 rad radiotherapy, and by 1400 rad, few reproductively viable cancer cells can be seen; compared with the combination of action chemotherapy and radiotherapy for the tumor without scraping, the latter requires at least 4000-5000 rad radiotherapy to achieve the above effect [33]. This was the basis for the reduction of radiation therapy. Sato later reduced the amount of radiation therapy to 400 rad and concluded that the recurrence rate was not higher than that of 1200 rad. In the former group, the amount of radiotherapy was mostly more than 6000 rad, including total and partial resection of the upper collar bone, while in the latter group, the amount of radiotherapy was about 5000 rad, mostly with 5-FU, with an average total of 2945 mg, and about 80% of partial resection of the upper collar bone. The 5-year survival rate was 45.9% (76.2% in stage 2, 50% in stage 3, and 16.7% in stage 4) in the former and 45.1% (63.6% in stage 2, 47.6% in stage 3, and 27.5% in stage 4) in the latter, with no significant difference, but most of the superior collar bone was preserved in the latter group. In Japan, there is also a combination with enlargement surgery, such as Konon [35] arterial chemotherapy 5-FU 250mg/dose (30 minutes), followed by radiotherapy, and after irradiation of 1000 rad, upper collar sinus opening and drainage was performed, and mobilization was performed 5 times a week for 15 times, totaling 3750mg, and radiotherapy totaling 6000 rad. A total of 70 cases of upper collar sinus cancer were treated with a 5-year survival rate of 71.9%. Mosley et al [36] reported alternating arterial perfusion with BLM and MTX for 24 hours each for 9 days, with BLM 0.75 mg/kg/24h for days 1, 3, 5, 7, and 9 and MTX 0.5 mg/kg/24h for days 2, 4, 6, and 8, and leucovoin 6 mg every 6 hours for 34 hours. once every 6 hours for 34 hours. The total amount of radiation therapy was 5000-6000 rad. 4-6 weeks after the end of radiation therapy, surgery was performed. A total of 13 cases were treated, of which 10 cases completed the whole treatment (T3 and T4 in total 9 cases), and no residual cancer cells were found in 4 cases on specimen examination. Zhang Xiaotao et al [37] treated 60 patients with maxillary sinus cancer, including 38 with squamous carcinoma, 15 with adenocarcinoma, and 7 with others; 39 males and 21 females were treated with induction chemotherapy - maxillary sinus opening - radiotherapy - consolidation chemotherapy. Results? The 5-year survival rate of the whole group was 46.7% (28/60), of which 16 patients could live or work normally and 12 patients were in long-term recuperation; 16 of the deceased patients died of recurrence of the primary site. Conclusion? The sequential non-surgical resection of maxillary sinus cancer can maximize the preservation of patients' facial and organ functions, reduce complications, and improve the quality of survival, which is more acceptable to patients. The sequential comprehensive treatment plan was completed in all cases, and the clinical symptoms gradually resolved after treatment without serious complications and sequelae in most patients. At the end of treatment, the maxillary sinus cavity was scraped and sent for pathological examination, and no cancer cells were found. After more than 5 years of follow-up, a total of 28 patients survived, with an average 5-year survival rate of 46.7%. In one case, because the tumor invaded the orbital floor, the radiotherapy field included the ipsilateral eye. Two years after radiotherapy, the vision of the eye began to deteriorate and gradually worsened. In terms of the quality of survival, 16 patients returned to work and labor, and 12 patients were recuperating for a long time due to the combination of other diseases, but they could take care of themselves. The 2 cases lost to follow-up were counted as death. Of the 32 patients who died, 50% (16) died from the deterioration of the primary site, 10 died from metastases or other tumors (undiagnosed primary or metastatic), and 4 died from other diseases. Tatsuya Hayashi et al [38] analyzed the treatment of seventy-four patients with squamous cell carcinoma of the maxillary sinus, 62 started a multidisciplinary and comprehensive treatment approach including preoperative radiotherapy including a total dose of 50 Gray radiotherapy, maxillary artery infusion with a total dose of 5000 mg 5-FU, plus total or partial maxillary osteotomy, 59 received complete treatment. 11 patients were treated with radiation alone, and only 1 received postoperative radiation therapy. The survival time for this follow-up patient was 117 months. The 5-year overall survival, disease-free survival, and local control rates for those who underwent multidisciplinary combination therapy were significantly better than those who received radiation therapy alone (68.5% vs. 9.1%; 73.2% vs. 18.2%, 84.0% vs. 18.2%). Hiroshi et al [39] reported that in 26 cases of maxillary sinus cancer with orbital invasion, after preoperative radiotherapy and chemotherapy, local conservative surgery, and postoperative radiotherapy and chemotherapy, the 5-year and 10-year survival rates were 68% and 51%, respectively; the 5-year and 10-year local control rates were 66% and 51%, thus indicating that the combination of treatment plus conservative surgery did not affect the survival and local control rates and improved the patients' The quality of survival was improved. However, this method should be determined according to the extent of tumor invasion in the orbit, and the quality of life should not be pursued at the expense of tumor control rate. In a study by Bai Yanxia et al [40], 43 patients with maxillary sinus cancer were treated with a sequential combination of induction chemotherapy with superficial temporal artery cannulation, surgery and radical radiotherapy. 18 patients were treated with consolidation chemotherapy at the end of the combination and followed up for 5 years. Results: All patients tolerated this treatment regimen, and after 5 years of follow-up, 5 patients were lost, with a follow-up rate of 88.4%. The 5-year survival rate was 46.5% (20/ 43) and the 3-year survival rate was 65.1% (28/ 43) for the whole group. No orbital contents were removed in any of the patients, and 12 patients returned to work and labor. Conclusion: Superficial temporal artery cannulation induced chemotherapy plus surgery plus radical radiotherapy for maxillary sinus cancer is an effective plan to improve the long-term outcome. Among them, superficial temporal artery cannulation induction chemotherapy has the advantages of high local drug concentration, obvious tumor regression in the primary foci with a single cycle of chemotherapy, and no delay in surgery; combined with surgery and postoperative radical radiotherapy can improve the local control rate. And postoperative consolidation chemotherapy can further reduce the risk of distant metastasis. Nakatani H et al [41] treated eight patients with advanced maxillary sinus cancer using intra-arterial high-dose infusion of cisplatin (4-6 times (mean 5.1) and total cisplatin dose of 690 to 910 mg (mean 771 mg)) in combination with radiotherapy and surgical resection; only one T4 patient had local recurrence and the other one had metastases on both sides of the neck. In conclusion, most of the maxillary sinus cancers require comprehensive treatment, which requires the collaboration of physicians from different disciplines and a planned treatment plan. With the continuous updating of imaging and radiotherapy equipment, the development of radiotherapy technology, the continuous improvement of surgical technology and the application of gene therapy, the treatment effect of maxillary sinus cancer will be more improved.