I. Radiotherapy for nasopharyngeal cancer
The clinical application of radiotherapy has a history of more than 100 years. With the advancement of radiotherapy equipment and improvement of technology, the efficacy of radiotherapy has been significantly improved. Nasopharyngeal cancer is treated mainly by radiation therapy. The 5-year survival rate of nasopharyngeal cancer has increased from 45% in the 1970s to 70% now. The improvement in survival rate of nasopharyngeal cancer is largely due to the advancement of radiotherapy technology. With the advancement of imaging and computer technology and the upgrading of gas pedal equipment, three-dimensional conformal radiotherapy techniques, in which the radiation dose distribution is consistent with the shape of the tumor in the three-dimensional spatial direction, and intensity-modulated conformal radiotherapy techniques, in which not only the dose distribution is consistent with the shape of the tumor but also the dose intensity can be adjusted, have been realized. With the guarantee of radiation physics, these techniques are becoming more and more popular in clinical application and experience is becoming more and more mature. In addition, as an emerging technology in radiation therapy, research related to proton therapy as well as heavy ion therapy is being conducted worldwide, which has the advantage of using Bragg’s peak to adjust the dose distribution more precisely, so that the high dose area can be concentrated at the tumor site, thus providing more advantageous protection to normal organs. Due to the improved efficacy of radiotherapy in the treatment of nasopharyngeal cancer and the prolonged survival of patients, how to reduce the late radiological damage has been a research topic in nasopharyngeal cancer today. The following are some basic introduction of radiotherapy for nasopharyngeal cancer.
(I) Basic irradiation methods of radiotherapy
There are two basic irradiation methods in radiotherapy, external distance irradiation and brachytherapy. External long-distance irradiation, or external irradiation for short, refers to placing the radiation source at a certain distance outside the patient’s body and irradiating the patient’s treatment area with a collimated beam, while brachytherapy refers to placing the radiation source directly into the treated tissue or into the natural cavity of the human body. External irradiation is mainly used for nasopharyngeal cancer treatment.
(2) Principles of nasopharyngeal cancer radiation therapy
1.A good body position must be fixed during radiation therapy to ensure the repeatability of each treatment, which is a prerequisite to ensure the quality of treatment.
2.External irradiation should choose rays with higher energy, lower skin energy and less bone absorption.
3.External irradiation should completely include the tumor and the invasion range, and preventive irradiation should be given to the uninvaded high-risk areas (such as skull base, cervical lymph node drainage area, etc.).
4.For some early stage patients, it can be supplemented with intracavitary irradiation to protect the surrounding normal tissues and organs as much as possible.
5.For locally advanced patients, field reduction and changing the angle of incidence should be used to increase the local tumor dose and protect normal tissues and organs as much as possible; and strive for comprehensive treatment.
6.The radiotherapy plan should be adjusted appropriately according to the changes of the disease during the course of radiotherapy.
7.The use of CT simulation positioning method can more accurately include the scope of irradiation, and is also conducive to the protection of surrounding normal organs.
8.Stereotactic radiotherapy can be used as a treatment method for patients with recurrence and limited lesions after external irradiation and supplemental dose after radiotherapy.
The use of three-dimensional conformal radiotherapy and intensity modulated conformal radiotherapy has been initially proved to be beneficial to improve the local control rate and survival quality.
(3) Indications and contraindications of radiotherapy for nasopharyngeal carcinoma
Except for obvious contraindications to radiotherapy, patients with nasopharyngeal carcinoma can be treated with radiotherapy, but radical or palliative radiotherapy should be administered according to patients’ specific conditions. Patients with the following conditions are not suitable for radiotherapy: extremely poor general condition, serious unremitting comorbidities; multiple distant metastases resulting in malignant mass; uncontrolled tumor, recurrence or re-metastasis after multiple courses of radiotherapy in the same area; obvious serious sequelae have occurred in the area requiring radiotherapy.
(4) External radiation technology for nasopharyngeal cancer radiotherapy
1.Conventional two-dimensional radiation therapy
The scope of irradiation includes the primary foci of nasopharynx, the adjacent areas of possible expansion and infiltration, and the nasopharyngeal lymphatic drainage area. The target area should include the tumor tissue and its subclinical foci, while minimizing the dose to the surrounding normal tissues. Isocentric irradiation of the irregular combined face-neck field and the irregular face-neck field after field reduction is performed by using low-melting lead blocks, which can better protect important tissues and organs such as brain, brainstem, spinal cord and crystals, reduce radiotherapy reactions and improve survival quality. Irradiation dose: 66-70Gy/(33-35 times, 6.5-7 weeks) for nasopharyngeal irradiation; 60-70Gy/(30-35 times, 6-7 weeks) for radical treatment of positive cervical lymph nodes; 50-56Gy/(25-28 times, 5-5.5 weeks) for prophylaxis of negative cervical lymph nodes.
2.Three-dimensional conformal radiotherapy.
It is a radiation technique which can make the spatial dose distribution in the high-dose area consistent with the three-dimensional shape of the target volume, while the surrounding normal tissues and organs are irradiated by the smallest dose.
3.Conformal intensity modulated radiation therapy.
It can make the shape of the irradiated area fit the shape of the irradiated tumor in three-dimensional direction, and also give different irradiation doses according to the needs of the tumor and the surrounding normal tissues, which can further reduce the irradiation dose to the normal tissues or organs adjacent to the tumor, which is more conducive to the protection of the functions of normal tissues and organs.
(V) Brachytherapy for nasopharyngeal cancer
The characteristics of nasopharyngeal cancer brachytherapy are that the source is placed in the nasopharyngeal cavity and as close to the tumor as possible, and the corresponding treatment plan is set according to the specific relationship between the source and the tumor and each anatomical structure and the specific area to be irradiated, and then the radiation source is introduced into the source for treatment. In the treatment of nasopharyngeal cancer, brachytherapy is mainly applied to superficial tumors confined to the nasopharyngeal wall (or residual in the cavity), and only as a supplementary irradiation means after external irradiation or planned external irradiation + intracavity brachytherapy for early lesions.
(VI) Complications of radiotherapy for nasopharyngeal cancer
Since there are many important organs around the nasopharynx that are at risk, it is difficult to avoid these tissues during radiation therapy, so there is a possibility of complications after radiation therapy for nasopharyngeal cancer. Complications of nasopharyngeal cancer radiation therapy include radiation reaction and radiation damage. Radiation reaction is a temporary and recoverable systemic or local reaction under the effect of radiation. Systemic reactions include insomnia, dizziness, weakness, nausea, vomiting, loss of appetite, abnormal taste, etc. Local reactions are mainly acute reactions of skin, oral and nasal mucosa and parotid gland. Radiation injury is irreversible permanent damage to tissues and organs caused by the action of radiation, such as radioactive parotid injury, radioactive otitis media, radioactive mandibular arthritis, radioactive mandibular osteomyelitis, radioactive dental caries, radioactive hypopituitarism, radioactive optic nerve injury, radioactive cerebrospinal cord injury, radioactive neck skin atrophy and muscle fibrosis.
Chemotherapy for nasopharyngeal cancer
Although radiotherapy is the main treatment for nasopharyngeal carcinoma, current clinical research believes that chemotherapy is also one of the important means of nasopharyngeal carcinoma treatment. For patients with mid- to late-stage nasopharyngeal carcinoma without distant metastases, chemotherapy is mainly used in combination with radiation therapy to improve the cure rate of the tumor; for patients with clinical and subclinical distant metastases, and patients with locally advanced cancer that cannot be cured by radiation therapy, chemotherapy is often the only effective treatment option.
Since the 1980s, the combination of cisplatin-based chemotherapy and radiation therapy for locally advanced nasopharyngeal carcinoma has been reported to be effective in improving the survival rate of these patients. However, the choice of chemotherapy regimen and the way of combining chemotherapy with radiotherapy have been controversial. In the treatment of nasopharyngeal carcinoma, the possible chemotherapies used depending on the purpose of treatment are induction chemotherapy, concurrent radiotherapy, adjuvant chemotherapy, palliative chemotherapy, and investigational chemotherapy. In a Meta-analysis of eight randomized controlled trials of 1753 patients with locally advanced nasopharyngeal carcinoma, chemotherapy reduced the risk ratio of tumor failure or death by 24%, increased the 5-year survival benefit by 6%, and increased the 5-year tumor-related event-free survival benefit by 10%, with the greatest benefit in the concurrent radiotherapy modality, and also improved the local control rate and distant metastasis control rate. Concurrent radiotherapy ± induction or adjuvant chemotherapy has now become the standard treatment modality for locally advanced nasopharyngeal carcinoma.
1.Induction chemotherapy
Induction chemotherapy, also known as neoadjuvant chemotherapy, is the chemotherapy used before radiation therapy. The main reasons for treatment failure of localized advanced nasopharyngeal cancer patients are distant metastasis and local recurrence, and the former accounts for 30-40% of treatment failure, while the emergence of distant metastases mostly occurs within 3 years after the end of radiation therapy, so it is generally believed that distant metastases have already existed insidiously before radiation therapy. Secondly, since nasopharyngeal carcinoma is more sensitive to chemotherapy, induction chemotherapy for localized patients in the middle and late stages can effectively shrink the primary tumor, help reduce tumor load and relieve clinical symptoms, reduce the lack of oxygen cells in the tumor center, enhance the radiosensitivity of the tumor and improve the local control rate. In addition, the local blood supply of tumor before radiation therapy is good, and there is no fibrosis and vascular occlusion caused by radiation therapy, so it is easier for chemotherapeutic drugs to reach the tumor interior and exert anti-tumor effects, and some chemotherapy has radiotherapy sensitizing effect, which may improve the recent efficacy of radiation therapy. Therefore, induction chemotherapy is still widely used in patients with localized mid- to late-stage nasopharyngeal carcinoma. However, the shortcomings of induction chemotherapy include delayed radiotherapy, decreased nutritional status, partially reduced tolerance of radiotherapy, increased side effects of radiotherapy, and increased treatment cost, etc.
2.Simultaneous chemoradiotherapy
Concurrent chemoradiotherapy is given at the same time as radiotherapy. The action mechanism of concurrent chemotherapy is mainly as follows
(1) to synchronize the cell cycle of tumor cells and increase the sensitivity of radiotherapy.
(2) Chemotherapeutic drugs interfere with the DNA repair of sublethal damage in tumor cells to enhance the effect of radiotherapy.
(3) The direct tumoricidal effect of chemotherapeutic drugs.
However, since the non-specific sensitization of concurrent radiotherapy may lead to severe mucositis and interruption of radiotherapy, it is necessary to select safe and effective chemotherapeutic agents. Since radiation therapy has the strongest killing effect on M- and G2-stage cells, and DDP is a cell cycle non-specific chemotherapeutic agent, the combination of the two can produce a good synergistic effect. A large number of experiments have also proved that DDP has its unique sensitizing effect on radiotherapy, and the toxicity of conventional dose is low, and its toxicity is not superimposed on the toxicity of radiotherapy, so DDP is considered as one of the relatively good chemotherapeutic drugs for concurrent radiotherapy.
3.Adjuvant chemotherapy
Adjuvant chemotherapy is the chemotherapy carried out after the end of radiotherapy for nasopharyngeal cancer. The purpose of adjuvant chemotherapy is to kill possible residual cancer cells in the local area and subclinical metastases in the whole body after radiotherapy, and may delay the occurrence of distant metastases. However, after radiotherapy, patients with nasopharyngeal cancer often have difficulty in tolerating adjuvant chemotherapy because of unrecovered mucosal inflammation, poor nutritional status and low immune function. In the most classic clinical trial 0099 of the Southwest Oncology Collaborative Group in the United States, for example, patients had poor compliance with adjuvant chemotherapy after concurrent radiotherapy, and more than half of them could not complete adjuvant chemotherapy as planned. Moreover, several prospective clinical studies have shown that adjuvant chemotherapy does not significantly improve the survival rate of nasopharyngeal carcinoma.
4.Palliative chemotherapy
Chemotherapy, as a means of systemic treatment, is of great significance to patients with distant metastases; moreover, for some patients with recurrence after radiotherapy, if the time between recurrence and the first course of radiotherapy is short, or serious sequelae have been produced after radiotherapy, palliative chemotherapy becomes an important treatment for them at this time. However, in recent years, we have seen many reports of a few patients with distant metastases who obtained long-term remission or survival through chemotherapy, suggesting that palliative chemotherapy has an important role in nasopharyngeal cancer.
III. Surgical treatment
1.Nasopharyngeal surgery (salvage surgery)
The anatomical location of nasopharynx is special, so it is not easy to excise the whole piece; coupled with the unique biological characteristics and radiosensitivity of nasopharyngeal cancer, so most cases should not be treated by surgery alone, but for cases with radiation insensitivity and residual or recurrence after partial radiation treatment, selective surgery can be adopted.
The indications for nasopharyngeal surgery are
(1) Recurrence of nasopharyngeal disease after radiotherapy with limited lesions.
(2) Restricted residual nasopharyngeal cancer foci after 3 months of radical radiotherapy.
(3) Comprehensive treatment and surgery for highly differentiated nasopharyngeal carcinoma (such as squamous carcinoma grade I, II, adenocarcinoma, etc.).
(4) Those in good general condition.
Contraindications to surgery.
(1) Tumor infiltration into the carotid sheath area and its contents.
(2) Tumor infiltration of the skull base/cranial nerve.
(3) Extensive bone destruction of the skull base or cervical spine.
(4) Distant metastasis.
(5) Poor general condition or poor liver and kidney function.
There are many approaches for nasopharyngeal cancer surgery, and the surgical pathways are complicated and poorly exposed, and so far there is no approach that can fully expose the nasopharynx with less trauma. The currently used surgical approaches are mainly as follows
I Lateral nasal approach.
II maxillary external approach.
III Transpalatal approach.
IV transmedial mandibular approach.
V transmandibular pterygoid approach.
VI lateral cervical approach.
VII Inferior temporal fossa approach.
VIII Transcranial base approach.
Sinus endoscopic resection of the nasopharyngeal tumor is also commonly performed, in which the posterior portion of the nasal diaphragm, the septal sinus, and the floor wall of the pterygoid sinus are removed under direct sinus endoscopy, resulting in complete resection of recurrent cancer in the anterior and/or parietal walls of the nasopharynx. The mucosa of the nasal cavity and nasopharynx is preoperatively infiltrated with 1‰ epinephrine to reduce bleeding. This procedure has no incision in the face and mouth, is less invasive and has quick recovery for recurrent carcinoma in the parietal and/or anterior parietal wall of nasopharynx.
2.Neck surgery
Those whose cervical lymph nodes have not disappeared 3 months after full radiotherapy for nasopharyngeal cancer are called residual cervical lymph nodes, and those who have enlarged cervical lymph nodes again after complete remission are called cervical recurrence. The rate of residual cervical lymph nodes and recurrence after full radiotherapy for nasopharyngeal cancer is about 18%. These residual or recurring lymph nodes are less effective in re-radiation therapy, and the five-year survival rate is about 11%-19.7%, and can cause serious cumulative radiation tissue damage and sequelae, such as radiation myelopathy, radiation skin ulcers, and soft tissue fibrosis in the head and neck. And chemotherapy is difficult to remove the lesions completely. The 5-year survival rate after surgery for residual or recurrent cervical lymph nodes after radiation therapy for nasopharyngeal carcinoma is 34.4%-67%. Wei WI et al. reported that the actual 5-year survival rate after radical surgery for residual or recurrent cervical lymph nodes after radiation therapy for nasopharyngeal carcinoma is 38%, and the 5-year control rate for neck lesions is 66%. This suggests that surgery can control and salvage residual or recurrent cervical lymph nodes after radiotherapy for nasopharyngeal cancer, and this salvage surgery can not only improve the survival rate of these patients, but also avoid the complications of re-course radiotherapy and improve the quality of survival. Surgery is the treatment of choice for residual or recurrent cervical lymph nodes after radiotherapy for nasopharyngeal carcinoma.
Indications for cervical lymph node dissection after radiotherapy.
(1) Those whose primary nasopharyngeal foci have been controlled (or not controlled but can be surgically removed) but metastatic lymph nodes appear in the neck.
(2) Metastatic lymph nodes remaining in the neck 3 months after radical radiotherapy.
(3) The procedure can also be used as a part of the comprehensive treatment of nasopharyngeal carcinoma.
(4) No distant metastasis.
(5) Good general condition.
Contraindications to surgery.
(1) Residual or recurrent metastatic lymph nodes in the neck with deep neck tissue fixation.
(2) Invasion of the common carotid artery or internal and external carotid arteries.
(3) Extensive skin infiltration.
(4) The presence of distant metastases.
(5) Old age and frailty, cardiopulmonary, hepatic and renal insufficiency and failure to correct.
3.Paranasal sinus surgery
Nasal endoscopy or nasopharyngeal fiberoptic microscopy can be used to perform nasal adhesion separation, posterior nostril or nasopharyngeal adhesion atresia rectification or paranasal sinus exploration to restore the patency of nasal cavity and nasopharynx, open drainage, eliminate local inflammation and reduce patients’ pain. If the diagnosis of nasopharyngeal cancer is unknown due to the presence of a mass in the sinus cavity with bone destruction on CT and other imaging examinations after radiotherapy, nasal endoscopic exploratory biopsy can clarify the diagnosis and give treatment in time to reduce misdiagnosis and mistreatment. Nasal endoscopic surgery is the best method for biopsy of sinus masses and treatment of non-cancerous lesions after radiotherapy for nasopharyngeal carcinoma.