头颈部癌调强适形放射治疗保护唾液腺功能的研究现状

大多数头颈部癌需要手术和放疗结合的综合治疗，鼻咽癌及某些早期头颈部肿瘤可通过放疗达到根治，约80％的患者有必要接受放疗。尽管放疗是头颈部癌的主要治疗手段，但由于头颈部的解剖关系复杂，传统的放疗技术会带来多种急慢性并发症。唾液腺损伤导致的口干是头颈部癌传统放疗的最常见并发症之一。尤其是鼻咽癌及口咽癌患者，由于需要行全程双侧对穿野照射，     

Thyroid dysfunction after radiation therapy in head and neck cancer patients

INTRODUCTION: The reported incidence of hypothyroidism following surgery and/or radiation therapy for head and neck cancer varies widely. Most patients undergo thyroid lobectomy during laryngectomy. Standard radiation treatment portals often include the thyroid gland. The insidious development of hypothyroidism may be misdiagnosed. This study examines the incidence of thyroid dysfunction in the setting of head and neck cancer therapy. MATERIALS AND METHODS: Thyroid function tests were performed on 100 consecutive patients treated in the head and neck tumor clinic. Statistical inferences on proportions were made using chi-square analysis. RESULTS: Therapy included surgery only (10 patients), radiation therapy only (28 patients), and combined therapy (62 patients). These patients experienced thyroid dysfunction in 0%, 29%, and 45% of individuals respectively. These differences were statistically significant (P < .05). The highest rate of dysfunction (69%) was associated with patients undergoing laryngectomy and radiation therapy. When laryngectomy was not performed, thyroid dysfunction occurred in 28%. CONCLUSION: The likelihood of thyroid dysfunction after radiation therapy is high particularly when combined with surgery in which thyroid lobectomy is performed and the contralateral lobe is potentially devascularized. These results suggest that radiation therapy is a primary factor in alteration of thyroid function. We recommend that routine thyroid function testing be part of follow-up of all head and neck cancer patients.     

Endoscopic management of hypopharyngeal stenosis after organ sparing therapy for head and neck cancer

OBJECTIVES: The objective of this study was to describe and evaluate the efficacy of an endoscopic technique for the management of postchemoradiation hypopharyngeal stenosis in head and neck cancer patients. STUDY DESIGN: Retrospective review. METHODS: Patients with postchemoradiation hypopharyngeal stenoses were identified from the Dana Farber Cancer Institute head and neck database. Patients who had undergone extirpative surgery and reconstruction were excluded. All patients underwent either anterograde dilatation (AD) by the lead author (C.A.S.) or transgastric retrograde esophagoscopy with anterograde dilatation (TREAD) (C.A.S., M.T.J.). Chemoradiation records, clinic notes, operative reports, and swallowing test data were reviewed. Removal of the gastric feeding tube was considered the endpoint of rehabilitation. RESULTS: Seventeen patients had postcricoid stenoses identified by modified barium swallow. Endoscopy confirmed 15 postcricoid stenoses and 2 proximal esophageal stenoses. Nine (53%) patients had partial stenoses, and eight (47%) had complete stenoses. Eight partial stenosis patients underwent 10 AD procedures and 3 TREAD procedures. Eight complete stenosis patients underwent 9 TREAD procedures and 26 subsequent AD procedures. Fifteen of 16 (93%) patients resumed swallowing after dilatation. Thirteen (81%) patients maintained their weight on an oral diet and had their gastric feeding tubes removed. Complications included hypopharyngeal perforation (13%), abdominal wall infection (6%), stomach wall dehiscence (6%), and chondroradionecrosis of the cricoid cartilage (6%). CONCLUSIONS: Postcricoid hypopharyngeal stenosis may be partial or complete after organ sparing chemoradiation for head and neck cancer. Using the TREAD technique, successful rehabilitation of swallowing can be achieved with a low incidence of complications.     

Recent advances in radiation therapy for head and neck cancer

The treatment of locally advanced or recurrent head and neck cancers has improved from single modality interventions of surgery and radiation therapy alone to include combined modality therapy with surgery, chemotherapy and radiation. Combined therapy has led to improved local control and disease-free survival. New developments in radiation oncology such as altered fractionation, three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, stereotactic radiosurgery, fractionated stereotactic radiotherapy, charged-particle radiotherapy, neutron-beam radiotherapy, and brachytherapy have helped to improve this outlook even further. These recent advances allow for a higher dose to be delivered to the tumor while minimizing the dose delivered to the surrounding normal tissue. This article provides an update of the new developments in radiotherapy in the management of head and neck cancers.     

Polymer chemotherapy for head and neck cancer

OBJECTIVES: To study a new method of delivery of chemotherapy for the treatment of squamous cell carcinomas (SCCs) of the head and neck, to evaluate the pharmacokinetics of four anticancer agents (cisplatin, fluorouracil [5-FU], methotrexate [MTX], and paclitaxel) loaded into the biodegradable polymer, polyanhydride polymer poly(FAD:SA), and to evaluate the effectiveness and toxicity of the drug-polymer combination against human SCCs, both in vitro and in vivo. STUDY DESIGN: Poly(FAD:SA) was loaded with different chemotherapeutic drugs and its in vitro and in vivo drug release and tissue penetration characteristics were studied. The biocompatibility and toxicity of the polymer-drug combination were determined. The effectiveness of the drug-polymer was evaluated against three different human SCCs (larynx O11, pharynx FADU, and floor of mouth UM- SCC1) cultured in vitro and in nude mice carrying human SCC xenografts. METHODS: The in vitro drug release pharmacokinetics of the drugs were performed using atomic absorption spectrometry for cisplatin and high-pressure liquid chromatography for the 5-FU, MTX, and paclitaxel studies. In vitro tumor cytotoxicity was assessed by growth assay. In vivo cytotoxicity was assessed by growth rate inhibition in a nude mouse model. RESULTS: All four chemotherapy drugs demonstrated a continuous release that followed first-order kinetics from the polymer. More than 95% of the MTX and 5-FU, 70% of the cisplatin, and 20% of the paclitaxel was released within the 10 days of the assay. Tumor cytotoxicity revealed that the polymer was very effective against the human SCCs O11, FADU, and UM- SCC1 in vitro. When a small amount of polymer (1-2 g) was added to the cell culture and left for 7 days, 96.6% of the UM-SCC1 cells, 86.9% of the FADU cells, and 94.6% of the O11 cells were killed. When the culture medium was then changed every 2 days to remove the effect of nutrient depletion or chemicals released by the degrading polymer, 74% of the UM-SCC1 cells, 94.5% of the FADU cells, and 66.1% of the O11 cells were killed at 7 days. The tumor animal model was the nude mouse carrying human floor of mouth SCC xenografts. Different amounts of cisplatin were incorporated into the polymers (5% and 7% drug/polymer at a weight/weight [wt/wt] load). Thirty-five days after implantation of the polymer in nude mice, the mean treated tumor size was 65.5% of controls in the 5% group and 31.8% in the 7% group. Seventy days after implantation the mean treated tumor size was 41.4% of controls in the 5% group and 38.1% in the 7% group, indicating a statistically significant delay of tumor growth compared with controls or with intraperitoneally injected cisplatin. The blank polymer was well tolerated by the mouse and had no effect on tumor growth. CONCLUSIONS: The study results indicate that polymer chemotherapy is effective against a variety of SCCs of the head and neck, both in vitro and in vivo, and may become a useful therapeutic option for head and neck cancer.     

New radiation therapy techniques for the treatment of head and neck cancer

This article reviews the most recent technology used in the treatment of head and neck cancer. It discusses brachytherapy, new ways to mix radionuclides for enhanced radiobiologic effects, and different fractionation schemes that have grown in clinical importance. Intensity-modulated radiotherapy has become a mainstay in head and neck cancer treatment, and the authors discuss several popular and emerging approaches. Patient immobilization and imaging are also discussed.     

Feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated concomitant-boost radiation therapy

OBJECTIVE: To assess the feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated radiotherapy (RT). DESIGN: Retrospective study. SETTING: University of Lausanne, Lausanne, Switzerland. PATIENTS: Thirty-three consecutive patients (male-female ratio, 4.5; median age, 54 years [age range, 39-76 years]). INTERVENTIONS: Between November 2000 and January 2003, the 33 patients were treated with curative definitive (n = 19) or postoperative (n = 14) RT with (n = 26) or without (n = 7) chemotherapy. All patients received conformal RT. Fractionation schedule consisted of concomitant-boost (Friday afternoon session) accelerated RT using 70 Gy (2 Gy per fraction) in 6 weeks in patients treated with definitive RT and 66 Gy (2 Gy per fraction) in 5 weeks and 3 days in the postoperative setting. Parotid glands received at least 50 Gy in all patients. Amifostine was administered to a total dose of 500 mg subcutaneously, 15 to 30 minutes before morning RT sessions. RESULTS: All patients received their planned treatment (including chemotherapy). Ten patients received the full schedule of amifostine (at least 25 injections), 9 received 20 to 24 doses, 4 received 10 to 19 doses, 5 received 5 to 9 doses, and 5 received fewer than 5 doses. Fifteen patients (45%) did not show any intolerance related to amifostine use. Amifostine therapy was discontinued because of nausea in 11 patients (33%) and hypotension in 6 patients (18%), and 1 patient refused treatment. No grade 3, amifostine-related, cutaneous toxic effects were observed. Radiotherapy-induced grade 3 acute toxic effects included mucositis in 14 patients (42%), erythema in 14 patients (42%), and dysphagia in 13 patients (39%). Late toxic effects included grade 2 or more xerostomia in 17 patients (51%) and fibrosis in 3 patients (9%). Grade 2 or more xerostomia was observed in 8 (42%) of 19 patients receiving 20 injections or more vs 9 (64%) of 14 patients receiving fewer than 20 injections (P = .15). CONCLUSIONS: Subcutaneous amifostine administration in combination with accelerated concomitant-boost RT with or without chemotherapy is feasible. The major adverse effect of subcutaneous administration was nausea despite prophylactic antiemetic medication, and hypotension was observed in only 6 patients (18%).     

Preoperative chemotherapy-sensitized radiation therapy for cervical metastases in head and neck cancer

OBJECTIVE: To determine the efficacy of concurrent preoperative cisplatin chemotherapy and radiotherapy (CT/RT) for patients with advanced head and neck cancer and cervical metastatic disease. DESIGN: Retrospective analysis. SETTING: University hospitals. PATIENTS: Eighty-eight patients with operable stage III and IV squamous cell carcinoma of the head and neck and palpable cervical lymphogenous metastases received preoperative concurrent CT/RT followed by planned neck dissection. INTERVENTIONS: All patients undergoing CT/RT received concomitant continuous infusions of cisplatin (20 mg/m2) on days 1 to 4 and 22 to 25 of CT/RT. Thirty-nine patients underwent single-fraction (1.8-Gy) radiotherapy to 45.0 Gy, and 49 patients received 10 single-fraction (1.8-Gy) treatments, which were hyperfractionated (1.2-Gy twice a day) to 46.8 Gy. MAIN OUTCOME MEASURES: The 71 patients for whom complete post-CT/RT data were available were evaluated for clinical response in addition to survival. Histologic complete response (HCR) was confirmed from planned neck dissection specimens (n = 48) after clinical complete response (CCR) from initial CT/RT. Kaplan-Meier statistical analysis for disease-specific survival and overall survival was performed on all 88 patients who received CT/RT. RESULTS: A CCR and an HCR were noted in 78% (18/23) and 59% (10/17) of patients with N1 lesions, respectively, and in 60% (29/48) and 45% (14/31) of patients with N2-3 lesions, respectively. The percentage of patients with CCR who also had HCR was 67% (10/15) for patients with N1 lesions and 54% (14/26) for patients with N2-3 lesions. With a median follow-up of 18.5 months, the Kaplan-Meier disease-specific survival rate at 54 months (n = 88) was 70% (21/30) for patients with N1 lesions, 60% (24/40) for patients with N2 lesions, and 39% (7/18) for patients with N3 lesions. The overall survival and disease-specific survival rates at 5 years for all nodal groups combined were 36% (32/88) and 59% (52/88), respectively. CONCLUSIONS: A CCR to CT/RT was achieved in nearly two thirds of patients with head and neck cervical lymphogenous metastases, independent of nodal tumor load. Most patients (59% [24/41]) with CCR were pathologically tumor free before neck dissection.     

Combination nonviral interleukin 2 gene therapy and external-beam radiation therapy for head and neck cancer

OBJECTIVES: To demonstrate that the combination of nonviral murine interleukin 2 (mIL-2) gene therapy and external-beam radiation therapy (XRT) have an enhanced therapeutic effect for the treatment of head and neck squamous cell carcinoma (HNSCC) in an orthotopic murine model and to elucidate the mechanism of action. METHODS: Randomized, controlled studies in the murine orthotopic model of HNSCC. Squamous cell carcinoma VII cells were injected into the floor of the mouth to establish tumors in immunocompetent mice. The intervention groups were treated with mIL-2, radiation therapy, empty plasmid, no treatment, combination mIL-2/XRT, and combination empty plasmid/XRT. Nonviral mIL-2 gene transfer was performed on days 5 and 9. The XRT was administered to the assigned groups 24 hours after first mIL-2 delivery. The mice were killed on day 13. Tumors and local lymph nodes were harvested and evaluated. Primary and secondary cytokine expression, cytotoxic T-lymphocyte activity, and apoptosis were assayed. RESULTS: The combination mIL-2/XRT demonstrated a significant increase in antitumor effects compared with single therapy or controls. Increased expression levels of primary and secondary cytokines were found in the group treated with mIL-2, and this effect was preserved when mIL-2 treatment was combined with XRT. Combination therapy significantly increased apoptosis compared with monotherapy. CONCLUSIONS: The present study demonstrates that combination mIL-2/XRT generates potent antitumor immune responses and significantly increases apoptosis in an orthotopic murine model of HNSCC. Further optimization of this strategy is warranted as well as consideration for human clinical trials.     

Decreased hearing after combined modality therapy for head and neck cancer

PURPOSE: Combined platinum-based chemoradiation therapy is frequently being used as therapy for head and neck cancer at multiple sites. These therapies are individually ototoxic, but little has been reported on their combined toxicity. MATERIALS AND METHODS: A retrospective investigation of 37 patients known to have undergone therapy with both agents, in combination, for head and neck malignancy was performed. Sixty percent of the patients had complaints of hearing loss subjectively. Reliable pretreatment and posttreatment audiograms were obtained on 15 of these patients. Audiograms were analyzed for sensorineural changes at 0.5, 1, 2, 4, and 8 kHz. RESULTS: By paired t test analysis, there were significant changes in the patients with pretreatment and posttreatment audiograms at all frequencies. More than 50% of the patients had a change of 10 dB or greater in their pure-tone average. More than 85% of the patients experienced changes in their hearing at 4 and 8 kHz. CONCLUSIONS: We conclude that patients undergoing combined modality therapy for head and neck cancer experience hearing loss. We recommend that hearing assessment, including pretreatment and posttreatment audiometry, be performed in all patients undergoing combined platinum-based chemotherapy and radiation for the treatment of head and neck cancer.     

The chemotherapy of head and neck cancer

Chemotherapy in head and neck cancer can be given in metastatic disease at presentation, in locally far advanced disease not amendable for curative treatment with surgery and/or radiotherapy, in the neo-adjuvant setting, in recurrent disease after previous surgery and radiotherapy and either concurrent or alternating with radiotherapy. Most data are gathered in the recurrent and locally far advanced disease setting. Combination therapy (with agents such as cisplatinum, 5-FU and methotrexate) have shown some improvements in response rate, however no obvious survival advantage over monotherapy in the treatment of patients with metastatic or advanced locoregional cancer of the head and neck has been observed. In the neo-adjuvant setting, chemotherapy is helpful in preserving the larynx and hypopharynx but has no proven impact (positive or negative) on survival. New compounds and approaches are needed to improve survival in head and neck cancer. Among the new options for chemotherapy in metastatic/recurrent disease are the taxanes. With monotherapy docetaxel, response rates of 23%-42% are seen, and, when used in combination with cisplatinum and 5-FU, response rates of 52-100% have been reported in phase I/II trials. A phase III trial of the addition of docetaxel to standard neo-adjuvant therapy with cisplatinum and 5-FU is now underway.     

Current use of chemotherapy for head and neck cancer

A postal survey of 100 members of the Association of Head and Neck Oncologists of Great Britain was conducted in the first 6 months of 1983. The sample consisted principally of Otolaryngologists (50 per cent), Radiotherapists (14 per cent), Medical Oncologists (10 per cent), Oral Surgeons (10 per cent) and Plastic Surgeons (10 per cent). More than 80 per cent of those who completed the questionnaire used chemotherapy for Head and Neck cancer (72 per cent used it for palliation, and 64 per cent as part of combined modality therapy). There was great variation in the chemotherapeutic regimens used by the various responders. Furthermore, most responders used more than one regimen. Methotrexate was the agent most frequently used. No specific regimen, either single-agent or multiple-agent, enjoyed universal acceptance, although the combination of Vincristine, Bleomycin and Methotrexate was popular. Chemotherapy was thought by most responders to have a useful but as yet undefined place in the management of Head and Neck cancer. This survey underlines the need for prospective, controlled, clinical trials into the efficacy of cytotoxic chemotherapy for Head and Neck cancer.     

Current thoughts on the role of chemotherapy and radiation in advanced head and neck cancer

PURPOSE OF REVIEW: The management of advanced malignancies of the head and neck continues to be a challenging clinical problem. During the last three decades, the traditional treatments of surgery and/or radiation have not yielded significant improvements in survival in this patient population. In addition, surgery for advanced disease can create significant functional and cosmetic defects that adversely impact a patient's quality of life. Newer "organ preservation" approaches using chemotherapy and radiation are currently being studied in an attempt to improve survival while maintaining the functional integrity of the disease site. RECENT FINDINGS: Recent studies have demonstrated that for advanced head and neck squamous cell cancers, concurrent chemoradiation is superior to radiation alone for local tumor control and perhaps overall survival. With the exception of laryngeal cancer, phase III data comparing chemoradiation with surgery is lacking for most head and neck subsites. However, comparisons with historical controls suggest that chemoradiation strategies may offer improved outcomes when compared with more traditional treatment regimens. SUMMARY: This review emphasizes recent phase III trials that support the use of chemoradiation strategies in the treatment of advanced head and neck squamous cell cancers.     

Concomitant chemotherapy and split-course radiation for cure and preservation of speech and swallowing in head and neck cancer

To assess the ability of simultaneous cisplatin, 5-Fluorouracil, and radiation to substitute for surgery and radiation in advanced head and neck cancer, we have retrospectively selected from our phase II study a subgroup of 29 patients having primary disease requiring either more than a hemiglossec-tomy or a laryngectomy for control. Patients included 22 with stage IV and 7 with stage III disease, 12 tongue, 10 hypopharynx, and 7 larynx primaries. The treatment consisted of concurrent cisplatin, 5-Fluo-rouracil, and split-course radiation every other week for a total of 7 cycles within 13 weeks. With a median follow-up of 5 years, 86% of patients had preservation of speech and/or swallowing function. Median survival was 45 months, with 14 (48%) patients currently alive and disease free, 11 (38%) dead from their cancer, and 4 (14%) dead of other causes. The overall failure rate was 38%. Advanced-stage presence of N3 nodal disease and fewer than 7 cycles of chemotherapy received were significantly associated with increasing failure rates. This program of concomitant cisplatin, 5-Fluorouracil, and radiation produced control rates quite competitive with surgery and radiation and is appropriate for definitive testing in a randomized trial.     

Biology of tumors and head and neck cancer chemotherapy

The management of advanced squamous cell carcinomas of the head and neck has shown disappointing results with surgery and radiation alone. Chemotherapy offers a third method of managing these patients. A background of basic tumor biology and cell cycle kinetics is essential in designing an effective head and neck chemotherapeutic protocol. The principles of the cell cycle, stem cell regulation, and doubling times are discussed. The kinetic classification of chemotherapeutic agents and experimental hypotheses of clinical relevance are reviewed.