Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer.

PURPOSE: A multi-institutional, prospective, randomized trial was undertaken in patients with advanced head-and-neck squamous cell carcinoma to address (1) the validity of using pathologic risk features, established from a previous study, to determine the need for, and dose of, postoperative radiotherapy (PORT); (2) the impact of accelerating PORT using a concomitant boost schedule; and (3) the importance of the overall combined treatment duration on the treatment outcome. METHODS AND MATERIALS: Of 288 consecutive patients with advanced disease registered preoperatively, 213 fulfilled the trial criteria and went on to receive therapy predicated on a set of pathologic risk features: no PORT for the low-risk group (n = 31); 57.6 Gy during 6.5 weeks for the intermediate-risk group (n = 31); and, by random assignment, 63 Gy during 5 weeks (n = 76) or 7 weeks (n = 75) for the high-risk group. Patients were irradiated with standard techniques appropriate to the site of disease and likely areas of spread. The study end points were locoregional control (LRC), survival, and morbidity. RESULTS: Patients with low or intermediate risks had significantly higher LRC and survival rates than those with high-risk features (p = 0.003 and p = 0.0001, respectively), despite receiving no PORT or lower dose PORT, respectively. For high-risk patients, a trend toward higher LRC and survival rates was noted when PORT was delivered in 5 rather than 7 weeks. A prolonged interval between surgery and PORT in the 7-week schedule was associated with significantly lower LRC (p = 0.03) and survival (p = 0.01) rates. Consequently, the cumulative duration of combined therapy had a significant impact on the LRC (p = 0.005) and survival (p = 0.03) rates. A 2-week reduction in the PORT duration by using the concomitant boost technique did not increase the late treatment toxicity. CONCLUSIONS: This Phase III trial established the power of risk assessment using pathologic features in determining the need for, and dose of, PORT in patients with advanced head-and-neck squamous cell cancer in a prospective, multi-institutional setting. It also revealed the impact of the overall treatment time in the combination of surgery and PORT on the outcome in high-risk patients and showed that PORT acceleration without a reduction in dose by a concomitant boost regimen did not increase the late complication rate. These findings emphasize the importance of coordinated interdisciplinary care in the delivery of combined surgery and RT.

Radiation effects on osteoblasts in vitro: a potential role in osteoradionecrosis.

OBJECTIVE: To evaluate the factors involved in bone remodeling and wound healing that may be altered by radiation therapy. DESIGN: A prospective, controlled study of biochemical activity in vitro. SUBJECTS: MC3T3-E1 mouse osteoblasts. INTERVENTIONS: Cells were irradiated at 0, 2, 4, or 6 Gy. Specimens were harvested at 1, 7, 14, 28, and 42 days following irradiation for immunohistochemical analysis of transforming growth factor beta(1) expression and transforming growth factor beta(1) type I and II receptor expression. Collagen production was measured at 1, 7, 28, 35, and 49 days after irradiation. The effects of dexamethasone on collagen production and cell proliferation were also examined. RESULTS: Irradiated cells demonstrated decreased cell proliferation and a dose-dependent, sustained reduction in collagen production when compared with control cells. An increase in transforming growth factor beta(1) type I and II receptor expression was noted in irradiated cells when compared with controls. CONCLUSION: Radiation-induced alterations of factors related to bone remodeling and wound healing have a potential role in the pathogenesis of osteoradionecrosis.

Risk factors associated with hypothyroidism after laryngectomy.

Hypothyroidism is a well-documented complication after treatment of head and neck cancer and is particularly significant among patients undergoing laryngectomy. The objective of this study was the identification of factors associated with the development of hypothyroidism in this population. Records of 136 patients treated with laryngectomy were retrospectively reviewed in an attempt to define a risk factor profile for patients in whom hypothyroidism is most likely to develop after laryngectomy. The Cox proportional hazards model was used to identify factors significantly related to an increased risk for development of hypothyroidism. The actuarial method was used to estimate the period of greatest risk for the development of hypothyroidism. Increased risks were found for patients who were female (P = 0.0049), received preoperative radiation therapy (P = 0.0022), had invasion of the thyroid gland by tumor (P = 0.0003), had presence of cervical metastases (P = 0.0022), and had postoperative fistula (P = 0.0095). From the actuarial method, we estimated that the period of time when patients were at greatest risk for development of hypothyroidism was between 0 and 14 months after surgical intervention. Wound complications were twice as frequent in hypothyroid patients. Perioperative awareness of risk factors associated with the development of hypothyroidism in patients undergoing laryngectomy allows for early recognition and management of hypothyroidism and may reduce the number of complications related to wound healing and fistula.

Transforming growth factor-beta type II receptors and smad proteins in follicular thyroid tumors.

OBJECTIVE: Resistance to transforming growth factor (TGF)-beta-mediated cell growth inhibition is a well-known pathogenic mechanism in epithelial neoplasia. TGF-beta signaling requires normal function of downstream mediators such as TGF-beta receptors (TbetaRs) and Smad proteins. The goal of this study is to investigate the expression of components of the TGF-beta signaling pathway in follicular tumors of the thyroid. STUDY DESIGN: Twenty follicular thyroid neoplasms were classified as adenomas (11) or minimally invasive follicular carcinomas (9) according to current pathological criteria. Protein expression was evaluated to identify differences between benign and malignant tumors that could be used as an adjunct to histopathological analysis. METHODS: Paraffin-embedded tissue sections containing tumor and adjacent nonneoplastic parenchyma were analyzed by immunohistochemistry for the expression of TbetaR type II (TbetaR-II) and Smad2, Smad4, Smad6, and Smad7. Expression of each protein in the tumor was compared with that of the corresponding adjacent nonneoplastic thyroid parenchyma. RESULTS: TbetaR-II expression was lost in 78% of the carcinomas. In the remaining 22%, TbetaR-II was preserved but Smad2 expression was lost. In all conventional adenomas, however, TbetaR-II expression was maintained. Furthermore, all tumors with normal expression of all proteins were adenomas. CONCLUSIONS: Downregulation of TbetaR-II is a consistent abnormality in follicular carcinomas and can be used to differentiate minimally invasive carcinomas from adenomas. Also, downregulation of Smad proteins is another mechanism by which carcinomas can become independent from TGF-beta-mediated growth inhibition.

Factors affecting survival for floor-of-mouth carcinoma.

OBJECTIVES: The treatment of extensive floor-of-mouth carcinoma has remained a challenging problem for head and neck surgeons. We have reviewed our experience in the surgical management of floor-of-mouth cancer in an attempt to identify factors influencing survival. METHODS: A total of 144 patients with cancer involving the floor of the mouth were treated between March 1988 and November 1995. A retrospective chart review was conducted that captured information including clinical staging, therapeutic modalities, pathologic findings, and patient follow-up. Factors affecting survival were assessed by nonparametric analysis and analysis of variance. RESULTS: There was no statistical significance for the effects of vascular invasion (P = 0.4019), lymphatic invasion (P = 0.3430), bone invasion (P = 0.1548), or positive margins (P = 0.1113) on survival. Extranodal extension and recurrent disease were strongly suggestive of influencing survival but were not statistically significant (P = 0.0650 and P = 0.0504, respectively). Nodal disease significantly affected survival (P = 0.0138) but did not affect recurrence (P = 0.451). CONCLUSION: Mean survival for this cohort was 30.6 months. Positive node status significantly affected mean overall survival in this series, whereas extracapsular disease did not. These data suggest that aggressive surgical management of neck disease is mandated to maximize survival.

Frontal sinus fractures: anterior skull base.

The frontal sinus is fractured in 30% of patients sustaining maxillofacial injury. The CT scan has simplified the treatment plan allowing the surgeon to be more selective in the treatment choice, surgical approach, and follow-up. Fractures may involve the anterior, posterior, or both tables of the sinus. The frontal sinus repair or surgery takes place when there is minimal displacement and the frontal ducts are in tact. Obliteration of the sinus is suggested when the ducts are injured, but there is no significant bone loss or comminution of the posterior table. More extensive injuries of the posterior table require cranialization. The mucosa of the sinus must be reviewed completely, sealing off the nasal cavity to help decrease mucocele formation and other intracranial complications. Tedious repair of the dura (pericranial flap) decrease persistent CSF leak and intercranial infections. The anterior table must always be carefully repaired to optimize the cosmetic result. Careful follow-up is required to direct potential mucocele formation or delayed or persistent CSF leak. Judicious use of postoperative scars help to confirm these diagnosis.

Assessment of plate use for mandibular reconstruction: has changing technology made a difference?

Reconstruction of mandibular defects with a variety of alloplastic materials during a 22-year period was reviewed. Outcomes were examined to determine whether specific plating technology affected the incidence of plate-related complications including plate exposure, plate fracture, and plate removal. Repair with the miniplate, reconstruction plate, titanium hollow screw reconstruction plate, and locking reconstruction plate was evaluated. Although the incidence of plate fractures has decreased, there was no significant change in the rate of plate exposure. Recurrent disease was noted to be a significant contributing factor in the development of plate-related complications.

Auricular carcinoma with temporal bone invasion: outcome analysis.

Invasion of the temporal bone by cutaneous carcinoma of the auricle and periauricular skin is an ominous prognostic sign. Management includes aggressive resection of cutaneous disease as well as resection of temporal bone to obtain a medial margin. Analysis of data from 21 patients with temporal bone invasion caused by cutaneous malignancy is presented. Overall survival is approximately 63%. Cumulative survival is significantly decreased in patients with squamous cell carcinoma when compared with other invasive malignancies. Univariate and covariate analyses demonstrate that nodal status, positive microscopic soft tissue margins, and persistent perineural disease at the skull base did not significantly affect survival in this series. There is a trend toward increased survival in patients receiving postoperative radiation in this series.

Cyclin D1 expression as a prognostic parameter in papillary carcinoma of the thyroid.

Papillary carcinoma of the thyroid is the most common thyroid cancer. At the time of clinical presentation, most papillary carcinomas are still confined to the thyroid gland, and appropriate surgical treatment achieves a 95% 5-year survival rate. Certain carcinomas, however, behave in a much more aggressive fashion. Because specific therapies do not exist, for those tumors that have escaped local control, patients with disseminated disease have little or no chance of permanent cure or long-term survival. Cyclin D1, a protein that plays a critical role in the control of the cell cycle, has been shown to be overexpressed in a variety of human neoplasias and may serve as a prognostic parameter of disease progression. To explore the role played by cyclin D1 in the pathogenesis of thyroid papillary carcinoma, we have quantitated, by computerized image analysis, the immunohistochemical expression of cyclin D1 in formalin-fixed, paraffin-embedded tissue from 35 conventional papillary carcinomas of the thyroid and correlated the results with established clinicopathologic parameters and available survival data.

Transforming growth factor beta receptors and p27kip in thyroid carcinoma.

OBJECTIVE: To investigate the role of cell cycle regulators in the pathogenesis of papillary carcinoma of the thyroid. DESIGN: Resistance to transforming growth factor beta-mediated inhibition is a well-known pathogenic mechanism in epithelial neoplasias. In a retrospective study, the expression of transforming growth factor beta receptors types I and II, cyclin D1, and the cyclin-dependent inhibitor p27kip, was analyzed by immunohistochemistry. Results were interpreted in the context of clinicopathological data. Patient follow-up ranged from 1 to 18 years, with a mean of 4 years. MATERIALS: Twenty conventional primary papillary carcinomas and their metastases were selected according to current pathologic criteria. Nonconventional papillary carcinomas (eg, tall-cell, columnar) were excluded from the analysis. RESULTS: Cyclin D1 was expressed more intensely in the tumor than in adjacent nonneoplastic parenchyma. Within a given tumor, however, there was significant heterogeneity in expression intensity and percentage of positive cells, particularly in metastases. Type I receptors were strongly expressed in 90% of tumors, while 80% of the tumors revealed low to no expression of type II receptors. In 10% of tumors, type I receptors were absent and type II receptors expressed. Simultaneous absence of both receptors was not observed. While p27kip was strongly expressed in nonneoplastic thyroid, it was not detected in any of the primary tumors or their metastases. CONCLUSIONS: The results strongly suggest that functional abnormalities in type II receptors result in increased levels of cyclin D1 and down-regulation of p27kip. This would maintain cells in a proliferative state and would promote tumor progression.

Reconstruction after temporal bone resection.

Reconstruction of soft tissue defects after temporal bone resection can vary from simple closure of the external auditory canal to complex flap coverage of extensive defects. Between 1987 and 1996, 34 patients underwent lateral skull base resections and reconstruction for invasive carcinoma of the temporal bone. Seven underwent sleeve resection and/or radical mastoidectomy. Sleeve resection was managed with tympanoplasty, canalplasty, or obliteration of the external auditory canal (10). There were 24 lateral temporal bone resections and four subtotal temporal bone resections. Larger defects created by lateral and subtotal temporal bone resections required closure with a combination of temporalis flaps and local rotational cutaneous flaps (13). Lower island trapezius flaps (five), free flaps (four), and pectoralis major flaps (two) were also used. Indications and efficacy of each method are discussed, and treatment outcomes are presented.

Postoperative accelerated radiotherapy in high-risk squamous cell carcinoma of the head and neck: long-term results of a prospective trial.

BACKGROUND: For patients treated with combination resection and postoperative radiotherapy, the interval between surgery and completion of radiotherapy represents an opportunity for tumor repopulation and treatment failure. A prospective trial to test the feasibility and efficacy of accelerated postoperative radiotherapy was concluded in August of 1990. METHODS: Thirty-two patients with high-risk pathologic findings were treated with 63 Gy in 35 fractions of 1.8 Gy over 5.2 weeks using a modified concomitant-boost technique. RESULTS: Acute mucosal and skin reactions were increased but tolerable. At a median follow-up of 6 years, the crude in-field recurrence rate for the entire group was 10/32 (31%), with 0/10 (0%) recurrences in patients commencing accelerated radiotherapy within 4 weeks of surgery and 10/22 (45%) recurrences in patients with a delay of more than 4 weeks (p = .006). The rate of late complications appears similar to that seen with conventional radiotherapy, with possibly a higher rate of "consequential"-type late effects. CONCLUSIONS: This pilot study suggests that prompt application of accelerated postoperative radiotherapy significantly improves local-regional control and supports the concept of rapid tumor repopulation in the postoperative setting. Various strategies to overcome tumor repopulation are discussed.

Evolution of the extracranial approach for repair of CSF leaks: review of the literature and clinical cases.

The management of cerebrospinal fluid rhinorrhea changed with the advent of endoscopes in the early 1990s. The majority of repairs are now approached endoscopically, i.e., extracranially. This article reviews the evolution of the extracranial approach, as reported in the literature, concluding with the experience of the authors. A total of 15 patients were treated by the primary author since 1987; an open external ethmoid approach was utilized in 3 patients, and an endoscopic approach was used to treat 12 patients. The success rate with the external ethmoid approach was 100%; with the endoscopic approach, the primary success rate was 75% (9/12). There were 3 failures: One was due to a graft shrinkage; another was secondary to inadequate visibility; and the reason for the third was unclear. Eventually, all three were successfully repaired. Based on this experience, cerebrospinal fluid rhinorrhea can be successfully managed via an extracranial approach 75% of the time.

Effects of radiation therapy on reconstruction of mandibular defects with a titanium reconstruction plate.

Titanium fixation plates are commonly used in reconstruction of mandibular defects resulting from tumor resections in head and neck surgery. The effects of radiation therapy on the interface of bone, plate, and soft tissue were examined in this in vivo study. Four conditioned beagles had 1-cm segmental mandibular defects that were reconstructed with titanium plates. Two of the four also had placement of vascularized bone grafts. Healing was evaluated with or without postoperative radiotherapy. After collection of tissues using histologic methods and analysis with energy-dispersive spectroscopy, we found that the effects of radiation on bone-plate and bone-screw interfaces is minimal. Although radiation decreased the bone density and the rate of bone repair at the bone-screw interface, this did not appear to affect stability of the plate repair or the viability of bone tissue.

Repair of mandibular fractures using the 2.0 mm system. A review.

The mandible is a commonly injured facial bone with mandibular fractures occurring 3 times more frequently than those in the zygoma. Requirements for repair vary with the type of fracture, the location of the fracture, and the condition of the teeth and bone. Repair of the mandible is complicated by the complex range of function of the mandible. This article presents a brief, historical overview of techniques and systems that have been used for fracture stabilization. The authors report on the results of a study in which the 2.0 mm plate was used to repair 89 fractures. The use of 2.0 mm mandibular plates appears to provide adequate stability for patients with healthy bone and minimal comminution.

Comparison of intravenous ketorolac and alfentanil as supplements to propofol anesthesia for diagnostic panendoscopy.

STUDY OBJECTIVE: To determine if ketorolac tromethamine is an acceptable alternative to alfentanil as a supplement to propofol for diagnostic panendoscopy. DESIGN: Randomized, double-blind study. SETTING: University medical center. PATIENTS: 40 patients scheduled for panendoscopy and laryngeal tissue biopsy. INTERVENTIONS: Patients were randomly assigned to receive either alfentanil 14.5 micrograms/kg or ketorolac 1.0 mg/kg in a double-blind fashion, 5 to 10 minutes before induction of general anesthesia. MEASUREMENTS AND MAIN RESULTS: Heart rate (HR) and noninvasive blood pressure (BP) were measured and recorded before and immediately after injection of the study drug, after laryngoscopy for the endotracheal tube placement, and after initiation of diagnostic panendoscopy. Bleeding in the operative field was rated by the endoscopist. Observation from discontinuation of the propofol infusion and nitrous oxide inhalation to eye opening, head lifting, and orientation to time and place was observed and recorded. The presence of stridor after extubation, and pulse oximeter-determined arterial blood oxyhemoglobin saturation immediately after extubation and 5 minutes later, were noted. In the recovery room, the ability to tolerate oral fluids, sit, stand, and walk were recorded. Supplementation with ketorolac provides faster recovery from anesthesia as evidenced by shorter time to eye opening, head lifting, and orientation to time and place. However, no intergroup differences were found in measured intraoperative variables (BP and HR following laryngoscopy, tracheal intubation, diagnostic panendoscopy, and tissue biopsy). Operative site bleeding was comparable in both groups. The variables reflecting street readiness and the incidence of nausea and vomiting were statistically comparable. CONCLUSION: Supplementation of propofol anesthesia with ketorolac is an efficacious alternative to supplementation with alfentanil. The faster recovery in the ketorolac group is explained by the mostly peripheral effect of this drug, whereas the slow decline in the alfentanil concentration at the effective site may be responsible for slower emergence from anesthesia.

Assessment of bone formation during osteoneogenesis: a canine model.

Distraction osteoneogenesis, callotasis, has been demonstrated to be an effective means of lengthening long bones. A variation of Ilizarov's technique produces a transport disk from one cut surface of bone within a defect and advances the disk to the opposite surface to close the defect. This process, previously described by Costantino et al. (Arch Otolaryngol Head Neck Surg 1990; 116:535-45), demonstrated bone formation within the distraction site. The precise mechanism of bone formation has not yet been described for the mandible. Four conditioned beagles were studied, with one control dog maintained in neutral fixation and three dogs distracted at 0.25 mm every 8 hours. A two-cm defect was closed, and dogs were kept in fixation for 1 week after closure, after which they were killed. Three sites were evaluated: (1) the distraction seam, (2) the interface of the cortical and distracted bone, and (3) the cortexes at the closed defect. Each site was bisected, and one half was decalcified for immunohistochemical and hematoxylin and eosin pathologic evaluation. The vascular basement membrane was labeled for laminin and type IV collagen. Both of these substances demonstrate the differentiation of the vascular matrix component predisposing primary bone formation. Labels were intense at the distraction seam where intense angiogenesis occurred. No hyalin cartilage was observed at the distraction site, which indicates that the fixation was stable and that ossification occurred primarily without intermediate callous formation. This model demonstrated that osteoclasts within the canine model produce bone through primary bone formation within an angiogenic matrix rich in basement membrane laminin and type IV collagen. Likewise, bone is species specific in mineral composition for dog mandible. Understanding the formation and composition of distracted bone is essential for understanding application of this technique within the clinical setting.