Richard L. Fabian

An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck.

This study examines the role of combination chemotherapy with surgery and/or radiotherapy in the initial treatment of patients with advanced stage III and IV squamous-cell carcinoma of the head and neck (SCCHN). Two courses of initial (induction) cisplatin, bleomycin, and methotrexate with oral calcium leucovorin (PBM) were used with the principal intent of increasing the effectiveness of subsequent surgery and/or radiotherapy. Following induction chemotherapy and local treatment, disease-free patients who had responded to initial chemotherapy were entered into a randomized trial of adjuvant PBM. The response rates to induction PBM chemotherapy were a complete response (CR) rate of 26% and a partial response (PR) rate of 52%, for an overall response rate of 78%. A response to induction PBM was highly correlated with failure-free survival (P less than .0001). A Cox multistep regression analysis of potential prognostic factors was performed. After adjusting for the significant prognostic factors of performance status, initial tumor size, and primary tumor site, a response to induction chemotherapy remained independently associated with improved survival (P = .0002). The randomized trial of adjuvant chemotherapy demonstrated that such treatment significantly improved failure-free survival by decreasing local-regional failures. The benefit of adjuvant chemotherapy was particularly evident in patients who had a PR to induction chemotherapy (P = .01). The toxicity of this multidisciplinary approach was predictable and acceptable. Surgery and radiotherapy were not compromised by induction or adjuvant chemotherapy. Definitive evidence that chemotherapy can favorably influence survival awaits confirmation of these results by a randomized trial using a control arm of patients treated with conventional surgery and/or radiotherapy alone.

Noninvasive Imaging of Human Oral Mucosa in Vivo by Confocal Reflectance Microscopy

Objectives/Hypothesis: To study the microscopic anatomy of normal oral tissues in vivo using confocal reflectance microscopy (CRM). This novel and noninvasive imaging modality can define and characterize healthy oral mucosa and thus this work serves as the foundation for studying oral diseases in vivo.

The current surgical management of carotid body paragangliomas

To determine if recent trends in evaluation and therapy have contributed to the successful surgical management of carotid body paragangliomas, we reviewed our experience over the past decade. Nineteen carotid body paragangliomas were identified in 17 patients. Eleven patients underwent complete, preoperative embolization of their afferent arteries with one complication. Calculated carotid body paragangliomas surface areas did not differ between the embolized 64.6 +/- 43.3 cm2 and nonembolized 63.0 +/- 57.9 cm2 lesions. Intraoperative blood loss was lower (p = 0.02) in the patients treated with embolization (372 +/- 213 ml) compared with their cohorts (609 +/- 564 ml). However, the operative times were equivalent 4.1 hours versus 4.5 hours in both groups. Intraoperative electroencephalographic (EEG) monitoring was used in 10 patients; in one patient the EEG indicated intraoperative thrombosis of the carotid artery, which was successfully treated by thrombectomy without complications. Two patients required carotid bifurcation resection and vascular reconstruction to remove the entire tumor; a late stroke manifested by contralateral hand weakness developed in one of these patients. The incidence of cranial nerve injury was low at 16%, with one transient ramus mandibularis paresis and two instances of vocal cord dysfunction. Two additional patients had a postoperative Horners syndrome. We conclude that by diminishing intraoperative blood loss through complete and careful preoperative embolization and use of intraoperative EEG monitoring along with careful surgical technique, the complications associated with this challenging operation are facilitated and diminished.

Incidence of hypothyroidism following multimodality treatment for advanced squamous cell cancer of the head and neck

The incidence of chemical hypothyroidism, as manifested by elevated thyroid stimulating hormone (TSH) levels, has been estimated to be as high as 25% after radiation therapy and 45% after radiation therapy and surgery to the neck for treatment of nodal metastases from squamous carcinoma of the head and neck. We prospectively evaluated 43 previously untreated patients seen in the Dana Farber Cancer Institute Interdisciplinary Head and Neck Service who were treated with aggressive combination chemotherapy in addition to standard surgery and/or radiotherapy. All patients were serially monitored for serum TSH, serum T4, and clincial evidence of hypothyroidism. Following cis‐platinum, bleomycin, and methotrexate chemotherapy and subsequent surgery and/or radiotherapy, decreased thyroid reserve appeared in 37% of patients at a median follow‐up of 9 months. Thirty percent of patients receiving radiotherapy alone and 43% of patients receiving surgery and radiotherapy developed elevated TSH levels. Only one patient developed clinical symptoms. Other patients were asymptomatic despite persistently elevated TSH levels. Abnormalities appeared within the first 4 months after completion of all therapy and were slowly progressive. The addition of combination chemotherapy does not appear to increase the incidence or severity of thyroid dysfunction following radiation therapy and surgery to the neck. In view of the extended survival seen in patients treated with interdisciplinary regimens, we recommend that all patients receiving irradiation to the neck – particularly those patients having neck dissections or total laryngectomies – have routine thyroid function studies performed following the cessation of treatment.

Adaptation to surgery for head and neck cancer

We examined the postoperative adjustment of 45 patients who underwent surgery for cancers of the head and neck: 23 who had laryngeal cancer, 18 who had oral cavity/oropharyngeal cancers, and 4 who had cancers of other sites. Patients were assessed preoperatively, and at 3 months and 9 to 12 months postsurgery. Interviews and questionnaires were used to assess depression, body image, limitations, pain, financial problems, need for help at home, and social interaction. Results revealed that pain, fatigue, weakness, and loss of speech were major concerns. Pain and financial concerns were worst at 3 months and then improved. Physical limitations increased steadily with time. Depression was a major factor in patients with oral cavity and oropharyngeal cancers. Of note, patients who underwent postoperative radiation therapy had the most difficulty adapting to their illness and treatment, with persistent limitations in function and social isolation. The implications of these findings are discussed.

Chemotherapy of advanced salivary gland neoplasms

Fourteen patients with advanced salivary gland malignancies were treated with combination chemotherapy. Five of 13 patients responded to cyclophosphamide and adriamycin and two patients in the responding groups underwent further potentially curable treatment, rendering them disease‐free. Three patients with mucoepidermoid carcinoma failed to respond to this regimen, but two of three patients treated with a combination of cisplatinum, bleomycin and methotrexate responded. The potential role for chemotherapy in the treatment of salivary gland malignancies is discussed.

Reconstruction of the laryngopharynx and cervical esophagus

The historical evolution of reconstruction of the cervical esophagus and laryngopharynx over the past 100 years is documented. The impact of these technical achievements is contrasted to the failure to improve the 5‐year survival rate of 24%.

Treatment complications after sequential combination chemotherapy and radiotherapy with or without surgery in previously untreated squamous cell carcinoma of the head and neck

One hundred consecutive patients with previously untreated advanced squamous cell carcinoma of the head and neck were treated with induction combination chemotherapy followed by definitive surgery and/or radiotherapy, and were evaluated for radiotherapy related toxicity. The induction regimen consisted of cisplatin, bleomycin and methotrexate/leucovorin. Acute toxicity consisted predominantly of mucositis and weight loss, and was mild or moderate by degree in 94% of patients. Six percent of patients experienced severe or life threatening acute toxicities. Two acute toxic deaths were noted in this series, one from a combination of mucositis, weight loss and infection and one from hypoglycemia of unknown origin. Thirty-five percent of patients had radiation treatment interrupted briefly because of acute toxicity. Toxicity was greatest in patients who were nonresponders to induction chemotherapy and such may have been related to the continued presence of advanced tumor. Radiotherapy dose, surgical intervention and age did not have an impact on the presence or degree of acute toxicity. Late toxicities included: hypothyroidism in 32% of patients tested: osteoradionecrosis in 5% of patients, associated primarily with a composite resection (4 of 5 cases); and soft tissue ulcerations in 3%. Taken together, these data indicate that induction combination chemotherapy did not significantly increase the toxicity of subsequent radiotherapy with or without surgery.

Clinical and histopathologic studies of two families with lattice corneal dystrophy and familial systemic amyloidosis (Meretoja syndrome).

Lattice corneal dystrophy associated with familial systemic amyloidosis (Meretoja syndrome) has rarely been described other than in patients of Finnish origin. The authors report two North American patients with this disease who manifest blepharochalasis, lattice corneal dystrophy, open-angle glaucoma, and cranial neuropathy. In one patient, a corneal intraepithelial and subepithelial pseudodendrite was managed by superficial keratectomy, and this same patient benefited from surgical brow suspension for facial muscular weakness. In the second patient, penetrating keratoplasty was complicated by a neurotrophic persistent epithelial defect. Corneal tissue from both superficial keratectomy and penetrating keratoplasty exhibited ultrastructurally characteristic amyloid filaments and associated elastoid material. Transmission electron microscopy of conjunctiva and skin biopsies similarly revealed amyloid deposits associated with most basement membranes, the perineurium and endoneurium of most peripheral nerves, and the intima and media of arteries. By immunoperoxidase staining, the corneal amyloid deposits were positive for the amyloid P-component protein but negative for the nonimmunoglobulin amyloid A protein and prealbumin. Serum prealbumin and amyloid A related protein were normal.

Pectoralis major myocutaneous flap reconstruction of the laryngopharynx and cervical esophagus

Advanced carcinoma of the hypopharynx and cervical esophagus is a formidable challenge to the skills of the head and neck surgeon. Radiation therapy is valuable as adjunctive therapy when combined with curative surgery, which is the primary treatment modality. The extent of anatomical disease associated with extensive neoplasia of the hypopharynx and cervical esophagus is frequently not amenable to total laryngectomy with local tissue repair. Surgical ablation usually requires an extended laryngectomy, which does not permit primary local repair.