Final results of a multi-institutional phase II trial of reirradiation with concurrent weekly cisplatin and cetuximab for recurrent or second primary squamous cell carcinoma of the head and neck.

Background: The optimal regimen of chemotherapy and reirradiation (re-XRT) for recurrent head and neck squamous cell carcinoma (HNSCC) is controversial. We report the final outcomes of a multicenter phase II trial evaluating cetuximab and cisplatin-based chemotherapy concurrent with re-XRT for patients with recurrent HNSCC. Materials and methods: Patients with unresectable recurrent disease or positive margins after salvage surgery arising within a previously irradiated field with KPS ≥ 70 were eligible for this trial. Cetuximab 400 mg/m2 was delivered as a loading dose in week 1 followed by weekly cetuximab 250 mg/m2 and cisplatin 30 mg/m2 concurrent with 6 weeks of intensity-modulated radiotherapy to a dose of 60-66 Gy in 30 daily fractions. Patients who previously received both concurrent cetuximab and cisplatin with radiation or who received radiotherapy less than 6 months prior were ineligible. Results: From 2009 to 2013, 48 patients enrolled on this trial, 2 did not receive any protocol treatment. Of the remaining 46 patients, 34 were male and 12 female, with a median age of 62 years (range 36-85). Treatment was feasible and only 1 patient did not complete the treatment course. Common grade 3 or higher acute toxicities were lymphopenia (46%), pain (22%), dysphagia (13%), radiation dermatitis (13%), mucositis (11%) and anorexia (11%). There were no grade 5 acute toxicities. Eight grade 3 late toxicities were observed, four of which were swallowing related. With a median follow-up of 1.38 years, the 1-year overall survival (OS) was 60.4% and 1-year recurrence-free survival was 34.1%. On univariate analysis, OS was significantly improved with young age (P = 0.01). OS was not associated with radiation dose, surgery before re-XRT or interval from prior XRT. Conclusions: Concurrent cisplatin and cetuximab with re-XRT is feasible and offers good treatment outcomes for patients with high-risk features. Younger patients had significantly improved OS. ClinicalTrials.Gov Identifier: NCT00833261.

Laryngeal squamous cell carcinoma with infradiaphragmatic presentation of skin metastases.

Distant metastases in squamous cell carcinoma of the larynx have an incidence of 6.5-7.2%, and most commonly involve the lungs, liver and bone. Metastases to the skin are exceedingly rare, with only 30 cases reported in the literature. Skin metastases may represent the first clinical evidence of impending locoregional recurrence, suggest distant metastatic spread, or rarely, be the first sign of 'silent' laryngeal tumour. They are usually considered a poor prognostic sign and most often affect the supradiaphragmatic area, i.e. the head, neck, thorax or upper extremities. Infradiaphragmatic presentation of metastatic laryngeal squamous cell carcinoma is exceptional, with only four cases reported in the literature. Here we present another.

In vivo interaction of cis-platinum and fosfomycin on squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Cis-platinum is the most frequently used chemotherapeutic agent for the treatment of head and neck squamous cell carcinoma (SCCA). Ototoxicity and nephrotoxicity continue to be the primary dose-limiting toxicities encountered. Fosfomycin, a broad-spectrum antibiotic, has been previously shown to be both otoprotective and nephroprotective against cis-platinum toxicity. Previous in vitro work demonstrated that fosfomycin does not inhibit the tumoricidal actions of cis-platinum. This study tests whether fosfomycin inhibits cisplatinum in vivo. METHODS: An SCCA cell line was grown in vivo in four groups of nude mice, which then received no treatment, standard-dose cis-platinum, high-dose cis-platinum, or high-dose cis-platinum with fosfomycin. RESULTS: Fosfomycin did not inhibit the tumoricidal activity of cis-platinum. Mice treated with fosfomycin also had longer survival, which is probably due to lessening of immediate cis-platinum systemic toxicity. CONCLUSION: This study shows that fosfomycin in combination with cis-platinum may be useful in treating advanced, and possibly relatively chemoresistant, SCCA of the head and neck.

Predictive markers for response to chemotherapy, organ preservation, and survival in patients with advanced laryngeal carcinoma.

OBJECTIVE: A systematic retrospective study of the largest randomized trial of induction chemotherapy and radiation for advanced laryngeal cancer was undertaken to determine whether specific tumor or biologic factors were predictive of chemotherapy response, organ preservation, or survival. METHODS: The variables analyzed included clinical and histologic factors, immunohistochemical expression of proliferating cell nuclear antigen and p53, and adjusted DNA index measurements. Variables were evaluated for correlation with outcomes of tumor response, organ preservation, and survival. RESULTS: Multivariate analysis revealed that the best predictor of complete response to induction chemotherapy was low T class. The full multivariate model for predicting larynx preservation in patients treated with induction chemotherapy plus radiation shows that T class, p53 overexpression, and elevated proliferating cell nuclear antigen index were independent predictors of successful organ preservation. CONCLUSIONS: These predictive markers should be included in future clinical trials of advanced laryngeal cancer to determine their usefulness prospectively.

Fosfomycin does not inhibit the tumoricidal efficacy of cisplatinum.

OBJECTIVES: This study investigates the effect of fosfomycin on the tumoricidal efficacy of cisplatinum. STUDY DESIGN: Prospective study utilizing the FaDu squamous cell carcinoma cell line and a nude mouse tumor xenograft model. METHODS: Tumor cell growth was assessed in vitro in the presence of cisplatinum and/or fosfomycin utilizing the MTT assay. An optimal cisplatinum dose and dosing schedule was established in a nude mouse tumor xenograft model of squamous cell carcinoma. Using this model, fosfomycin was tested at three dosages and tumor growth monitored over 4 weeks. RESULTS: Mice treated with cisplatinum and fosfomycin had smaller tumors than those treated with cisplatinum alone (P<.01). CONCLUSIONS: This study is the first demonstration that fosfomycin does not inhibit the tumoricidal efficacy of cisplatinum in vivo. This suggests that fosfomycin may be useful in preventing cisplatinum-induced ototoxicity and nephrotoxicity in humans without altering the tumor response rate.

Lateral thigh flap reconstruction in the head and neck.

The lateral thigh free flap is a fasciocutaneous flap based on the cutaneous perforators of the deep femoral vessels. Although originally described in 1983, it has had very few reports in the literature. This article describes the flap and reports our findings and outcomes in nine cadavers (18 thighs) and 33 clinical cases. The position of the vascular pedicle may vary in each case but has always been found to be present. Successful transfer occurred in 30 of 33 cases. Flap loss was attributable to infection, fistula, and hematoma in three of four cases. The flap was especially useful in large defects, most commonly total and base-of-tongue defects. We have found this flap to be reliable and to result in minimal morbidity.

Infrequency of BRCA2 alterations in head and neck squamous cell carcinoma.

Alterations of BRCA2 result in increased susceptibility to breast cancer in both men and women (relative lifetime risks of 0.06 and 0.8 respectively). BRCA2 maps to 13q12-q13 and encodes a transcript of 10,157 bp. Other cancers that have been described in BRCA2 mutation carriers include those of the larynx. Human chromosome 13q has been shown previously by LOH studies to harbor several tumor suppressor genes for head and neck squamous cell carcinoma (HNSCCs). We therefore examined the role of BRCA2 in the development of these cancers. Only 6/22 (27%) of the laryngeal cancers we examined demonstrated LOH of the BRCA2-containing region. These and 10 other HNSCCs of different origins that were demonstrated by LOH studies to have lost the region of chromosome 13 containing BRCA2 were examined for alterations in this gene. SSCP analysis failed to reveal any alterations leading us to conclude that BRCA2 alterations are not frequently involved in the pathogenesis of HNSCCs and that the observed LOH of chromosome 13 loci is due to other, as yet, unidentified tumor suppressor gene(s). Interestingly tumors with LOH in this region (proximal to D13S118) were far more likely to be derived from women than men. This is unusual since HNSCCs are usually fourfold more common in men than in women.

Tongue reconstruction procedures for treatment of cancer.

Cancer of the tongue is the second most common oral cavity malignancy seen in the general population. When otolaryngologists decide to treat patients surgically, perioperative nurses must institute special nursing interventions directed toward patients' tongue reconstruction procedures and rehabilitation. Surgical management of patients undergoing tongue reconstruction procedures requires extensive knowledge of the tongue's anatomy and both current and new physiology created by surgical reconstructive procedures. Equally important is the multidisciplinary care provided to patients during rehabilitation.

Intensive radiation therapy concurrent with up to 7-week continuous-infusion paclitaxel for locally advanced solid tumors: phase I studies.

Patients with locally advanced solid tumors of the lung, head and neck, and malignant astrocytomas usually succumb to their disease despite aggressive standard therapy. Laboratory data suggest that the addition of 1.0 to 10 nmol/L paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a microtubule stabilizing drug, to radiation therapy may result in significant radiation sensitization, perhaps due to accumulation of cells at G2/M. Relatively low concentrations (1.0 to 10 nmol/L) appear to be optimal for direct cytotoxicity and radiosensitization in vitro. Within this dose range, more prolonged exposure seems to result in higher response rates. The phase I trials reported here are designed to test the combination of paclitaxel, administered by continuous intravenous infusion (24 hours a day, 7 days a week), and standard, curative-intent radiation therapy. The ultimate goal of this study is to improve local and systemic control and survival for patients with these three tumor types. To date, 39 evaluable patients are enrolled in this study; there has been no dose-limiting toxicity up to 6.5 mg/m2/d. Observed toxicities include anemia, lymphopenia, mucositis, and cutaneous toxicities.

Genetic alterations of chromosome band 9p21-22 in head and neck cancer are not restricted to p16INK4a.

Although genetic alterations of chromosome band 9p21-22 occur frequently in head and neck squamous cell carcinoma (HNSCC) cell lines, alterations of the cyclin-dependent kinase inhibitor p16INK4a located in this region are less common in corresponding primary tumors. To further investigate genetic alterations at 9p21-22 and p16INK4a in primary HNSCC, a paired set of 21 tumors and blood specimens that were shown previously to exhibit allelic loss at 3p and elsewhere, were tested for LOH at 9p21-22 using eight different highly polymorphic marker. Sixteen of the samples (81%) exhibited LOH for at least one marker. Frequent LOH was found surrounding p16INK4a and at three additional non-contiguous regions of 9p21-22. No homozygous deletions were identified. SSCP screening and direct sequence analysis led to the identification of mutations the p16INK4a gene in two tumors. p16INK4a was not hypermethylated in any of the samples studied. Furthermore, there was no correlation between LOH at 9p21-22 and the RB1 tumor suppressor gene. These findings indicate that in the set of tumors that we tested, LOH at 9p21-22 is common in primary HNSCC but that genetic alterations of p16INK4a located in this region are unusual. Additional tumor suppressor genes at 9p21-22 may therefore be involved in the pathogenesis of this tumor.

Increased immunogenicity of tumors bearing mutant p53 and P1A epitopes after transduction of B7-1 via recombinant adenovirus.

The majority of human solid tumors are likely to express protein epitopes which can act as targets for cytotoxic T cells, but these are frequently not effectively recognized. We tested whether the introduction of the costimulatory molecule B7-1 using a recombinant adenovirus (Ad-B7) can result in effective induction of epitope-specific immunity in two tumor models that express defined endogenous protein epitopes: D459, a fibroblast-derived cell line transfected with a human missense mutant p53 (C to Y at position 135), and P815, a mastocytoma expressing the endogenous tumor epitope P1A. Under the conditions studied, both of these tumors grow and kill their hosts without evidence of significant immune rejection. However, after transduction with the adenovirus containing B7-1, both of these tumors lose tumorigenicity and elicit specific cellular immunity to the mutant p53 epitope in D459 and P1A in P815. In addition, animals exposed to B7-transduced tumor cells were protected from subsequent challenge with nontransduced tumor. Adenovirus has distinct advantages for this approach, as it has high infectivity not requiring in vitro culture, low lytic potential, and transient expression of sufficient duration for immunologic effectiveness but without significant concern over permanent genetic modification. We conclude that transduction of tumor cells with Ad-B7 can increase the immunogenicity of endogenous protein epitopes and may represent a practical therapeutic approach to system human cancers.

Sensory recovery in noninnervated flaps used for oral cavity and oropharyngeal reconstruction.

OBJECTIVES: To assess the clinical recovery of sensation in noninnervated flaps used for oral cavity and oropharyngeal reconstruction. To correlate the return of flap sensation to articulation and swallowing. DESIGN: Prospective nonrandomized study. Six months minimum follow-up. SETTING: Tertiary care center. PATIENTS: From April 1, 1991, to May 31, 1993, 12 patients underwent resection of stage III or greater squamous cell carcinoma of the oral cavity or oropharynx. Ten patients were previously untreated; two had failed previous full-course radiation therapy. Reconstruction was performed with either a pedicled musculocutaneous flap (four patients) or a fasciocutaneous free flap (eight patients). Flap sensation to touch, sharp vs dull, two-point discrimination, and warm vs cold was evaluated in each of these patients at monthly intervals by two independent observers. In addition, an extensive evaluation of articulation and swallowing was performed on all 12 patients a minimum of 6 months after surgery. 10 patients (83%) (eight of eight with fasciocutaneous free flaps and two of four with musculocutaneous flaps), with a strong trend for sensory recovery with the fasciocutaneous free flaps over the musculocutaneous flaps (P = .09). Sensory recovery correlated statistically with articulation (P = .045) and oral intake (P = .045). Patients who underwent reconstruction of base of tongue defects had significantly worse articulation and swallowing than those who underwent reconstruction of other sites (P = .04). No statistically significant correlation was found between patient age, flap size, history of irradiation, or length of follow-up (> 6 months) and flap sensation, articulation, or swallowing. CONCLUSIONS: Spontaneous return of flap sensation was documented by clinical testing in the majority (83%) of patients who underwent reconstruction of oral cavity or oropharyngeal defects with noninnervated flaps. Sensory recovery occurred more often in patients with fasciocutaneous free flaps (100%) than in those with musculocutaneous flaps (50%). Articulation and swallowing correlated statistically with the return of flap sensation.

Phase I studies of continuous-infusion paclitaxel given with standard aggressive radiation therapy for locally advanced solid tumors.

Currently available therapies are unsatisfactory for locally advanced solid tumors of the lung, head and neck, and brain. Laboratory data suggest that the addition of paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ), a microtubule-stabilizing drug, to radiation therapy may result in significant radiation sensitization, perhaps because paclitaxel induces cell cycle arrest at G2/M. Relatively low concentrations, 1 to 10 nmol/L, appear to be optimal for direct cytotoxicity and radiosensitization in vitro. Within this dose range, more prolonged exposure seems to result in higher response rates. We are conducting phase I trials designed to test continuous infusion (24 hours per day, 7 days per week) intravenous paclitaxel combined with standard curative-intent radiation therapy. To date, 22 patients are evaluable, and the maximum tolerated dose of paclitaxel has not been reached at up to 2.5 mg/m2/d. Observed toxicities include anemia, lymphopenia, mucositis, and cutaneous erythema/desquamation.

Traditional methods vs rigid internal fixation of mandible fractures.

OBJECTIVE: To compare traditional methods (ie, intermaxillary fixation with interosseous wiring or external fixation) with newer techniques (ie, plating, use of lag screws) of open reduction and fixation of mandible fractures. DESIGN: Retrospective analysis of data from medical records. SETTING: Academic urban medical center. PATIENTS: Nonrandomized sample of 356 patients admitted to the hospital for treatment of mandible fractures from 1987 through 1991; 155 patients treated with open reduction and fixation were studied. INTERVENTIONS: Sixty-nine patients were treated with interosseous wire fixation or external fixation, 86 patients with rigid internal fixation. MAIN OUTCOME MEASURES: Presence of infection, nerve impairment, nonunion, malunion, operative time, and follow-up. RESULTS: No significant difference was noted between the two groups for sex, treating service, delay in presentation, antibiotic coverage, mechanism of injury, or type of fracture. The incidence of infection, nerve injury, and unavailability for follow-up were greater in patients treated by the newer techniques. Overall expense and operative time were greater in the group treated with plates and lag screws. CONCLUSIONS: We advocate traditional techniques for patients with mandible fractures requiring open reduction and fixation.

Reliability of microvascular free flaps in head and neck reconstruction.

Reliable reconstructive techniques are essential in the surgical treatment of head and neck cancer patients. Free flaps have often been used as reconstructive options of last resort in the head and neck because of the need for added technical skill, a longer operating time, and a perception of poor reliability. This study reviews our experience with 39 free flaps performed by the Otolaryngology-Head and Neck Surgery Service. For the first 17 cases, an interrupted anastomotic technique was used; a running technique was performed in the remaining 22 cases. The average total ischemic time (3.7 vs. 2.7 hours; p < 0.001) was significantly less with a running technique. There were 10 complications: 7 minor would problems, 1 death from aspiration without surgical wound/flap problem, and 2 cases requiring second flaps (1 flap necrosis, 1 fistula with healthy free flap). No statistical correlation was found between complications and ischemic time, suture technique, age, or hospital (five hospitals). Free flaps are reliable and may obviate the need for sacrifice of trunk muscles for wound closure (e.g., fascicocutaneous free flaps instead of myocutaneous flaps); therefore we recommend revascularized free flaps as the primary mode of reconstruction for head and neck defects.

In vitro interaction of cisplatin and fosfomycin on squamous cell carcinoma cultures.

OBJECTIVE: Fosfomycin has been shown to be otoprotective and nephroprotective against cisplatin-induced toxic reactions. This study tests whether fosfomycin inhibits the anticancer effect of cisplatin. METHODS: Three squamous cell carcinoma cell lines were used to determine the effect of fosfomycin on cisplatin-induced tumoricidal activity. Cells were grown in 96 well plates with fosfomycin alone, cisplatin alone, or fosfomycin and cisplatin together. Cell survival was then measured by a colorimetric technique using 3-4,5-dimethylthiazol-2-yl 2,5 diphenyltetrazolium bromide (MTT). RESULTS: There was no decrease in the effectiveness of cisplatin in killing human squamous cell carcinoma in vitro when fosfomycin was present in concentrations of up to 400 mg/L. One cell line also showed killing at high concentrations of cisplatin, but not at low concentrations. CONCLUSIONS: Fosfomycin protects against cisplatin-induced toxic reactions and does not inhibit tumoricidal activity in vitro. In addition, one cell line showed relative resistance to cisplatin at low doses, but was effectively killed with high doses of cisplatin. This is the ideal situation for use of fosfomycin so that higher doses of cisplatin may be given with renal and otologic protection.

DNA content and regional metastases in patients with advanced laryngeal squamous carcinoma. Department of Veterans Affairs Laryngeal Study Group.

Abnormal DNA content of cancer cells in a primary tumor is thought to reflect the altered proliferative capacity of that cancer and overall patient prognosis. Recently, increased DNA content has been associated with early tumor recurrence in patients with advanced laryngeal cancer. To determine if DNA content correlates with a tumor's metastatic behavior, 94 previously untreated patients with stage III (n = 54) or stage IV (n = 40) squamous carcinoma of the larynx were prospectively studied. The adjusted DNA index (aDI) of the primary tumor was measured by computerized cytomorphometry, and correlations with regional metastases, number of positive nodes, extracapsular spread, and pattern of relapse were determined. Median follow-up was 35 months. Of 94 patients, 73 underwent neck dissection. Positive nodes were found in 51 patients (70%) and three or more positive nodes were found in 31 patients (42%). High aDI (> .024) was significantly associated with the presence and number of histologically positive nodes (P = .016). Among patients with high aDI, 19 (50%) of 38 had three or more nodes positive compared to 12 (21%) of 56 of those with low aDI. Median aDI levels in patients with three or more nodes were significantly higher than in patients with 1 or 2 nodes (P = .003). Time to recurrence was shorter in patients with high aDI (P = .0078). These findings provide further evidence that increased DNA content is associated with more aggressive laryngeal cancers having high rates of multiple lymph node metastases and worse overall prognosis.