Base-of-tongue cancer: survival, function, and quality of life after external-beam irradiation and brachytherapy.

OBJECTIVE: Base-of-tongue cancer has traditionally been treated by surgical resection followed by radiation therapy. Primary radiation therapy with brachytherapy has recently been proposed as an alternative. In a prior analysis, we found that patients with advanced tongue-base cancer treated by total glossectomy and postoperative radiation therapy can be cured while potentially maintaining good quality of life. Therefore, we designed the current study to assess survival, function, and quality of life in our patients with tongue-base cancer who were treated with primary radiation therapy and brachytherapy with neck dissection as indicated. STUDY DESIGN: Consecutive case series. METHODS: Twenty patients were treated between 1993 and 1997 using the approach just named. The T stages were T1 (3), T2 (10), T3 (6), and T4 (1). The N stages were N0 (3), N1 (3), N2 (11), and N3 (3). At the time of brachytherapy catheter placement, neck dissections were performed in all 14 patients with N2 or N3 disease. Surviving patients completed a functional status survey and quality of life questionnaire. RESULTS: The 3- and 5-year Kaplan-Meier corrected actuarial survival rates were 57% and 38%, respectively. Eight patients remained alive at the time of this writing and completed the functional status survey and quality of life assessment. Function and quality of life were well maintained in patients treated with external-beam irradiation followed by brachytherapy and neck dissection. However, none of our patients with T3 disease had long-term survival. CONCLUSION: Although we do not endorse external-beam irradiation and brachytherapy for advanced tongue-base cancers, this treatment should be strongly considered for patients with T1 or T2 tumors in whom preservation of function and quality of life is a priority.

Clinical experience with HLA-B7 plasmid DNA/lipid complex in advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To investigate the safety and efficacy of alloantigen plasmid DNA therapy in patients with advanced head and neck squamous cell carcinoma using Allovectin-7 (Vical Inc, San Diego, Calif), a DNA/lipid complex designed to express the class I major histocompatibility complex antigen HLA-B7. DESIGN: Multi-institutional prospective trial. SETTING: Academic medical setting. PATIENTS: A total of 69 patients were enrolled in 3 sequential clinical trials: a single-center phase 1 trial and 2 multicenter phase 2 trials. Eligibility criteria included unresectable squamous cell carcinoma that failed conventional therapy, Karnofsky performance status score of 70 or greater, and no concurrent anticancer or immunosuppressive therapies. INTERVENTION: Patients received 2 biweekly intratumoral injections of 10 microg (phase 1 and first phase 2 trials) or 100 microg (second phase 2 trial) of Allovectin-7 followed by 4 weeks of observation. Patients with stable or responding disease after the observation period were given a second treatment cycle identical to the first. MAIN OUTCOME MEASURES: Patients were assessed for toxic effects, and tumor size was measured after cycles 1 (at 6 weeks) and 2 (at 16 weeks). RESULTS: Allovectin-7 treatment was well tolerated, with no grade 3 or 4 drug-related toxic effects. Of 69 patients treated, 23 (33%) had stable disease or a partial response after the first cycle of treatment and proceeded to the second cycle. After the second cycle, 6 patients had stable disease, 4 had a partial response, and 1 had a complete response. Responses persisted for 21 to 106 weeks. CONCLUSIONS: Intratumoral plasmid DNA immunotherapy for head and neck cancer with Allovectin-7 is safe, and further investigations are planned in patients with less advanced disease, where it could potentially improve patient survival and reduce the need for radical high-morbidity treatments.

Centrosome hyperamplification in head and neck squamous cell carcinoma: a potential phenotypic marker of tumor aggressiveness.

OBJECTIVES/HYPOTHESIS: There is currently no single histological or genotypic marker that reliably predicts the biological behavior of head and neck squamous cell carcinoma (HNSCC). While multiple genetic mutations have been investigated, no single genotypic alteration has consistently correlated with tumor aggressiveness. Phenotypic markers may prove more predictive, because they can represent many different genetic alterations. We investigated the frequency of centrosome hyperamplification in HNSCC and examined its usefulness as a marker for tumor recurrence. STUDY DESIGN: Analysis of archived paraffin blocks using immunohistochemistry. METHODS: Eighteen patients who underwent resection of oral cavity squamous cell carcinoma were reviewed. Ten patients had cancers that recurred locally within 1 year of resection, and 8 patients were tumor free at 5 years. The amount of centrosome hyperamplification in the cancer specimens and all surgical margins was graded as follows: 0, none; 1+, rare hyperamplification; 2+, greater than 10% of cells per high-powered field; and 3 +, greater than 20% of cells per high-powered field. RESULTS: Centrosome hyperamplification was found in 17 of 18 tumors (94%). Grade 2+ or 3+ hyperamplification was found more in cancers that recurred (9 of 10) than in those that did not (3 of 8) and was more prevalent in the histologically normal margins of patients with recurrence (8 of 10) than in those without recurrent cancer (3 of 8). CONCLUSIONS: Our results demonstrate the extremely frequent occurrence of centrosome hyperamplification in HNSCC. Centrosome hyperamplification is a phenotypic marker for HNSCC and can reflect multiple genotypic changes. Its presence in histologically normal margins suggests that it may be useful for analysis of primary tumors and tumor margins.

Esthesioneuroblastoma and sinonasal undifferentiated carcinoma: impact of histological grading and clinical staging on survival and prognosis.

OBJECTIVES: Hyams proposed a histological grading system for esthesioneuroblastoma in which grade I tumors have an excellent prognosis and grade IV tumors are uniformly fatal. The Hyams grading system predated advanced craniofacial techniques, extensive use of immunohistochemistry, and the recognition of sinonasal undifferentiated carcinoma (SNUC) as a distinct entity. Therefore we aimed to determine whether Hyams classification is useful in predicting outcome for esthesioneuroblastoma and SNUC. STUDY DESIGN: A retrospective review of cases from 1970 to 1999. METHODS: Twenty-six patients (12 with esthesioneuroblastoma and 14 with SNUC) were reviewed. The Kadish clinical stage was determined, and histopathological slides were reviewed and graded using the Hyams system. RESULTS: Kadish staging was available for 26 patients (2 patients with stage A tumors; 7 with stage B; and 17 with stage C). Of the 8 evaluable patients with Kadish stage A or B tumors, 6 remained disease free for more than 2 years compared with only 5 of the 17 Kadish stage C tumors. Slides were available for Hyams grading in 21 patients (2 patients with grade I tumors; 4 with grade II; 4 with grade III; and 11 with grade IV). Of the 6 patients with Hyams grade I or II tumors, 4 remained disease free for more than 2 years compared with only 4 of the 15 patients with Hyams grade III or IV tumors. Of note, three patients with Kadish stage C tumors (two with esthesioneuroblastoma, one with SNUC) and two patients with Hyams grade IV tumors (one with esthesioneuroblastoma and one with SNUC) survived for more than 5 years. CONCLUSIONS: Both the Hyams grading system and the Kadish staging system can be used as independent predictors of outcome. Although limited by small numbers, the results of this study demonstrate that patients with either advanced clinical stage or pathological grade of esthesioneuroblastoma or SNUC have poor prognosis, but that long-term survival is possible in these patients if aggressive treatment is used.

Gene therapy for head and neck cancer.

OBJECTIVES/HYPOTHESIS: New treatment methods are needed for head and neck cancer to improve survival without increasing morbidity. Gene therapy is a potential method of improving patient outcome. Progress in gene therapy for cancer is reviewed with emphasis on the limitations of vector technology and treatment strategies. Given the current technological vector limitations in transmitting the therapeutic genes, treatments that require the fewest number of cells to be altered by the new gene are optimal. Therefore an immune-based gene therapy strategy was selected in which the tumors were transfected with the gene for an alloantigen, human leukocyte antigen (HLA)-B7, a class I major histocompatibility complex (MHC). This would restore an antigen presentation mechanism in the tumor to induce an antitumor response. This gene therapy strategy was tested in patients with advanced, unresectable head and neck cancer. STUDY DESIGN: Prospective trial. METHODS: Twenty patients with advanced head and neck cancer who had failed conventional therapy and did not express HLA-B7 were treated with gene therapy using a lipid vector by direct intratumoral injection. The gene therapy product contained the HLA-B7 gene and the beta2-microglobulin gene, which permits complete expression of the class I MHC at the cell surface. Patients were assessed for any adverse effects, for changes in tumor size, for time to disease progression, and for survival. Biopsy specimens were assessed for pathological response, HLA-B7 expression, apoptosis, cellular proliferation, CD-8 cells, granzyme, and p53 status. RESULTS: There were no adverse effects from the gene therapy. At 16 weeks after beginning gene therapy, four patients had a partial response and two patients had stable disease. Two of the tumors completely responded clinically, but tumor was still seen on pathological examination. The time to disease progression in the responding patients was 20 to 80 weeks. The median survival in patients who completed gene therapy was 54 weeks, compared with 21 weeks in patients whose tumors progressed after the first cycle of treatment. One patient survived for 106 weeks without any additional therapy. HLA-B7 was demonstrated in the treated tumors, and increased apoptosis was seen in the responding tumors. CONCLUSION: Significant advances have been made in the field of gene therapy for cancer. Alloantigen gene therapy has had efficacy in the treatment of cancer and can induce tumor responses in head and neck tumors. Alloantigen gene therapy has significant potential as an adjunctive treatment of head and neck cancer.

Management implications of evaluating the N2 and N3 neck after organ preservation therapy.

OBJECTIVES/HYPOTHESIS: To determine if metastatic squamous cell carcinoma with proliferative potential persists in N2 and N3 necks after conventional radiation. STUDY DESIGN: Retrospective case series. MATERIALS AND METHODS: We identified 17 patients from our head and neck tumor database who underwent organ-preserving radiotherapy for primary aerodigestive squamous cell cancer and N2-3 regional metastasis. Archival tissue from these 17 neck specimens was evaluated for routine histopathologic evidence of tumor, as well as immunohistochemically for cytokeratin and Ki-67 activity. An assay for apoptosis was also performed on 10 of the specimens. RESULTS: Routine H&E evaluation suggested metastatic cancer in 11 of 17 irradiated neck specimens. Cytokeratin immunostaining confirmed squamous cell carcinoma in these 11 necks as well as 1 additional specimen that had tested H&E negative. Ki-67 staining demonstrated proliferating tumor in 3 of 17 necks. The apoptosis assay confirmed regions of apoptosis in all of the specimens analyzed. CONCLUSIONS: The discovery of proliferating cancer cells in 3 of 17 irradiated specimens (18%) supports the practice of planned neck dissection after primary radiotherapy for patients with pretherapeutic N2+ metastatic disease.

Surgical management of hard palate malignancies.

OBJECTIVE: A variety of surgical procedures can be used to treat malignancies of the hard palate and inferior maxilla. This study was designed to evaluate the efficacy of alveolectomy, palatectomy, and infrastructure maxillectomy in the treatment of cancers in these areas. METHODS AND MATERIAL: A retrospective review of 50 patients who underwent alveolectomy, palatectomy, or infrastructure maxillectomy from 1971 to 1997 was performed. The pathology of these lesions included squamous cell carcinoma (25), adenoid cystic carcinoma (11), adenocarcinoma (6), and others (8). RESULTS: The 5-year survival rate by Kaplan-Meier analysis for all lesions was 85%. The 5-year survival rate for squamous cell carcinoma was 76%, and that for adenoid cystic carcinoma was 90%. The 10-year survival rate for adenoid cystic carcinoma was 75%. There was minimal morbidity associated with these procedures. DISCUSSION: Alveolectomy, palatectomy, and infrastructure maxillectomy are the procedures of choice for lesions in the region of the hard palate. The differences between these surgical techniques are presented, and indications, contraindications, and results for each technique are discussed.

Variable genetic alterations and survival in head and neck cancer.

OBJECTIVE: To evaluate multiple genetic loci in patients with head and neck cancer to determine if, as in colorectal carcinoma, there is an orderly occurrence of genetic alterations, and if an accumulation of alterations affects patient survival. DESIGN: Cohort study of patients with head and neck cancer in which fresh tissue was retrieved. SETTING: Academic medical center. PATIENTS: Forty-three patients treated surgically for squamous cell carcinoma of the head and neck from 1991 to 1994. MAIN OUTCOME MEASURES: The DNA from tumor and healthy tissue was evaluated for loss of heterozygosity at p53, retinoblastoma, and chromosome 16q and for amplification of cyclin D1. The respective RNA was probed for levels of p53, p 16, p21, and p27 messenger RNA. These findings were compared with tumor stage and patient survival. RESULTS: DNA analysis showed that loss of heterozygosity occurred at p53 in 21% of tumors, at retinoblastoma in 35%, and at 16q in 21%, and that cyclin D1 was amplified in 42%. Messenger RNA levels of the assessed proteins were variably increased and decreased compared with healthy tissues obtained from the same patients with no discernable pattern. There was no correlation between any one of these genetic alterations and overall survival. When patients were analyzed for loss of heterozygosity at p53, retinoblastoma, 16q, or altered cyclin D1 in combination, 19 patients had no detectable alterations, 13 had 1, 6 had 2, and 5 had 3. Single genetic alterations did not affect survival; however, there was a trend toward decreased survival with multiple alterations. The 2-year Kaplan-Meier survival in patients with less than 1 genetic loss was 78% vs 58% in patients with 2 or more losses. CONCLUSIONS: The lack of a pattern of genetic alterations in head and neck cancer demonstrates that its progression can be mediated by a multitude of pathways, complicating its genetic evaluation. Single genetic alterations do not appear to affect survival; however, when multiple alterations are detected-regardless of combination-survival is affected. This observation lends credence to the theory that multiple genetic alterations contribute to cancer progression; however, the lack of a pattern of this genetic change is a significant obstacle to applying genetic findings to routine cancer therapy.

Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression.

We have previously reported that loss of p53 tumor suppressor protein results in centrosome hyperamplification, which leads to aberrant mitosis and chromosome instability. Since p53 is either deleted or mutated in human cancers at a high frequency, we investigated whether human cancers showed centrosome hyperamplification. Screening of advanced stage breast ductal carcinomas and squamous cell carcinomas of the head and neck (SCCHN) revealed that centrosome hyperamplification is frequent in both tumor types. Moreover, through the analyses of p53 in SCCHN samples by direct sequencing and by loss-of-heterozygosity test, we found that p53 mutations correlated with occurrence of centrosome hyperamplification. However, in some cases, we observed centrosome hyperamplification in tumors that retained wild-type p53. These tumors contained high levels of Mdm2. Since Mdm2 can inactivate p53 through physical association, we investigated whether Mdm2 overexpression induced centrosome hyperamplification. We found that Mdm2 overexpression, like loss of p53, induced centrosome hyperamplification and chromosome instability in cultured cells.

Cervical metastases of head and neck squamous cell carcinoma correlate with loss of heterozygosity on chromosome 16q.

To assess the potential involvement of putative tumor suppressors or metastasis suppressors on chromosome 16q in head and neck squamous cell carcinoma (HNSCC), we have examined 42 primary HNSCCs for loss of heterozygosity (LOH) at 16q and correlated these findings with the occurrence of cervical nodal metastases and other clinical parameters. Seven of the 42 (17%) HNSCCs examined displayed LOH at chromosome 16q24. Three of the seven HNSCCs showed LOH at all of the informative loci analyzed along the chromosome arm, whereas the other four showed only loss of a subset of markers. When LOH at 16q was correlated with clinical parameters, there was no significant correlation with age, sex, clinical stage, T stage, N stage or survival. However, there was a correlation between LOH at chromosome 16q24 and involvement of cervical lymph nodes. Of the seven HNSCCs that had lost heterozygosity at 16q24, six had local metastases to lymph nodes indicating that LOH at 16q24 may have predictive value for the metastatic potential of HNSCCs.

Alloantigen gene therapy for squamous cell carcinoma of the head and neck: results of a phase-1 trial.

OBJECTIVE: To determine the safety and efficacy of an immunogenic gene therapy using a drug designed to produce expression of a foreign class I major histocompatibility complex protein in patients with head and neck cancer. DESIGN: Phase 1 prospective clinical trial. SETTING: Academic medical setting. PATIENTS: Nine patients with advanced head and neck squamous cell carcinoma who had failed conventional therapy and did not express HLA-B7, a class I major histocompatibility complex protein. INTERVENTION: Patients were treated with Allovectin-7 (Vical Inc, San Diego, Calif) by direct intratumoral injection. Allovectin-7 contains a plasmid complementary DNA complexed with a cationic lipid, which results in expression of HLA-B7. MAIN OUTCOME MEASURES: Patients were assessed for any toxic effects and for any change in tumor volume. Biopsy specimens obtained before and after therapy were evaluated by immunohistochemistry to detect HLA-B7 expression and with the terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay to detect any induction of apoptosis. RESULTS: There were no toxic effects of the gene therapy. In 4 of these 9 patients there was a partial response to treatment, evidenced by a gradual reduction in tumor size. One patient has remained alive for more than 17 months since commencing treatment, with no clinical evidence of disease but with persistent histological evidence of cancer. Analysis of the biopsy specimens from 2 of the patients who responded to therapy demonstrated HLA-B7 expression. The TUNEL assay demonstrated extensive apoptosis in both of these patients, suggesting that this may be the mechanism of tumor reduction. CONCLUSIONS: These data demonstrate the potential efficacy and lack of toxicity of this form of alloantigen gene therapy. A multi-institutional study has been initiated to expand on these findings.

Silent gastroesophageal reflux disease in patients with pharyngolaryngeal cancer: further results.

BACKGROUND: Gastroesophageal reflux disease is associated with various head and neck manifestations. The aim of this retrospective study was to determine the incidence of asymptomatic, or "silent," gastroesophageal reflux disease (GERD) in patients treated for pharyngolaryngeal squamous cell carcinoma. METHODS: Twenty-four-hour pH monitoring was performed in 72 consecutive patients without digestive manifestations (pyrosis, retrosternal heartburn) of GERD treated for pharyngolaryngeal carcinoma. Statistical analysis of the relationship between reflux scores achieved and various patient parameters (age, tobacco and alcohol consumption, gastric ulcers, medications which decrease esophageal sphincter pressure), tumor parameters (staging), and therapeutic parameters (drugs administered during neo-adjuvant chemotherapy) was performed. RESULTS: Incidence of silent GERD varied from 36% to 37% according to the reflux scores. No relationship was found between the reflux scores and the patient or tumor parameters. Among the therapeutic parameters, a statistical relation was noted between the total dose of Cisplatin and the reflux scores (p = .005). CONCLUSIONS: Silent GERD is a common finding in patients treated for squamous cell carcinoma of the pharyngolarynx. Additionally, chemotherapy including Cisplatin may aggravate GERD during the course of therapy.

Angiogenic inhibition for the treatment of head and neck cancer.

Tumor angiogenesis is a fundamental step in tumor growth and proliferation. Fumagillin is an anti-angiogenic agent which is secreted by Aspergillus, but is also toxic. A fumagillin analogue, TNP-470, has been developed which is a potent angiogenic inhibitor with few side effects. TNP-470 has inhibited tumor growth in Lewis lung cancer and melanoma in animal models. This study was designed to test this proven anti-angiogenic agent's effects on head and neck cancer growth. Fort,v Harlan nude mice were injected subcutaneously with cancer cells from a human oral squamous cell carcinoma. After 3 weeks of tumor growth 25 mice were injected with TNP-470 subcutaneously at a distant site every other day for 30 days while 10 control mice received saline injections. Five mice began TNP-470 injections at the time of tumor injection to determine if TNP-470 can prevent tumor development. The tumor growth and development was unaffected by TNP-470 as compared to the control group. Therefore, the use of an angiogenic inhibitor had no effect on oral cancer growth. Analysis of the cell line utilized found abnormal mRNA expression, which included high p53 expression and low cyclin Dl expression. These results suggest that oral cancers are less dependent on angiogenesis than other tumor types. The genetic abnormalities may explain the angiogenesis independence that was demonstrated. Results found in other tumor types with angiogenic inhibitors cannot be extrapolated to oral cancer since genetic mutations may allow oral tumors to grow without neovascularization.

Survival, function, and quality of life after total glossectomy.

Advanced tongue cancer is associated with poor survival despite aggressive therapy. In an attempt at cure, many patients undergo total glossectomy, which significantly affects function and quality of life (QOL). This study was designed to determine the survival rate and QOL of patients who had undergone total glossectomy. A total of 54 patients underwent total glossectomy, with or without total laryngectomy, for advanced tongue cancer from 1970 to 1996. Patient outcomes were assessed for the following: 1. disease-free survival, 2. function, utilizing the Performance Status Scale (PSS), and 3. QOL, using two general cancer questionnaires (FACT-G and EORTC QLQ-C30) and a series of questions specific for head and neck cancer patients. Corrected actuarial survival was 51% and 41% at 3 and 5 years, respectively. Functional assessment using the PSS demonstrated significant deficits in speech and deglutition. QOL questionnaires revealed problems with eating, speaking, socializing, and shoulder function. However, the overall responses demonstrated that these patients have adjusted to their deficits and have a good QOL. It was concluded that total glossectomy, with or without total laryngectomy, can result in meaningful survival and an adequate QOL can be achieved in selected patients.

Prognostic indicators for squamous cell carcinoma of the oral cavity: a clinicopathologic correlation.

Fifty-three patients with T1 squamous cell cancer of the floor of mouth and ventral surface of the tongue with a known clinical outcome were retrospectively analyzed and arbitrarily divided into "aggressive" and "nonaggressive" groups based on their clinical behavior. Various host and tumor factors were then evaluated in an attempt to determine whether the tumor behavior could have been predicted. The paraffin-embedded tumor specimens were evaluated for tumor differentiation, tumor thickness and tumor invasion, microvessel density, and p53 expression. In addition, a composite morphologic grading score was obtained by combining cell differentiation, nuclear polymorphism, mitosis activity, depth of infiltration, type of infiltration, and lymphatic infiltration. No single technique appeared capable of identifying "aggressive" behavior, although possibly an evaluation of composite factors might show promise in the future.

Tumor angiogenesis as a prognostic indicator in T2-T4 oral cavity squamous cell carcinoma: a clinical-pathologic correlation.

BACKGROUND: Tumor angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis in breast and other cancers. Studies in head and neck cancer have suggested a similar correlation, but results have been inconclusive. This study was performed to determine the correlation between angiogenesis and oral tumor behavior. METHODS: Tumor angiogenesis was evaluated in 31 T2-T4 primary oral cavity squamous cell carcinomas by quantitating the microvessel density with two different anti-endothelial cell antigens, factor VIII antigen (FVIIIAg) and CD-31. The stains were compared to assess whether these antigens yielded complimentary results. The microvessel densities were correlated with T stage and N stage and patient survival. RESULTS: FVIIIAg and CD-31 staining yielded consistent microvessel densities, but FVIIIAg was generally more uniform and easier to interpret. Increasing microvessel density was seen with increasing T stage and N stage; however, there was considerable overlap and no correlation with survival. CONCLUSIONS: These results suggest that oral tumors are less angiogenesis dependent than tumors in other sites. Tumor angiogenesis, as currently measured, is not of value in predicting tumor aggressiveness in patients with oral cavity carcinoma.

Overexpression and amplification of glutathione S-transferase pi gene in head and neck squamous cell carcinomas.

Human glutathione S-transferase pi (GST-pi) may serve as a useful tumor marker because of the high frequency with which it is found in elevated levels in several tumor types. To determine whether GST-pi is useful as an indicator for cancers of the head and neck, expression of GST-pi mRNA was investigated by Northern analysis in this tumor type. Overexpression of GST-pi mRNA was detected in 9 of 36 (25%) primary head and neck squamous cell carcinomas (HNSCCs). When Southern blot analysis was used to examine the relationship between overexpression and amplification of the GST-pi gene, only 3 of 36 tumors (8%) showed GST-pi gene amplification. Thus, gene amplification is not critical to GST-pi mRNA overexpression in HNSCCs. Moderately and poorly differentiated HNSCCs tended to manifest elevated GST-pi mRNA compared with well differentiated tumors (30% for moderately and poorly differentiated tumors versus none of the well differentiated tumors examined). However, there was no significant correlation between GST-% mRNA overexpression and clinical stage, T stage (tumor size), N stage (neck nodal status), pathological nodes, or patient survival.