OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer.

BACKGROUND: Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. PATIENTS AND METHODS: Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%-50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity. RESULTS: Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P < 0.0001). CONCLUSIONS: Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. CLINICAL TRIAL REGISTRATION: Clinical trials.gov identifier: NCT02258659.

Response-adapted volume de-escalation (RAVD) in locally advanced head and neck cancer.

BACKGROUND: Efforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiotherapy (RT) dose de-escalation. In this phase I/II protocol investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction. PATIENTS AND METHODS: Patients with measurable LA-HNSCC received two cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus). Patients with ≥50% reduction in the sum of tumor diameters [good response (GR)] received TFHX (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to a dose of 75 Gy with the single planning target volume (PTV1) encompassing exclusively gross disease. Patients with <50% response [non-response (NR)] were treated with TFHX encompassing PTV1 and the next nodal station at risk (PTV2) to a dose of 45 Gy followed by a sequential boost to PTV1 to a dose of 75 Gy. RESULTS: Ninety-four patients were enrolled. Randomization to everolimus was discontinued on interim analysis after 50 patients due to futility. IC response was evaluable in 89 patients. Thirty-seven patients (41.6%) had GR and 52 (58.4%) had NR. There was a trend for improved progression-free (P = 0.086) but not overall survival (P = 0.94) for GR versus NR. The 2-year PFS and OS were 86.0% and 83.5% for GR and 68.7% and 85.4% for NR, respectively. NR were significantly more likely to undergo G-tube placement during treatment (50.0% GR versus 73.5% NR, P = 0.040) and be G-tube dependent at 6-month follow-up (5.7% GR versus 32.6% NR, P = 0.005). CONCLUSIONS: The addition of everolimus to IC was not beneficial. The elimination of elective nodal coverage in patients with GR to IC did not appear to compromise outcomes and resulted in significantly decreased late toxicity. Further investigation of RAVD is warranted. CLINICALTRIALSGOV: NCT01133678.

Comparison of outcomes of locoregionally advanced oropharyngeal and non-oropharyngeal squamous cell carcinoma over two decades.

BACKGROUND: Human papillomavirus (HPV) has emerged as a causative agent and positive prognostic factor for oropharyngeal (OP) head and neck squamous cell cancer (HNSCC). This prompts inquiry into whether therapy improvements or increasing incidence of HPV drives the apparent improvements in HNSCC outcomes observed in non-randomized clinical trials. PATIENTS AND METHODS: We reviewed all locoregionally advanced HNSCC patients treated with chemotherapy and radiation in prospective institutional trials at a single institution. Patients were divided into three groups (1, 2, 3) according to treatment time period (1993-1998, 1999-2003, 2004-2010, respectively). We reasoned that if a favorable trend was observed over time in OP but not non-OP patients, HPV status may be confounding treatment effects, whereas this would be unlikely if both subgroups improved over time. RESULTS: Four hundred and twenty-two patients were identified with OP (55.7%) and non-OP (44.3%) HNSCC. Five-year OP overall survival (OS) improved from 42.3% (group 1) to 72.5% (group 2), and 78.4% (group 3), adjusted P = 0.0084. Non-OP 5-year OS was 51.0% (group 1), 58.8% (group 2), and 66.3% (group 3), adjusted P = 0.51. Five-year recurrence-free survival (RFS) improved for OP groups from 42.3% to 68.4% to 75.8% (adjusted P = 0.017). Non-OP 5-year RFS was 42.9%, 53.6%, and 61.7% for sequential groups (adjusted P = 0.30). Five-year OP distant failure-free survival (DFFS) improved from 42.3% to 71.1% to 77.8% (adjusted P = 0.011). Five-year non-OP DFFS was 46.9%, 57.1%, and 66.0% for sequential groups (adjusted P = 0.38). CONCLUSIONS: Over the past two decades, OP HNSCC outcomes improved significantly, while non-OP outcomes only trended toward improvement. Although our patients are not stratified by HPV status, improving OP outcomes are likely at least partly due to the increasing HPV incidence. These data further justify trial stratification by HPV status, investigations of novel approaches for carcinogen-related HNSCC, and current de-intensification for HPV-related HNSCC.

A phase I dose escalation study of Ad GV.EGR.TNF.11D (TNFerade™ Biologic) with concurrent chemoradiotherapy in patients with recurrent head and neck cancer undergoing reirradiation.

BACKGROUND: AdGV.EGR.TNF.11D (TNFerade™ Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-α) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-α has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFerade™ Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). METHODS: TNFerade™ Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 10(9) to 4 × 10(11) PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1-5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment. RESULTS: Fourteen patients were treated. DLT was reached at a dose level of 3 (4 × 10(11) PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-α, and TNF-α receptors. Adenoviral DNA was detected in three biopsies from one patient. CONCLUSIONS: TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 10(10) PU. Monitoring for thrombotic events is indicated.

Phase II trial of pemetrexed-based induction chemotherapy followed by concomitant chemoradiotherapy in previously irradiated patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Concurrent chemoreirradiation therapy (CRRT) offers a therapeutic option for patients with locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that response to induction chemotherapy (IC) would improve outcome and predict increased survival. PATIENTS AND METHODS: Subjects with recurrent SCCHN not amenable to standard therapy were eligible. IC consisted of two 28-day cycles of gemcitabine and pemetrexed on days 1 and 14, followed by surgical resection, if appropriate, and/or CRRT consisting of carboplatin, pemetrexed, and single daily fractionated radiotherapy. RESULTS: Thirty-five subjects were enrolled, 31 were assessable for response, with 11 responders [response rate = 35%; 95% confidence interval (CI) 19.2-54.6]. Among 24 subjects who started CRRT, 11 were assessable for radiographic response, 4 complete response, 2 partial response, and 5 progressive disease. Median progression-free survival and overall survival (OS) were 5.5 months (95% CI 3.6-8.3) and 9.5 months (95% CI 7.2-15.4), respectively. One-year OS was 43% (95% CI 26% to 58%). Subjects who responded to IC had improved survival (P = 0.02). Toxic effects included mucositis, dermatitis, neutropenia, infection, hemorrhage, dehydration, and pain. CONCLUSIONS: The combination of pemetrexed plus gemcitabine was active and well tolerated in recurrent SCCHN. Response to IC may help stratify prognosis and offer an objective and dynamic metric in recurrent SCCHN patients being considered for CRRT.

A randomized phase II study of 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared with bevacizumab plus 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy for intermediate-stage and T4N0-1 head and neck cancers.

INTRODUCTION: We conducted a randomized phase II study to evaluate the impact of adding bevacizumab (B) to 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (FHX) for intermediate-stage and select T4 head and neck squamous cell cancers (HNSCC). PATIENTS AND METHODS: Eligible patients had newly diagnosed HNSCC. Randomization was 2:1 in favor of BFHX. All patients received 500 mg HU p.o. b.i.d., 600 mg/m(2)/day continuous infusion 5-FU, and b.i.d. radiotherapy with or without bevacizumab 10 mg/kg administered on day 1 of each 14-day cycle. Patients received five cycles consisting of chemoradiotherapy for 5 days followed by 9 days without therapy. RESULTS: Twenty-six patients were enrolled (19 BFHX and 7 FHX). The study was halted following unexpected locoregional progression. Two-year survival was 68%; 89% treated with FHX and 58% (95% confidence interval 33% to 78%) treated with BFHX. Two-year locoregional control was 80% after chemoradiotherapy and 85% after surgical salvage. All locoregional progression occurred in T4 tumors randomized to BFHX. Two patients receiving BFHX died during therapy, and one died shortly after therapy. No catastrophic bleeding events were seen. CONCLUSIONS: Locoregional progression seen in T4N0-1 tumors treated with BFHX was unexpected and led to study termination. The addition of bevacuzimab to chemoradiotherapy for HNSCC should be limited clinical trials.

Minor salivary gland inflammation in Devic's disease and longitudinally extensive myelitis.

Devic's disease is often considered as a variant of multiple sclerosis (MS). However, evidence suggests that Devic's disease may be distinct from MS. Devic's disease can coexist with connective tissue diseases, particularly Sjögren's disease, but this association is rare with MS. Diagnosis of Sjögren's disease in patients with neurological symptoms is often difficult. During early stages of Sjögren's disease, patients may not fulfill all criteria for Sjögren's disease. A high percentage of patients with Sjögren's disease have inflammatory infiltrates in minor salivary glands, and this may be a reliable indicator of early or subclinical disease. We show high prevalence (80%) of salivary gland inflammation in Devic's disease and longitudinally extensive transverse myelitis (LETM). We diagnosed 16 patients with Devic's disease, and 2 of these satisfied criteria for Sjögren's disease as did 2 of 9 patients with LETM. Anti-SSA/B titers were infrequently elevated. Although most did not satisfy criteria for Sjögren's disease. 9 of 12 Devic's disease patients and 7 of 8 LETM patients had severe salivary gland inflammation. Thus: (1) patients with Devic's disease or with LETM who have positive labial biopsies but do not satisfy criteria for Sjögren's disease could have subclinical Sjögren's diseases. Alternatively, (2) as patients with Devic's disease have elevated titers of several autoantibodies, so there may exist a set of antibodies that react with antigens in minor salivary glands and cause inflammation. Minor salivary gland biopsy is more sensitive than anti-SSA/B serology in providing histological evidence for possible Sjögren's disease with CNS lesions.

Upper airway complications of smoking.

Tobacco smoke has a myriad of acute and chronic effects on the upper airway. These problems can range from aggravating inflammatory reactions to life threatening malignancies. Cessation of smoking is the key to successful resolution of many upper airway complaints. An increased awareness of these disease processes can improve early diagnosis and appropriate treatment. A better awareness of these processes may facilitate physicians in counseling patients about smoking.

Effect of topical antibiotic therapy on recovery after tonsillectomy in adults.

OBJECTIVE: Systemic antibiotics given during the first week after tonsillectomy appear to be effective in reducing postoperative morbidity. We assessed the effectiveness of perioperative topical antibiotic rinses in reducing posttonsillectomy morbidity. METHODS: A randomized, double-blinded, placebo-controlled pilot study of 36 patients undergoing tonsillectomy was used to evaluate the effects of a standard 7-day systemic regimen of perioperative intravenous ampicillin/oral amoxicillin and 2 single-day topical antibiotic regimens: (1) clindamycin (Cleocin) and (2) amoxicillin/clavulanate (Augmentin) and ticarcillin/clavulanate (Timentin). RESULTS: Mean aerobic and anaerobic oral bacterial counts were decreased in both topical treatment groups compared with the placebo group on the first postoperative day, achieving statistical significance with Augmentin/Timentin (aerobic and anaerobic bacterial counts) and Cleocin (aerobic counts). Significantly less postoperative pain and mouth odor were reported for both Cleocin (P = 0.014 and P = 0.005, respectively) and Augmentin/Timentin (P = 0.026 and P = 0.05, respectively) topical treatment groups when compared with the placebo group. CONCLUSIONS: Preliminary results indicate a reduction in oral bacterial counts and postoperative morbidity in adult patients receiving topical antibiotics compared with patients receiving placebo; further investigation is warranted.

Ciprofloxacin plus piperacillin is an equally effective regimen for empiric therapy in febrile neutropenic patients compared with standard therapy.

The purpose of this study was to test the comparative efficacy and toxicity of empiric gentamicin and ciprofloxacin, in combination with piperacillin, in febrile patients with treatment-induced neutropenia. Fifty patients were prospectively randomized to receive piperacillin plus gentamicin (PG), and 46 were randomized to receive piperacillin plus ciprofloxacin (PC). The groups were similar in age, sex, diagnosis, duration of neutropenia, and incidence of positive cultures. The two antibiotic regimens were associated with comparable rates of defervescence in the patients with gram-positive bacteremia. In the patients with gram-negative bacteremia and those with negative cultures, however, defervescence was more prompt in the PC group. In particular, 27% of the culture-negative patients on PC, compared to only 5% of those on PG, defervesced within 72 hr (P = 0.015). Because of the more prompt defervescence in the PC group, amphotericin B was used less frequently; 78% of the patients on PG compared with only 56% of those on PC were started on amphotericin B (P = 0.025). PC is an effective alternative to the more traditional PG for treatment of febrile neutropenic hosts who have not been given prophylactic quinolones. More important, PC appears to hasten defervescence compared with PG, especially in culture-negative patients and those with gram-negative bacteremia, and may decrease the necessity of additional antimicrobial agents such as amphotericin B.

Cost analysis of antibiotic prophylaxis in clean head and neck surgery.

OBJECTIVE: This study was undertaken to assess the excess cost of hospitalization accrued to patients who develop postoperative wound infection following neck dissection in which the wound was not exposed to secretions from the upper aerodigestive tract. DESIGN: A retrospective cohort of patients who underwent "clean" neck dissection from 1976 to 1989 were evaluated. Antibiotic administration (yes or no), post-operative wound infection (yes or no), and duration and cost of hospitalization were assessed. SETTING: All surgeries were performed in a university medical center. PATIENTS: All patients underwent neck dissection in which the procedure was clean, ie, there was no exposure to secretions from the upper aerodigestive tract. MAIN OUTCOME MEASURES: Patients were assessed to determine administration of antibiotics (yes or no), development of postoperative wound infection (yes or no), and duration and cost of hospitalization. RESULTS: Wound infection developed in 10 (10%) of 99 patients who did not receive antibiotics. Of 93 patients who received perioperative antibiotics, three (3.3%) developed wound infection. This difference was not statistically significant. The type II (beta) error was greater than 0.2, suggesting that a significant difference may have been missed (false-negative) as a result of the small number of patients studied. The excess cost accrued to each patient who developed a postoperative wound infection was in excess of $36,000 (1992 dollars). The cost of administration of antibiotic prophylaxis to 100 patients is less than this amount. CONCLUSION: The decision to withhold antibiotic prophylaxis should not be made in an effort to reduce hospital costs.

Effect of neuromuscular blockade on facial nerve monitoring.

Direct facial nerve stimulation and monitoring during cerebellopontine angle (CPA) tumor surgery are critical for identification and preservation of function. Electrically evoked facial nerve monitoring was compared with ulnar train-of-four monitoring under progressive neuromuscular blockade. Using a rabbit model, the facial nerve function of six controls was compared to that of six specimens with acute or chronic injuries. Eight of 18 patients who had undergone CPA tumor resection during one year were also studied. Regression analysis correlated between ulnar nerve monitoring and facial electromyographic (EMG) peak voltage in all groups. Facial EMG was measurable, even with 75 percent receptor blockade. The results of this study support the hypothesis that high degrees of neuromuscular blockade do not preclude satisfactory EMG monitoring of the facial nerve during CPA tumor surgery. This study did demonstrate that chronically injured facial nerves may show greater sensitivity to the effects of neuromuscular blockade. Lower levels or avoidance of neuromuscular blockade should be employed under these circumstances.

Head and neck cancer. The problem.

Advanced carcinomas that involve the head and neck present a major therapeutic challenge because of their poor prognosis, the frequently associated medical problems of the patients, and the adverse effect of treatment on oral and pharyngeal function. Collaboration and communication of multidisciplinary teams have had a profound effect on the treatment of head and neck cancer.

Proteoglycan sulfation and storage parallels storage of basic secretory proteins in exocrine cells.

Increased storage of basic proline-rich secretory proteins induced in rat parotid acinar cells by isoproterenol is accompanied by increased storage of a chondroitin sulfate-containing proteoglycan. Amino acid analysis of the purified proteoglycan and the chondroitinase digestion products reveals that the polypeptide backbone is a proline-rich protein. Most sulfation occurs in Golgi elements; however, a small fraction of the proteoglycan can be labeled by incubating isolated secretion granules with [35S]phosphoadenosine phosphosulfate ([35S]PAPS), and the amount of sulfate incorporation decreases with increased granule maturity. In vitro incorporation is sensitive to inhibitors of PAPS transport and occurs in intact granules as shown by radioautography. Both the increased production of a chondroitin sulfate proteoglycan following isoproterenol treatment and its sulfation at sites of secretory condensation and storage suggest that sulfation may aid secretory packaging by reducing the known fixed positive charge that stems from the large concentration of basic secretory proteins.

Sealed rupture of abdominal aortic aneurysms.

Sealed rupture of abdominal aortic aneurysms, even if uncommon, deserves particular attention for the possibility of misdiagnosis and for the deleterious effects of such a misdiagnosis. Sixteen patients (mean age 72 years; range 65 to 84 years) with chronic sealed rupture of abdominal aortic aneurysms are reported. Two patients had acute rupture of the aneurysm, and at operation chronic contained rupture was found along with the recent hemorrhage. One patient died after surgery. The remaining patients underwent successful resection with long-term survival and regression of symptoms. Consideration of sealed abdominal aortic aneurysm rupture should be included when examining elderly patients with history of unexplained back pain or femoral neuropathy. Computed tomography is a useful aid in the diagnosis of sealed rupture. Ultrasonography is less accurate; in three patients ultrasonography failed to diagnose the presence of the rupture.

Identification of abdominal aortic aneurysm patients with different clinical features and clinical outcomes.

To determine the clinical characteristics and factors influencing outcome in patients with atherosclerotic abdominal aortic aneurysms (AAA), 526 patients who underwent aneurysmal resection were retrospectively reviewed: Group I had clinical evidence of atherosclerotic occlusive disease; Group II had no evidence of atherosclerotic occlusive disease. The incidence of ruptured AAA, multiple aneurysms, and a family history of AAA was higher in Group II patients. We concluded that patients with AAA and without atherosclerotic occlusive disease in other areas represent a subgroup with peculiar clinical characteristics. In planning operative treatment and during the follow-up period, it should be kept in mind that Group II patients have a higher incidence of aneurysm rupture; the incidence of late pseudoaneurysm is higher; and there is a greater possibility of aneurysm in other arterial segments. It remains to be seen if the pathogenetic mechanism of AAA formation in Group II patients is different from that in Group I patients.

Seeding with endothelial cells derived from the microvessels of the omentum and from the jugular vein: a comparative study.

Segments of an experimental polytetrafluoroethylene graft (9 cm long, 6 mm I.D.) of high porosity were implanted in 25 dogs as aortic interposition grafts. Nine grafts were seeded with a mean of 7 x 10(5) viable endothelial cells (ECs) derived from the jugular vein (group A) and eight were seeded with a mean of 7 x 10(5) viable ECs derived from the microvessels of the omentum (group B). Eight grafts were not seeded and they served as controls (group C). Animals were put to death 5 weeks after graft implantation. The thrombus-free area was measured at 81% +/- 10% in group A, 65% +/- 22% in group B, and 25% +/- 13% in group C (p less than 0.05, group A vs group B; p less than 0.05, group B vs group C). The thickness of the subendothelial layer was 151 +/- 60 microns in group A, 280 +/- 60 microns in group B, and 100 +/- 75 microns in group C (p less than 0.001, group B vs groups A and C). The production of 6-keto-PGF1 alpha in the presence of sodium arachidonate was higher in seeded grafts (p less than 0.05). Omentally derived microvessel ECs can be seeded in vascular grafts; refinements in the technique of EC procurement are required to minimize contamination and to obtain ECs with more effective biologic activity.