D.B. Chepeha

Radiation Concurrent With Gemcitabine for Locally Advanced Head and Neck Cancer: A Phase I Trial and Intracellular Drug Incorporation Study

PURPOSE To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. PATIENTS AND METHODS Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. RESULTS Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). CONCLUSION A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Commentary: Clinical nodal staging of human papillomavirus-related oropharyngeal cancer

The head and neck oncology program at the University of Virginia has published an article about the clinical nodal staging differences between human papillomavirus (HPV) (p16)-positive and human papillomavirus (HPV) (p16)-negative patients, which is timely and important. They demonstrated that patients whose primary tonsillar tumor stained positive for p16 had a 25% chance of contralateral lymph nodes, whereas patients whose tonsillar cancer did not stain positive for p16 did not demonstrate any contralateral lymph modes. This finding was statistically significant but is underpowered, a weakness that is acknowledged by the oncology group at University of Virginia (UVA). Previous literature has suggested that homolateral radiation of tonsil cancer is safe if the primary tumor does not involve the tongue base and does not spread along the palate to within 1 cm of the midline. The University of Toronto has presented large, thoughtfully analyzed, retrospective cohorts of patients whose disease was well controlled by a homolateral field.1 The authors from UVA highlighted that we now have a newly evolving disease, the patient with HPV-positive cancer, who may have different patterns of nodal involvement compared with HPV-negative patients. By choosing to study patients with small tonsil primaries confined to the tonsil site, they strengthen the assertion that the molecular biology of p16-positive tumors is driving the phenotype of contralateral metastasis. A weakness of the study is the fact that the contralateral nodes were involved according to the radiologic criteria but were not confirmed with a fine needle aspiration biopsy. Future work will have to better determine the proportion of contralateral nodes that are positive for carcinoma by prospective studies using positron emission tomography/computed tomography or fine needle aspiration biopsy. Nevertheless, this report corroborates the clinical experience with patients who are HPV positive: despite a better prognosis, these patients present with more extensive lymph node metastasis compared with patients whose oropharyngeal cancer is related to smoking and alcohol consumption. Bilateral disease, involvement of multiple nodal levels, and large metastatic nodal sizes may be more frequent in patients with HPV-positive oropharyngeal carcinoma. It is important that we characterize these differences and tailor treatment appropriately, so that patients are neither over nor undertreated. The oncology group at UVA has suggested a bilateral treatment field based on these findings. This suggestion raises more questions than it answers (as most good research does). If there are contralateral nodes seen on imaging, what additional testing is required to justify an increase in the size of the treatment field or the extent of the treated targets? Should bilateral neck radiation be used for all p16-positive patients, all HPV-positive patients, or just patients who manifest contralateral neck disease? If the treatment fields or targets are designed to treat the neck bilaterally, what anatomic subsites of the oropharynx should also be treated bilaterally? Most interestingly, these research findings from UVA come at a time when there is a move by the National Cancer Institute and the Radiation Therapy Oncology Group to deescalate therapy. However, studies of deescalation of therapy that involve reducing the doses should not be mixed up with reducing the extent of the targets receiving prophylactic irradiation. Intensity-modulated radiation therapy has reduced the morbidity of the therapy for head and neck cancer by careful selection of the treated volume. For the design of treatment volumes, this study by the UVA group is a cautionary note about the need to take into account the biology of the tumor, rather than just its anatomic extent because the spread patterns of HPVpositive versus HPV-negative tumors may be different. Demographic and behavioral differences between patients who are HPV positive and HPV negative have been demonstrated.2–4 Now that much has been accomplished with this step, more work needs to be done to describe the phenotype of the HPV-positive patients. Many of the patients with oropharyngeal cancer who are HPV positive also have smoking and alcohol abuse histories.5 We have to be prepared to investigate, describe, and treat this blended phenotype, whose behavior may be different from either HPVrelated patients who have never smoked or patients with smokingrelated, HPV-negative oropharyngeal cancer. In this study, 70% of the HPV-positive patients have smoked. Whether smoking history in HPV-positive patients affected, or did not affect, the occurrence of contralateral metastasis could not be assessed in this relatively small populations. This issue, as well as other issues regarding the pattern of disease, failure, and prognosis of HPV-related patients with and without a history of smoking, requires a careful assessment in large patient cohorts. At present, we know that there are 2 unique etiologies and 2 different survival rates. We now have to learn more about these disease presentations and how to treat the large group of patients who are HPV positive and also smoke and consume alcohol.

Intensity-modulated chemoradiotherapy aiming to reduce dysphagia in patients with oropharyngeal cancer: Clinical and functional results

The present study evaluated, both clinically and with fiberoptic endoscopic evaluation of swallowing (FEES), oral feeding volume, swallowing physiology, and aspiration risk in infants with Robin sequence treated exclusively with nasopharyngeal intubation (NPI) and specific feeding facilitation techniques (FFT). Eleven infants younger than 2 months participated. Criteria for NPI included recurrent crises of pallor and/or cyanosis and/or apnea and oxygen saturation less than 90%. The following FFT were used throughout the study period: use of a pacifier and massage to relax and move the tongue forward prior to feeding if the infant exhibited severe lingual retroposition (n = 11); manual support to maintain mandibular stability due to severe micrognathia (n = 1); both a long and a short nipple with a 1-mm-diameter enlarged hole (n = 9); nipple placement precisely on the tongue during suction (n = 11); rhythmic movement of the nipple in the mouth during sucking (n = 6); manual support of the cheek to facilitate lip closure (n = 3); and thickened liquids (n = 9). NPI improved the respiratory status of all infants which resulted in consistent improvement in oral feeding capacity and uniform weight gain. FEES was both well tolerated and useful in determining dysphagia and aspiration status throughout the study period.

PD.237 Leech therapy for the salvage ofrevascularized free tissue transfer with surgically unsalvageable venous obstruction

Results: All flaps were successfully transferred, the results of facial aesthetics were satisfactory in all patients. There was one partial necrosis in the region most to the pedicle ofthe FRF and one wound dehiscence. The complications were heated with local conservative methods, the wuom s were delayed healing. Follow-up periods varied between 9 and 20 months (mean follow up 13.2 months) and all of the patients are survival during uhich lhere was one recurrence. Conclusioni The TMF and the FRF are easy to haruest and low morbidity, and compatible with the principles ofoncologic resection. which should be considered the method of choice in repair of large orbito-ma\illofacial surface defects after resection of the tumors.