Therapy For Head And Neck Cancer Research Articles

HDAC4 degradation by combined TRAIL and valproic acid treatment induces apoptotic cell death of TRAIL-resistant head and neck cancer cells

Although TRAIL can directly induce cell death in some cancer cells, it appears that TRAIL resistance exists in many cancers. This study focuses on anti-cancer drugs for TRAIL-resistant head and neck cancer (HNC) to provide further progress toward effective cancer therapy. Results indicate in TRAIL-resistant HNC cells, that combined TRAIL and VPA treatment greatly reduced cell viability and therefore induced cell death, relative to treatment with TRAIL or VPA alone. A caspase-dependent signaling pathway was demonstrated, and combined treatment with TRAIL and VPA also significantly decreased the expression of HDAC4. When we pretreated cells with z-VAD followed by combined treatment with TRAIL and VPA, cell death was blocked with no reduction in expression of HDAC4. To confirm that cell death involved HDAC4 in HNC cells, we knocked down expression of HDAC4 with siRNA, followed by treatment with TRAIL and VPA. Results showed that loss of HDAC4 sensitized the TRAIL-resistant HNC cells to apoptotic cell death. Finally, we showed elevated expression of HDAC4 in HNC tissues compared to normal tissues obtained from the same patients. In conclusion, we suggest that combined VPA and TRAIL treatment may be a promising therapy for HNC via HDAC4 degradation.

Abstract 3986: HDAC4 degradation by combined TRAIL and valproic acid treatment induces apoptotic cell death of TRAIL-resistant head and neck cancer cells

Abstract Purpose: Although TRAIL can directly induce death in cancer cells via DR4 and DR5 receptors, it appears that TRAIL resistance exists in many cancers. This study focuses on anti-cancer drugs for TRAIL-resistant head and neck cancer (HNC) to provide a further step toward effective cancer therapy. Materials and Methods: The combined effects of TRAIL and VPA on cell viability were assessed via MTT and flow cytometric assays. Western blotting was used to determine cell death signaling. Results: The results indicate that combined TRAIL and VPA treatment greatly reduced the cell viability and thus induced cell death relative to treatment with TRAIL or VPA alone in TRAIL-resistant HNC cells. A caspase-dependent signaling pathway was shown, and combined treatment with TRAIL and VPA also significantly decreased the expression of HDAC4. When we pretreated cells with z-VAD followed by combined treatment with TRAIL and VPA, the cell death was blocked with no decreased expression of HDAC4. To confirm the cell death involved in HDAC4 in HNC cells, we pretreated siRNA of the HDAC 4, followed by treating the TRAIL and VPA. The results showed that the knock down of HDAC4 sensitized the TRAIL-resistant HNC cells to apoptotic cell death. Finally, we showed a high expression of HDAC4 in HNC tissues compared to normal tissues obtained from the same patients. Conclusion: Combined VPA and TRAIL treatment may be a promising therapy for HNC via HDAC4 degradation. Citation Format: Bok-Soon Lee, Yeon Soo Kim, Jeon Yeob Jang, Hyo Jeong Kim, Myeong-Hoon Lee, Jae Won Chang, Bon Seok Koo, Ho-Ryun Won, Yong-Sung Kim, Chul-Ho Kim. HDAC4 degradation by combined TRAIL and valproic acid treatment induces apoptotic cell death of TRAIL-resistant head and neck cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3986.

Survival impact and toxicity of metformin in head and neck cancer: An analysis of the SEER-Medicare dataset

ObjectivesRecent preclinical research has renewed interest in the interplay between glucose dysregulation and cancer. Metformin holds promise as an adjunctive antineoplastic agent in head and neck cancer (HNC). We aimed to explore the impact of metformin in HNC patients from a population-based dataset. Patients & MethodsPatients diagnosed with HNC from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked dataset and categorized into three groups: non-diabetics (nD), diabetics not taking metformin (DnM), and diabetics taking metformin (D + M). Overall survival (OS) and cancer-specific survival (CSS) were compared between groups using Kaplan-Meier and Cox regression controlling for sociodemographic, clinical, and treatment covariates. The incidence of toxicities associated with HNC therapy was compared among groups using χ2 analysis. ResultsAmong 1646 patients, there were 1144 nD, 378 DnM, and 124 D + M. 2-year OS rates was 65.6% for nD, 57.7% for DnM, and 73.4% for D + M by Kaplan-Meier (p < 0.01), and corresponding rates of 2-year CSS were 73.7%, 66.1%, and 88.8% (p < 0.01), respectively. On Cox multivariable analysis, OS among the three groups did not significantly differ; however, CSS was significantly worse among both nD versus DnM as compared to D + M. Toxicity rates were not significantly increased among D + M. ConclusionHNC patients with diabetes taking metformin experience improved CSS. Prospective investigation of the addition of metformin to standard-of-care HNC therapy is warranted.

Esophageal squamous cell neoplasia is an independent negative prognostic factor for head and neck cancer patients.

Patients with head and neck cancer (HNC) have a high incidence of esophageal squamous cell neoplasms (ESCN). ESCN also has a negative impact on the survival of HNC patients. However, recent endoscopic advances enable the early detection of ESCN, and novel treatments may lead to improving survival rates for HNC patients with ESCN. HNC patients who underwent magnifying esophagogastroduodenoscopy (EGDS) from 2005 to 2012 were included in this study (n = 226). We analyzed the prevalence and prognostic value of ESCN in HNC patients and the difference in overall survival between HNC patients with and without ESCN. Thirty-four patients (15%) developed an ESCN during their clinical course. Of the 34 patients, 10 patients underwent endoscopic resection for ESCN and 10 patients underwent simultaneous chemoradiation therapy for HNC and ESCN. The 3-year survival rates in HNC patients with and without ESCN were 53% and 70%, respectively. Multivariate analysis identified the advanced clinical stage of the HNC [hazard ratio (HR) = 2.15; 95% confidence interval (CI) = 1.18-3.93; p = 0.012] and the presence of ESCN (HR = 1.73; 95% CI = 1.00-2.97; p = 0.049) as significant and independent determinants of overall survival. Our study suggests that although the survival of HNC patients with ESCN may be improved by routine EGDS during tumor surveys and by advances in endoscopy, the presence of ESCN still remains an independent negative prognostic factor for HNC patients.

Targeted nanoparticles for head and neck cancers: overview and perspectives.

Head and neck cancer (HNC) is common in several regions and is associated with high morbidity and mortality worldwide. This review summarizes the recent progress in the development of targeted nanoparticle systems for HNC therapy. WIREs Nanomed Nanobiotechnol 2017, 9:e1469. doi: 10.1002/wnan.1469 For further resources related to this article, please visit the WIREs website.

The effect of smoking on the quality of life enhancement following prosthetic rehabilitation in head and neck cancer patients who underwent surgical treatment

It is known that the quality of life (QoL) of patients surgically treated for head and neck cancer (HNC) is significantly enhanced by rehabilitation. It is also known that some of these patients will not quit smoking. To assess if smoking hampers rehabilitation-related QoL enhancement after surgery. Applying the H&N 35 questionnaire of EORTC, we assessed the QoL of 38 smoking and non-smoking patients who underwent surgical therapy for HNC and subsequent rehabilitation. QoL was assessed after surgery (after the healing period) and 6 months after rehabilitation. While the QoL enhancement of nonsmokers was significant in almost all aspects, that of smoking patients did not reach the level of significance on a number of scales. The results suggest that smoking does not hamper rehabilitation directly, rather, it prevents rehabilitation from exerting its beneficial effects through its own effects. Smoking is a factor that measurably acts against the efforts to enhance the QoL of the surgically treated HNC patient. Therefore, it is essential that emphasis is put on smoking cessation right from the cancer diagnosis also for this reason. Orv. Hetil., 2017, 158(5), 172-177.

Free Thyroid Transfer: A Novel Procedure to Prevent Radiation-induced Hypothyroidism

The incidence of hypothyroidism after radiation therapy for head and neck cancer (HNC) has been found to be ≤53%. Medical treatment of hypothyroidism can be costly and difficult to titrate. The aim of the present study was to assess the feasibility of free thyroid transfer as a strategy for the prevention of radiation-induced damage to the thyroid gland during radiation therapy for HNC. A prospective feasibility study was performed involving 10 patients with a new diagnosis of advanced HNC undergoing ablative surgery, radial forearm free-tissue transfer reconstruction, and postoperative adjuvant radiation therapy. During the neck dissection, hemithyroid dissection was completed with preservation of the thyroid arterial and venous supply for implantation into the donor forearm site. All patients underwent a diagnostic thyroid technetium scan 6weeks and 12months postoperatively to examine the functional integrity of the transferred thyroid tissue. Free thyroid transfer was executed in 9 of the 10 recruited patients with advanced HNC. The postoperative technetium scans demonstrated strong uptake of technetium at the forearm donor site at 6weeks and 12months for all 9 of the transplanted patients. The thyroid gland can be transferred as a microvascular free transfer with maintenance of function. This technique could represent a novel strategy for maintenance of thyroid function after head and neck irradiation.

Swallowing assessment and management pre and post head and neck cancer treatment.

Head and neck cancer (HNC) imposes significant structural, functional, and cosmetic burdens upon those affected. Although advances in multimodality organ preservation therapy have assisted in ameliorating a number of previous treatment-related sequelae, dysphagia remains a foremost concern for members of the multidisciplinary team. Given its acute and long-term impact on physical and psychological wellbeing, and subsequent bearing on delivery of treatment, treatment-related morbidity and overall mortality, prompt recognition, and accurate assessment and optimization of management are pivotal. Qualitative research has provided greater insight into the psychosocial burdens dysphagia imposes on HNC patients and carers, highlighting the need for holistic strategies of management. There is a growing body of evidence to support dietary alterations and preventive swallowing exercise regimens for maintenance of oral intake throughout and following HNC therapy. The role of prophylactic enteral feeding, however, remains uncertain, with conflicting institutional data and lack of high-quality prospective studies for meaningful systematic literature assessment. Endoscopic surgical techniques hold promise in relieving stricture-related dysphagia; however, multiple treatments are required and recurrence is common. Swallowing rehabilitation encompassing education, dietary modification, and swallowing exercises comprise the mainstay of current evidence-based dysphagia management in HNC patients.

Non-thermal plasma induces AKT degradation through turn-on the MUL1 E3 ligase in head and neck cancer.

Recent research on non-thermal plasma (NTP, an ionized gas) has identified it as a novel cancer therapeutic tool. However, the molecular mechanism remains unclear. In this study, we demonstrated NTP induced cell death of head and neck cancer (HNC) through the AKT ubiquitin-proteasome system. NTP increased the gene expression of mitochondrial E3 ubiquitin protein ligase 1 (MUL1), an E3 ligase for AKT, and NTP-induced HNC cell death was prevented by MUL1 siRNA. We also showed that MUL1 inhibited the level of AKT and p-AKT and MUL1 expression was increased by NTP-induced ROS. Furthermore, we optimized and manufactured a new type of NTP, a liquid type of NTP (LTP). In syngeneic and xenograft in vivo tumor models, LTP inhibited tumor progression by increasing the MUL1 level and reducing p-AKT levels, indicating that LTP also has an anti-cancer effect through the same mechanism as that of NTP. Taken together, our results suggest that NTP and LTP have great potential for HNC therapy.

Computed Tomography Number Changes Observed During Computed Tomography–Guided Radiation Therapy for Head and Neck Cancer

To investigate CT number (CTN) changes in gross tumor volume (GTV) and organ at risk (OAR) according to daily diagnostic-quality CT acquired during CT-guided intensity modulated radiation therapy for head and neck cancer (HNC) patients. Computed tomography scans acquired using a CT-on-rails during daily CT-guided intensity modulated radiation therapy for 15 patients with stage II to IVa squamous cell carcinoma of the head and neck were analyzed. The GTV, parotid glands, spinal cord, and nonspecified tissue were generated on each selected daily CT. The changes in CTN distributions and the mean and mode values were collected. Pearson analysis was used to assess the correlation between the CTN change, organ volume reduction, and delivered radiation dose. Volume and CTN changes for GTV and parotid glands can be observed during radiation therapy delivery for HNC. The mean (±SD) CTNs in GTV and ipsi- and contralateral parotid glands were reduced by 6 ± 10, 8 ± 7, and 11 ± 10 Hounsfield units, respectively, for all patients studied. The mean CTN changes in both spinal cord and nonspecified tissue were almost invisible (<2 Hounsfield units). For 2 patients studied, the absolute mean CTN changes in GTV and parotid glands were strongly correlated with the dose delivered (P<.001 and P<.05, respectively). For the correlation between CTN reductions and delivered isodose bins for parotid glands, the Pearson coefficient varied from -0.98 (P<.001) in regions with low-dose bins to 0.96 (P<.001) in high-dose bins and were patient specific. The CTN can be reduced in tumor and parotid glands during the course of radiation therapy for HNC. There was a fair correlation between CTN reduction and radiation doses for a subset of patients, whereas the correlation between CTN reductions and volume reductions in GTV and parotid glands were weak. More studies are needed to understand the mechanism for the radiation-induced CTN changes.

Depression as a predictor of postoperative functional performance status (PFPS) and treatment adherence in head and neck cancer patients: a prospective study.

BackgroundHead and neck cancer (HNC) is a debilitating disease due in part to its effects on function, including speech, swallowing, and cosmesis. Previous studies regarding depression in HNC have focused on demographic predictors, incidence, and quality of life studies. There is, however, a paucity of studies that objectively address depressive symptoms in HNC patients and the resultant effects on post-treatment functional performance status. The aim of this study was to assess the relationship between preoperative depressive symptoms (PDS) and postoperative functional performance status (PFPS), in addition to other predictors of rehabilitation and survival.MethodsA prospective cohort study was undertaken at the University of Alberta, including all new adult HNC patients undergoing surgery as primary therapy for HNC from May 2013 to January 2014. Baseline depressive symptoms were measured on the Quick Inventory of Depressive Symptoms (QIDS) questionnaire 2 weeks preoperatively and PFPS was assessed 12 months postoperatively on the Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN) scale. Secondary outcomes included completion of adjuvant therapy, narcotic dependence, return to detrimental habits, loss of follow-up, and length of hospital stay (LOHS). Differences between the Normal-Mild and Moderate-Severe QIDS groups were assessed using Mann–Whitney and Fischer Exact statistical analyses.ResultsSeventy-one patients were included in the study. Mild and Moderate-Severe PDS were 35.2 % and 18.3 %, respectively. Significantly lower FACT-HN scores were noted in the Moderate-Severe group at 12 months (p = 0.03). The risk ratio (RR) for FACT-HN score < 50 % at 12 months in the Moderate-Severe group was 5.66. In addition, significantly lower completion of adjuvant treatment (p = 0.03), significantly higher incidence of narcotic dependence (p = 0.004), and significantly higher LOHS (24 days vs. 18 days; p = 0.02) was observed in the Moderate-Severe group. There was no significant difference in loss of follow-up between the 2 groups (p = 0.64).ConclusionsThe incidence and severity of PDS in HNC patients treated with surgery is high (53.5 %). Patients with Moderate-Severe PDS have significantly decreased PFPS, increased narcotic use, decreased completion of adjuvant therapy, and a longer LOHS. HNC patients should be monitored closely for depressive symptoms.

Late dysphagia after radiotherapy‐based treatment of head and neck cancer

Changing trends in head and neck cancer (HNC) merit an understanding of the late effects of therapy, but few studies examine dysphagia beyond 2 years of treatment. A case series was examined to describe the pathophysiology and outcomes in dysphagic HNC survivors referred for modified barium swallow (MBS) studies ≥ 5 years after definitive radiotherapy or chemoradiotherapy (January 2001 through May 2011). Functional measures included the penetration-aspiration scale (PAS), performance status scale-head and neck (PSS-HN), National Institutes of Health Swallowing Safety Scale (NIH-SSS), and MBS impairment profile (MBSImp). Twenty-nine patients previously treated with radiotherapy (38%) or chemoradiotherapy (62%) were included (median years posttreatment, 9; range, 5-19). The majority (86%) had oropharyngeal cancer; 52% were never-smokers. Seventy-five percent had T2 or T3 tumors; 52% were N+. The median age at diagnosis was 55 (range, 38-72). Abnormal late examination findings included: dysarthria/dysphonia (76%), cranial neuropathy (48%), trismus (38%), and radionecrosis (10%). MBS studies confirmed pharyngeal residue and aspiration in all dysphagic cases owing to physiologic impairment (median PAS, 8; median NIH-SSS, 10; median MBSImp, 18), whereas stricture was confirmed endoscopically in 7 (24%). Twenty-five (86%) developed pneumonia, half requiring hospitalization. Swallow postures/strategies helped 69% of cases, but no patient achieved durable improvement across functional measures at last follow-up. Ultimately, 19 (66%) were gastrostomy-dependent. Although functional organ preservation is commonly achieved, severe dysphagia represents a challenging late effect that may develop or progress years after radiation-based therapy for HNC. These data suggest that novel approaches are needed to minimize and better address this complication that is commonly refractory to many standard dysphagia therapies.

Organ-sparing radiation therapy for head and neck cancer

To improve locoregional tumor control and survival in patients with locally advanced head and neck cancer (HNC), therapy is intensified using altered fractionation radiation therapy or concomitant chemotherapy. However, intensification of therapy has been associated with increased acute and late toxic effects. The application of advanced radiation techniques, such as 3D conformal radiation therapy and intensity-modulated radiation therapy, is expected to improve the therapeutic index of radiation therapy for HNC by limiting the dose to critical organs and possibly increasing locoregional tumor control. To date, Review articles have covered the prevention and treatment of radiation-induced xerostomia and dysphagia, but few articles have discussed the prevention of hearing loss, brain necrosis, cranial nerve palsy and osteoradionecrosis of the mandible, which are all potential complications of radiation therapy for HNC. This Review describes the efforts to prevent therapy-related complications by presenting the state of the art evidence regarding advanced radiation therapy technology as an organ-sparing approach.

SCV-07 treatment leads to alterations in VEGF, MIF, IL-1alpha, and MIP-1beta levels in patients with head and neck cancer

Abstract Introduction: Serum was collected before and after chemoradiation therapy from head and neck cancer (HNC) patients enrolled in a phase 2, randomized, double-blind, dose-ranging, placebo-controlled trial designed to test the safety, tolerability and efficacy of an immunomodulatory peptide, gamma-D-glutamyl-L-tryptophan (SCV-07) as an intervention for oral mucositis (OM). Results of the trial demonstrated that the high dose of SCV-07 (0.1 mg/kg daily on days of radiation) was safe and effective in attenuating the course of OM. The objective of this study was to determine if the administration of high dose SCV-07 affected detectable levels of peripheral blood cytokines that may be involved in the host response to chemoradiation therapy for HNC. Experimental Procedures: Samples were analyzed via multiplex (Affymetrix Procarta cytokine assay), evaluating 35 proteins expected to be affected by SCV-07, which has been shown to stimulate a Th1 cytokine profile and to inhibit IL-6 dependent STAT3 signaling. For each of the 35 proteins, the null hypothesis “average subject protein value in high-dose regimen subjects equals average subject protein value in placebo regimen subjects” was tested against the alternative hypothesis “average subject protein value in high-dose regimen subjects does not equal average subject protein value in placebo regimen subjects.” A two tail test (=0.05) was used as there was no a priori knowledge of a relationship between protein levels and treatment regimen. Unequal population variances were assumed as the samples were not assumed to be random draws from the same population. The dataset analyzed 26 subjects given the high dose SCV-07 regimen and 23 subjects given placebo. Summary of Results: MIF, MIP-1beta, and VEGF were found to be significantly higher (p &amp;lt; 0.049, p &amp;lt; 0.049, p &amp;lt; 0.015 respectively) in high dose SCV-07 treated individuals compared to placebo, whereas IL-1alpha was found to be significantly lower (p &amp;lt; 0.045) in high dose SCV-07 treated individuals compared to placebo. Conclusions: SCV-07 treatment leads to increases in circulation of some immune-related cytokines (MIF, MIP-1beta, and VEGF) and leads to a decrease in another (IL-1alpha). These results can be used to better understand SCV-07's mechanism of action, and to follow biomarkers during future clinical trials evaluating SCV-07. Basic Research, Epigenetics, Immunology, Noncoding RNAs, Tumor Microenvironment, Metastasis, Target Identification, Validation, Lead Discovery, and Optimization

Vanderbilt Head and Neck Symptom Survey Version 2.0 (VHNSS 2.0): A tool for the study of long-term oral health consequences of therapy for head and neck cancer (HNC).

9055 Background: HNC therapy causes adverse late oral health outcomes (LOHO), the prevalence, severity, and functional implications of which are largely unknown. VHNSS 1.0 was developed to measure treatment-related symptom burden, but common LOHO were not included. We report the development of a LOHO subscale. Methods: Questions were developed by an expert panel and review of oral health measures for the general population. Final tool included 50 items which scored symptoms or functional manifestations from 0 (none) to 10 (severe). It was administered to 70 subjects who completed radiation ± chemotherapy. Results: Completion time <10 minutes. To focus on late effects, we report on 48 participants ≥ 6 months post-treatment. 60% reported moderate/severe (M/S) xerostomia which impacted chewing/swallowing (54%), speaking (39%), and sleeping (30%). 44% reported M/S thick mucous resulting in choking/gagging (22%), difficulty swallowing (22%), and altered sleep (15%). 28% reported M/S voice changes with hoarsene...

Patterns of self-reported neurocognitive (NC) deficits in head and neck cancer (HNC) patients during concurrent chemoradiation therapy (CCR).

e16015 Background: Although changes in NC function are often reported by patients with cancer, few studies have examined this issue in HNC patients receiving CCR. We conducted a prospective observational cohort study to examine NC impairment before, during, and after HNC therapy. Almost half (49%) of patients exhibited impaired baseline neuropsychological function. Here we describe the patterns of self-reported NC function during treatment. Methods: NC deficits were assessed in 59 patients undergoing CCR using the following self-report measures: the Alertness Behavior Subscale (ABS) of the Sickness Impact Profile, the Neurocognitive Subscale of the modified Memorial Symptom Assessment Scale – Short Form (MSAS-SF), and the Confusion Subscale of the Profile of Mood States (POMS). Patients underwent assessments at baseline and weekly during CCR. A group-based, log-likelihood, trajectory modeling approach was used to detect clusters of trajectories (patterns of change) in NC function. Results: The HNC patients were predominantly male (80%), Caucasian (92%), and married (76%), with at least a high school education (86%). Mean age was 55 years (SD 9.2; Range 33-70). Primary sites included: oropharynx (54%), larynx (14%), paranasal sinus/nasal cavity (7%), unknown (7%), nasopharynx (5%), and other (13%). A majority of patients (76%) received induction chemotherapy followed by CCR; the remainder had CCR postoperatively or as primary treatment. Similar patterns of self-reported NC deficits were noted across the three instruments. Three distinct patterns of NC function were identified: (1) patients who perceived higher levels of NC deficits at baseline which persisted through CCR, (2) patients who perceived none to minimal NC deficits at baseline or at any point during therapy, and (3) patients who perceived minimal NC deficits at baseline but reported increasing deficits during therapy. Conclusions: As with other cancers, a proportion of patients present with self-reported NC deficits. In addition, a subset of patients develops perceived NC deficits during CCR. The cause and social/medical implications of NC impairment in these patients are unknown and need to be explored. No significant financial relationships to disclose.

The persistence of symptom burden after radiation treatment for head and neck cancer (HNC).

5573 Background: Radiation therapy (RT) for HNC causes significant toxicity. Most patients do not return for medical follow up for about 6 weeks after completing RT. There is no symptom data reported about this interval, and most patients do not receive ongoing symptom assessment or intervention. We performed a longitudinal study including this interval using the M.D. Anderson Symptom Inventory - Head and Neck module (MDASI-HN). Methods: 161 HNC patients participated. Patients completed the MDASI-HN using paper and pencil before RT/chemo-RT and weekly during the 6-7 weeks of treatment, and for another 8 weeks using an interactive voice response (IVR) system. We report the prevalence of symptom burden over time using descriptive statistics. Results: Fewer than 10% HNC patients had moderate or severe (M/S) symptoms before treatment. Symptom burden peaks for most patients by the end of treatment, but some patients reach their M/S symptom peak after treatment. For the selected potentially serious symptoms for which interventions exist, the proportions of patients experiencing M/S symptoms at any time versus those experiencing the M/S peak after treatment, respectively, are: pain (67%, 20%), mouth/throat sores (73%, 18%), problems with mucus (71%, 34%), appetite (67%, 25%), choking (aspiration) (50%, 31%), skin problems (59%, 35%), and fatigue (71%, 24%). Only 4 of the top 10 symptoms returned to within 10-percentage points of baseline by 2 months after treatment. At 2 month follow up, ≥15% of the patients reported M/S problems with tasting food (37%), mucous (29%), mouth/throat sores (16%), chewing (26%), voice (17%), appetite (33%), drowsiness (15%), dry mouth (49%), pain (15%), and fatigue (27%). Conclusions: While most HNC patients have modest symptom burden pre-treatment, the majority experience moderate to severe symptoms from treatment that do not return to baseline by 2 months. For a significant proportion of patients, moderate to severe symptom severity peaks after treatment, during an interval with no routine medical surveillance or intervention. Monitoring patient symptoms after therapy, including by use of an IVR system, may allow for a reduction in symptom burden with simple validated interventions. No significant financial relationships to disclose.

Response evaluation in head and neck oncology

In this issue you will find the review article ‘‘assay-basedresponse evaluation in head and neck oncology: require-ments for better decision making’’ by Dietz and co-workers[1]. This interesting review addresses a major issue in headand neck cancer therapy. A major problem in the treatmentof head and neck cancers, particularly head and necksquamous cell carcinomas (HNSCCs), accounting for over90% of all malignancies in this area, is unpredictableresistance to chemotherapy and failure after multimodalitytreatment in general. Being able to identify responders andnon-responders prior to therapy induction is therefore ofutmost importance.The authors indicate the difficulties in predicting thetreatment outcome of tumors since these are frequentlyhighly heterogeneous in their biological behavior [2] andemphasize the need for a reliable predictive assay. Theyintroduce and discuss different types of assays that havebeen used for prediction of chemosensitivity in solid can-cers such as breast, lung, ovarian, brain and HNSCCtumors [3–5]. The authors particularly point out that inthese so-called ex vivo assays, which use the patients owncancer tissue, all cell types that build up a tumor mass arepresent such as fibroblasts, endothelial cells and the epi-thelial carcinoma cells themselves. This should have aclear advantage since these assays will likely mimic thereal in vivo situation of the tumor. The authors also indi-cate that for the same reason cell lines are not suitable forthe development of reliable assays since cell lines arehighly selected tumor stem cells and important cellulartumor tissue constituents such as fibroblasts and endothelialcells are lacking.However, as much as ex vivo tissues appear suitable tomimic the real in vivo situation there is one importantdrawback. By having at least three different cell types,chemosensitivity testing can be distorted if one does notdistinguish between the single cell types. Stromal cells ofthe tumor usually are derived from normal body cells,which in general are significantly more resistant to che-motherapy than the respective tumor cells. Therefore, it isessential that a suitable HNSCC chemosensitivity test iscapable of selectively testing the epithelial tumor cellpopulation.Next to these features Dietz et al. define further testcriteria such as high feasibility, high predictive accuracy,robust SOPs, quantitative results, getting the results in areasonable time and being able to perform the tests onsmall amounts of tumor tissues such as those obtained fromtumor biopsies. The authors also discuss the importantquestion if a single biopsy is representative of the wholetumor. Their own data supports the view that single biop-sies indeed are representative of the whole tumor.Lastly, the authors explain why the chemosensitivitytest, known as the FLAVINO assay is advantageous oreven superior to other test systems. Particularly, they stressthe tests ability to account for the flavin-dependent inhib-iting effect of cell culture media on chemotherapeuticagents, its ability to correct for the presence of stromal cellsand that it carries control (KB) cells for quality purposes.Dietz et al. conclude that chemosensitivity tests are nowsuitable and technically mature to be investigated as anadditional tool for therapeutic decision making in clinicaltrials. The authors blamed the low acceptance of chemo-sensitivity assays as stated by the ASCO in 2004 on thesevere lack of controlled clinical studies [6]. Therefore, to

A Randomized, Placebo-Controlled Trial of Citalopram for the Prevention of Major Depression During Treatment for Head and Neck Cancer

To determine whether prophylactic treatment with the antidepressant citalopram hydrobromide, compared with placebo, could prevent major depressive disorder in patients undergoing therapy for head and neck cancer (HNC). Prospective, randomized, placebo-controlled trial. Academic medical center. Thirty-six subjects were randomized, and 23 completed the study. Subjects were randomized to receive 40 mg of citalopram hydrobromide or matching placebo (herein after, citalopram group and placebo group, respectively) for 12 weeks with a final visit at 16 weeks. The Hamilton Depression Rating Scale, psychiatric interview, and the University of Washington Quality of Life (UW-QOL) and Clinician Global Impression-Severity (CGI-S) scales. The numbers of subjects who met predefined cutoff criteria for depression during the 12 weeks of active study were 5 of 10 (50%) taking placebo and 2 of 12 (17%) taking citalopram (Fisher exact test, P = .17). No patients in the citalopram group became suicidal, compared with 2 in the placebo group. Global mood state at the conclusion of the study as measured by the CGI-S scale was rated as at least mildly ill in 15% of those receiving citalopram compared with 60% in the placebo group (Fisher exact test, P = .04). Quality of life, measured by the UW-QOL, deteriorated in both groups from baseline but less so in the citalopram group. This study reports data from the first depression prevention trial in HNC and suggests that prophylactic treatment may decrease the incidence of depression during HNC therapy. The clinical significance of the reduction in depression was best demonstrated by the CGI-S scale, which showed a notable difference in global psychiatric and physical well-being.

Phase I study of panitumumab, chemotherapy and intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC): Early results

6083 Background: Both chemotherapy and epidermal growth factor receptor (EGFR) antibody therapy improve outcomes in HNC when added to radiotherapy. This phase I study investigates the addition of the fully human anti-EGFR antibody, panitumumab, to chemoradiotherapy (CRT) for HNC. Methods: Treatment naïve adults with stage III/IV HNC (primary sites include oropharynx and unknown primary) with normal hematologic, renal, and liver function are currently enrolling in a 2-part study. Part A determines the maximum tolerated dose (MTD) of paclitaxel in 2 dose levels (DLs) (15 and 30 mg/m2 wkly×7 wks) with fixed-dose carboplatin and panitumumab (AUC of 1.5 and 2.5 mg/kg wkly, respectively) plus IMRT (70 Gy). Patients (pts) are enrolled in sets of 3. Part B determines the MTD of 5-FU in 2 DLs (800 and 900 mg/m2 days 1–4, Q21d) with fixed-dose docetaxel, cisplatin and panitumumab (75 mg/m2, 100 mg/m2 and 9 mg/kg, Q21d, respectively) for 3 cycles followed by panitumumab + CRT, as determined in Part A. Results: To date, 8 pts (n=3 at DL 1, n=5 at DL 2) have enrolled in Part A. One dose-limiting toxicity has occurred in DL 2: grade (gr) 4 febrile neutropenia. Other adverse events include gr 3/4 mucositis (n=6), gr 3/4 radiation dermatitis (n=6), gr 2 acneiform rash (n=6), gr 3 dysphagia (n=6) and gr 2 oral pain (n=6). Dose-reduction has not been necessary thus far. Enrollment will continue in a cohort of 10 pts in DL 2. Of 4 pts evaluated for response, 4 had complete response in the primary and neck, and 1 had a residual neck mass. This pt had 1 positive node on neck dissection. Conclusions: Preliminary results suggest that panitumumab can be added to CRT for treatment of HNC without magnifying the expected toxicities with CRT. Part B will investigate panitumumab + sequential therapy for HNC once the MTD of Part A is established. No significant financial relationships to disclose.