Treatment Of Adenoid Cystic Carcinoma Research Articles

A phase II study of suberoylanilide hydroxamic acid (SAHA) in subjects with locally advanced, recurrent, or metastatic adenoid cystic carcinoma (ACC).

6045 Background: SAHA is a small molecule inhibitor of histone deacetylases (HDAC). Based on confirmed responses noted in 2 ACC patients treated with SAHA at our institution; we initiated this phase II trial. Methods: Patients with LA, recurrent or metastatic ACC and adequate organ function were eligible. Any prior number of chemotherapy regimens was allowed. Tumor tissue and blood were collected for correlative studies. SAHA was administered orally 400 mg daily for 28 days. The primary objective was to evaluate response rate (RR). Secondary endpoints included: time to tumor response (TTR); response duration (RD); progression-free survival (PFS); overall survival (OS); and adverse events (AE). 29 evaluable patients were needed in a Simon 2-stage optimal design to distinguish RR of at most 5% vs. at least 20%, with alpha = 0.15 and power = 0.90. Results: 30 evaluable patients (overenrolled by 1) were accrued from at 5 different centers between August 2010 and June 2012. Median follow up among the censored patients is 3.8 months for PFS, and 7.2 months for OS. 19 patients were female, 24 were Caucasian, median age was 53 years (range 21-73); 21 patients had a performance status of 1; 20 patients were chemo-naïve. The median number of cycles completed was 5 (range 1-27+). Lymphopenia (n=5), hypertension (n=3), oral pain (n=2), thromboembolic events (n=2) and fatigue (n=2) were the only grade 3 AEs that occurred in more than 1 patient. 5 patients were dose reduced due to AEs. At the time of data cut-off, 9/30/2012, 1 patient with lung metastasis had a PR, with RD of 11.2+ months. TTR was 7.7 months. SD was the best response in 25 patients. Median PFS is 12.7 months (90% confidence interval lower limit: 3.7 months). Median OS has not been reached. There were 6 patients with PFS > 1 year. The correlative studies results will be presented. Conclusions: SAHA shows promise in the treatment of ACC. We are awaiting genomic analysis of the tumors to study the basis of clinical benefit (PR and SD) of SAHA in ACC. Future drug combination studies in ACC are being considered focusing on the epigenetic mechanism of SAHA. Supported by 5U01CA062487/19. Clinical trial information: NCT01175980.

EGFR inhibition prevents in vitro tumor growth of salivary adenoid cystic carcinoma

BackgroundEpidermal growth factor receptor (EGFR) is involved in the development of many human malignant tumors and plays an important role in tumor growth and metastasis. Antagonists of EGFR can suppress the growth of several malignancies; however, their therapeutic effect in adenoid cystic carcinoma (ACC) is controversial.ResultsThe increased proliferation of two ACC cell lines induced by EGF-treatment was reversed by nimotuzumab. Regardless of EGF stimulation, nimotuzumab-treated ACC cells were arrested in G1 phase and showed decreased expression of Ki67. In addition, EGF activated the MAPK-dependent pathway and up-regulated the expression of matrix metalloproteinase-9 and Snail, enhancing the invasive potential of an ACC cell line (ACC-M). The effects of EGF were down-regulated by nimotuzumab treatment.ConclusionsThese results suggest that nimotuzumab can inhibit the growth and invasion of ACC cells induced by EGF, probably through inactivation of ERK phosphorylation. Thus, nimotuzumab should be considered as a promising novel agent for the treatment of ACC.

Neutron Radiation Therapy for Treatment of Adenoid Cystic Carcinoma and Other Primary Salivary Gland Malignancies: A Patterns of Practice Survey

Surgery followed by postoperative radiation therapy for resectable tumors and primary radiation therapy for unresectable tumors is the standard of care for Adenoid Cystic Carcinoma (ACC) and other primary salivary gland malignancies (PSGM). A randomized clinical trial demonstrated the superiority of neutron radiation therapy (NRT) to conventional radiation therapy (CRT) in patients with unresectable tumors, but the role of NRT in the postoperative setting for resectable tumors is less well defined.

Implementation of Intensity Modulated Radiation Therapy in the Treatment of Carcinoma of the Nasopharynx and Oropharynx: A Retrospective Single Institution Analysis

Conclusions From February 2003 to August 2008, 51 patients with nasopharyngeal (n=8) or oropharyngeal (n=43) carcinoma were treated with intensity-modulated radiation therapy (IMRT) at the National Naval Medical Center. The majority of patients received treatment for squamous cell carcinoma (n=50) with one patient undergoing IMRT for treatment of adenoid cystic carcinoma of the oropharynx. One patient treated for nasopharyngeal squamous cell carcinoma was lost to follow-up after 7 months with exclusion from this analysis. Of the 50 patients, 49 were treated with definitive IMRT and 1 received re-treatment for recurrent base of tongue squamous cell carcinoma. Materials/Methods

Patterns of Practice in the Treatment of Adenoid Cystic Carcinoma Compared With NCCN Guidelines: A National Survey

Patterns of Practice in the Treatment of Adenoid Cystic Carcinoma Compared With NCCN Guidelines: A National Survey

Overexpression of macrophage migration inhibitory factor in adenoid cystic carcinoma: correlation with enhanced metastatic potential

Adenoid cystic carcinoma (ACC) is a malignant tumor frequently arising in salivary glands with poor long-term prognosis due to high rates of local recurrences and distant metastases. Macrophage migration inhibitory factor (MIF) is a multi-functional cytokine and has recently emerged as a pro-tumorigenic factor in various cancers. This study is designed to investigate the expression status and functional significance of MIF in ACC. Immunohistochemical staining was performed to evaluate the expression levels of MIF, HIF-1α, MMP-9, p53, and p-JNK in ACC tissues. In vitro, ACC-2 cells were exposed to recombinant human MIF (rMIF) or ISO-1 (an inhibitor of MIF) at different concentrations and times, followed by the detection of cell growth, viability, migration, and invasion, as well as the expression levels of several cellular signals. The immunohistochemical results demonstrated the overexpression of MIF in ACC tissues as well as its association with the distant metastasis. Further analyses showed a significant correlation between the staining of MIF and p-JNK. Moreover, the in vitro studies revealed that the treatment for ACC cells with ISO-1 significantly attenuated cell migratory and invasive capacity, as opposed to the limited promotive effects of rMIF. More importantly, MIF inhibition could cause the activation of JNK, correlating with the immunohistochemical findings on ACC tissues. The results suggest that MIF is likely to be an important player in the pathogenesis of ACC and may promote cancer metastasis, which possibly involves JNK inactivation. Further investigation of MIF-mediated molecular events may provide novel insights into the treatment for ACC.

Synchronous metastatic adenoid cystic and squamous cell carcinoma of the cervical lymph nodes 31 years after ablation of the primary palatal tumour

The coexistence of different types of malignancy in cervical lymph nodes has been reported previously. We report the first case, to the best of our knowledge, of concurrent metastatic adenoid cystic carcinoma and squamous cell carcinoma (SCC) in cervical lymph nodes. A primary SCC developed three decades after treatment for adenoid cystic carcinoma of the palate, and the synchronous metastases became clinically apparent the following year. The aetiology of the SCC may have been related to radiotherapy or smoking. Whether the adenoid cystic carcinoma would have remained dormant, or was reactivated after perturbation of host defence mechanisms, is not known.

Antitumor effect of human TRAIL on adenoid cystic carcinoma using magnetic nanoparticle–mediated gene expression

To overcome treatment limitations of adenoid cystic carcinoma, we developed a novel treatment combining gene therapy and nanotechnology. In this study, we created a plasmid, pACTERT-TRAIL, which used the human telomerase reverse transcriptase promoter, a tumor-specific promoter, to drive tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). A Fe3O4-PEI-plasmid complex (FPP) was generated, in which the iron oxide nanoparticles were modified by positively charged polyethylenimine (PEI) to enable them to carry the negatively charged plasmid. In vitro transfection assays showed that efficiency of magnetofection (i.e., FPP transfection) was sixfold higher compared to PEI alone or Lipofectamine 2000 (hereafter referred to as lipofectin) (P < 0.05). Importantly, apoptotic assays demonstrated that FPP-mediated TRAIL gene transfer could efficiently induce apoptosis of SACC-83 cells in vitro and in vivo. These results demonstrate that magnetofection of the plasmids driven by the tumor-specific promoter hTERT provides an effective way to deliver therapeutic genes for the treatment of adenoid cystic carcinoma in the future. From the Clinical EditorIn this novel study addressing adenoid cystic carcinoma, the authors created a plasmid to drive tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Following that, a Fe3O4-PEI-plasmid complex (FPP) was generated, in which the iron oxide nanoparticles were modified by positively charged polyethylenimine (PEI) enabling them to carry the negatively charged plasmid, giving rise to sixfold higher transfection rates compared to standard technology.

Non-circumferential tracheal resection with muscle flap reconstruction for adenoid cystic carcinoma

Circumferential airway resection with primary anastomosis has been widely adopted as a treatment for adenoid cystic carcinoma (ACC) of the trachea. However, carinal resection is a complicated procedure with high mortality and morbidity rates. We describe a technique of non-circumferential tracheal resection performed to treat ACC arising from the lower membranous trachea adjacent to the carina. The tumor was resected while preserving the tracheo-carinal cartilage. A silicone Y-stent was placed at the bifurcation to ensure airway patency before closing the defect. The airway defect, measuring 4×2.5cm, was closed using an autologous pericardial patch and pedicled latissimus dorsi muscle flap. These procedures were technically easy, and no postoperative airway complication occurred.

Abstract 4973: Telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines

Abstract There is no effective treatment of adenoid cystic carcinoma (ACC) in oral region, which low sensitivity of chemotherapy and radiation therapy. We previously showed that telomerase-specific replication-competent adenovirus (Telomelysin, OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter controls the adenoviral E1 gene expression, induces a selective antitumor effect in oral squamous cell carcinoma (OSCC) cells in vitro and in vivo orthotopic graft model. We conducted to evaluate the effectiveness of OBP301 against ACC. First, we could confirm that the expression of hTERT in two types of ACC cell lines (ACC2, ACCM) by Western blotting. Then, we examined the antitumor effect of OBP301 in human ACC cells in vitro. OBP-301 infection induced cell death in human ACC cells in a dose-dependent manner. We also examined the expression levels of coxsackievirus and adenovirus receptor (CAR) on the cell surface of each type of cell by flow cytometric analysis. Apparent amounts of CAR expression were detected on human ACC cells. Relative hTERT mRNA expression in ACC was analyzed by real-time RT-PCR, which showed high expression time dependent. In addition, OBP-401 is a genetically engineered adenovirus that expresses GFP by inserting the GFP gene under the control of the cytomegalovirus promoter at the deleted E3 region of OBP-301. Human ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a dose-dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by floating, highly light-refractile cells under phase-contrast photomicrographs. In conclusion, our data clearly indicate that telomerase-specific oncolytic adenoviruses have a significant therapeutic potential against human ACC in vitro. These results suggested that treatment of OBP-301 and OBP-401 are possible to improvement of QOL of oral cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4973. doi:1538-7445.AM2012-4973

Treatment of adenoid cystic carcinoma in the head and neck: A clinical study

当科で1983年4月から2009年12月までに手術を行った腺様嚢胞癌23例（男性12例，女性11例）について検討した。初診時の年齢は28歳から80歳であり，平均64.1歳であった。原発巣は耳下腺7例，顎下腺5例，口腔5例，上顎洞2例，上咽頭2例，中咽頭1例，気管1例であった。対象症例全体の累積10年生存率は69.7%であり，無病生存率は32.9%であった。組織亜型では充実型において生存率，無病生存率が低い傾向にあった。術後放射線療法は，生存率に有意差は認めなかったが，局所制御率を改善させる可能性が示唆された。予防的頸部郭清術は頸部リンパ節再発を制御可能であるが，肺などの遠隔転移により，長期的には予後に影響しない可能性が考えられる。

Flavokawain B induces apoptosis of human oral adenoid cystic cancer ACC-2 cells via up-regulation of Bim and down-regulation of Bcl-2 expression

Novel effective drugs are still urgently needed in the prevention and treatment of oral adenoid cystic carcinoma (ACC). In this study, we have assessed the antitumor potential and molecular mechanisms of flavokawain B (FKB) as a kava chalcone on the ACC-2 cell line in vitro. The results demonstrated that FKB could significantly inhibit the cell proliferation of ACC-2 in a dose-dependent manner that was associated with induced apoptosis and cell cycle G2-M arrest, and the half maximal inhibitory concentration (IC50) of flavokawain-B treatment for 48h was estimated to be 4.69± 0.43µmol/L. Mechanistically, FKB could induce the release of cytochrome c from mitochondria into the cytosol, and activate the cleavage of caspase-3 and, eventually, the poly(ADP-ribose) polymerase (PARP), in a dose-dependent manner, leading to marked apoptotic effect of ACC-2 cells. The apoptotic action of FKB was associated with the increased expression of proapoptotic proteins: Bim, Bax, Bak and a decreased expression of antiapoptotic Bcl-2. Among them, Bim expression was significantly induced by FKB, and knockdown of Bim expression by short-hairpin RNAs attenuated the inhibitory effect induced by FKB on ACC-2 cells. These results suggest Bim may be one of the potential transcriptional targets, and suggests the potential usefulness of FKB for the prevention and treatment of ACC.

Abstract B120: In vivo evaluation of dovitinib (TKI258) alone and in combination in patient-derived salivary gland tumor models: Identification of a potential treatment for adenoid cystic carcinoma.

Abstract Background: Adenoid Cystic Carcinoma (ACC) is an uncommon cancer of the head and neck which typically originates in the salivary glands. We and others have previously performed preclinical and clinical screens of FDA-approved and investigational agents in an attempt to identify useful therapies for ACC. However, to date no approved standard of care drug therapy exists. Fibroblast growth factors (FGF) and their receptors (FGFR 1–4) are a highly conserved group of functional proteins involved in cell migration, proliferation and survival and have been found important in initiation and progression of certain cancer types. Recently FGFR1 has been found over-expressed and phosphorylated in a majority of ACC tumors and FGF2, a known ligand of FGFR1, is a known downstream target of MYB which is rearranged in most ACC tumors. These data provide the rationale for testing the efficacy of FGFR inhibitors in ACC. Dovitinib (TKI-258) is an orally bioavailable multi-tyrosine kinase inhibitor (TKI) selectively targeting a number of proteins including VEGFR, PDGFR and FGFR. Preclinical and clinical activity of this agent has been demonstrated in solid tumors including breast and renal cancers. However, whether dovitinib is active towards ACC is unclear. Methods: We have developed and characterized a panel of patient-derived ACC tumor models including ACC×5M1, ACC×6, ACC×9, ACC×14 and ACC×16. To evaluate potential activity of dovitinib towards ACC we tested this agent alone and in combination with docetaxel, a taxane previously found active in our preclinical ACC screens, in these five models. Single agent and combination tumor growth inhibition was evaluated with a mean control tumor volume of 1cm3 or seventy-days following treatment initiation as study endpoints. Results: In these studies dovitinib was well tolerated at the evaluated treatment regimens. Dovitinib alone demonstrated statistically significant (p&amp;lt;0.05) tumor growth inhibition in four of five tested models (TGI&amp;gt;58%) and combination with docetaxel resulted in additive tumor growth inhibition in sensitive models, including partial and compete tumor responses in some models. Dose and schedule-dependent activity was also demonstrated with dovitinib in these studies. Conclusion: These results identify dovitinib as a potential treatment for ACC and suggest combination benefit with docetaxel. Based on these studies and correlative molecular characterization data clinical trials have been initiated to evaluate dovitinib in patients with ACC. These studies further demonstrate the utility of patient derived tumor models as translational tools for improved identification of potential anticancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B120.

Nelfinavir treatment of adenoid cystic carcinoma: A case report

Adenoid cystic carcinoma (ACC) accounts for about 1% of all head and neck cancers and most commonly arises from the major and minor salivary glands, but may also develop in other sites.1 Complete resection with negative margins, the recommended surgical treatment, is commonly compromised by extensive perineural spread. Anatomic constraints such as extension to or through the skull base may also preclude meaningful resection, in which case the standard postoperative radiation therapy may serve as primary therapy instead. Despite displaying an indolent behavior, ACC is highly lethal. Disease-free survival at 5 years is around 50% and decreases to 30% to 40% at 15 years.2,3 Management options for recurrence are usually limited by the location and extent of the cancer (which is often metastatic), precluding further surgery or reirradation. Systemic treatment has been limited to toxic chemotherapy regimens with low efficacy. As a result, management of recurrent disease warrants further investigation.

Rak gruczołowato-torbielowaty głowy i szyi – doświadczenie 10 lat

Adenoid cystic carcinoma (ACC) was first described in 1853 and 1854 by three french scientists, Robin, Lorain and Laboulbène. ACC is a rare cancer of the head and neck (about 1%) and it comprises from 6% to 10% of all malignant tumors of the salivary glands. 15%–30% of these tumors are located in submandibular gland, 30% occur in small salivary glands (in the palate, tongue, mouth, nose, sinuses, mucous membrane of the cheeks) and about 6% in parotid gland. Because of its specificity ACC is a challenge for the doctor – it is usually recognized at an advanced stage, spreads along the nerves, it has a high propensity for recurrence, often gives distant metastases, 10-year survival are very small. Aim of this study is the epidemiological and clinical analysis of patients with adenoid cystic carcinoma. Includes a retrospective analysis of 21 cases of patients with ACC of the head and neck were hospitalized at the ENT Clinic of the Warsaw Medical University between 2001 and 2011. Data from medical records contain information about the location of the tumor, symptoms and clinical signs, diagnostic methods, method of treatment and local recurrences and distant metastases. most cases ACC occurred in the large salivary glands (14 cases), in 5 cases in the nasal cavity and maxillofacial region, in 2 cases in the tongue. In order to accurately determine the extent of the tumor, its relationship to adjacent structures was performed computed tomography and magnetic resonance imaging. Most of patients before treatment have been made biopsy of the tumor or download tissues by forceps for histopathological examination. Reported symptoms depend on the location of the tumor. In 20 cases the patients were treated by surgical therapy and followed by radiotherapy, in one case because of the extent of the tumor was sent to radiotherapy. Surgical treatment of ACC requires a wide margin of healthy tissues; For the risk of local recurrences affected positive surgical margins, skull base locations of primary tumor and perineural invasion; Because of unpredictable nature of the tumor (local recurrences, distant metastasis), observation of patients after treatment should be carried out permanently, along with periodic imaging studies.

Adenoid Cystic Carcinoma: Benefit of Surgery Plus Adjuvant Radiation

Objective: Evaluate the role of adjuvant radiation compared with surgical resection alone in treatment of adenoid cystic carcinoma of the head and neck. In addition, given the varied course and presentation of the disease, to analyze the impact of perineural invasion, margin status, and AJCC Tumor stage on survival. Method: Retrospective review of 92 patients treated for adenoid cystic carcinoma of the head and neck between 1978 and 2010 at a single tertiary care academic center. Kaplan-Meier survival curves and Cox Proportional Hazards Model were used to evaluate the impact of treatment modality and clinical and pathological parameters on survival. Results: The oropharynx was the most common site (30.4%). Overall 2-, 5-, and 10-year survival rates were 75%, 51%, and 22%. Mean follow-up was 75.9 months. All but 3 patients were treated with surgery and 60 out of 92 (65.2%) underwent postoperative radiation. Mean time to recurrence was 45.6 months and occurred in 45 out of 90 patients (50%). Significantly more T3/T4 staged patients underwent surgery plus adjuvant radiation than T1/T2 patients ( P &lt; .045). Conclusion: Despite being classified with more advanced disease (T3/T4 Stage), patients in the surgery plus radiation group had similar outcomes to patients who received surgery alone. Adjuvant radiation should be considered in all patients with adenoid cystic carcinoma of the head and neck.

Orbitocranial Approach for Treatment of Adenoid Cystic Carcinoma of the Lacrimal Gland

Multiple treatment options exist for management of adenoid cystic carcinoma of the lacrimal gland. Our objective was to perform an analysis of outcomes in a cohort of patients with adenoid cystic carcinoma of the lacrimal gland treated identically with an orbitocranial approach. We performed a retrospective review of 7 consecutive patients who presented to a tertiary care academic medical center between 1995 and 2009 with adenoid cystic carcinoma of the lacrimal gland. All patients were treated with an orbitocranial approach to tumor resection followed by postoperative radiotherapy. The mean and median follow-up times were 39 and 19 months, respectively (range, 7 to 138 months). Six patients had orbital reconstruction using free tissue transfer, and 1 patient had a split-thickness skin graft to line the orbital cavity. Two patients developed distant metastases 18 months and 29 months after surgery and ultimately died with disease. Five patients are alive without disease. The orbitocranial approach followed by postoperative irradiation achieves excellent local and regional control rates for adenoid cystic carcinoma of the lacrimal gland, although patients remain at risk long-term for distant metastases. Orbital bone removal to obtain adequate margins should be a routine part of tumor resection for these malignancies.

Carcinome adénoïde kystique du cuir chevelu

Few cases of adenoid cystic carcinoma of the scalp have been described in the literature. Herein, we report a new case illustrating the difficulties of diagnosis and treatment of this rare form of tumour. A 49-year-old man consulted for a large ulcerated scalp tumour. The biopsy sample exhibited an aspect of cystic adenoid carcinoma. Bone invasion had occurred. Extremely wide surgical excision was carried out, extending down to the dura mater, with covering by means of a frontal flap with left temporal pedicle. Since the edges of the resection were also tumoural, postoperative radiotherapy at 56Gy was given. Twelve months later, the patient was still in remission. The standard treatment for adenoid cystic carcinoma is complete surgical excision but this approach may be complicated by difficulties relating to the degree of tumour spread or to the anatomical site. Postoperative radiotherapy appears to improve local control, as illustrated by our case.

Combined treatment of adenoid cystic carcinoma with cetuximab and IMRT plus C12 heavy ion boost: ACCEPT [ACC, Erbitux®and particle therapy

BackgroundLocal control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent leading to the establishment of particle therapy in this indication. However, even modern techniques leave space for improvement of local control by intensification of local treatment. Radiation sensitization by exploitation of high EGFR-expression in ACC with the EGFR receptor antibody cetuximab seems promising.Methods/designThe ACCEPT trial is a prospective, mono-centric, phase I/II trial evaluating toxicity (primary endpoint: acute and late effects) and efficacy (secondary endpoint: local control, distant control, disease-free survival, overall survival) of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 49 patients with histologically proven (≥R1-resected, inoperable or Pn+) ACC. Patients receive 18 GyE carbon ions (6 fractions) and 54 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy.DiscussionThe primary objective of ACCEPT is to evaluate toxicity and feasibility of cetuximab and particle therapy in adenoid cystic carcinoma.Trial RegistrationClinical Trial Identifier: NCT 01192087EudraCT number: 2010 - 022425 - 15

Perineural Invasion in Adenoid Cystic Carcinoma of the Salivary Glands: Anatomical Influences on Oncological Management

The evidence as to the prognostic significance of perineural invasion in adenoid cystic carcinoma of the sali- vary glands is equivocal. Nevertheless, many head and neck surgeons and oncologists take account of histologically proven perineural invasion when planning treatment for adenoid cystic carcinoma. This review presents a digest of the data showing how neural involvement by adenoid cystic carcinoma of the salivary glands relates to local anatomy, and how this influences the extent of surgery and planning of radiotherapy.