I. Bing Tan

mTHPC‐mediated photodynamic therapy for early oral squamous cell carcinoma

Surgery and radiotherapy are standard treatments for early oral squamous cell carcinoma, both resulting in good tumour control. However, neither of these modalities is without consequent functional or cosmetic impairment, and there are patients in whom both are contraindicated. Furthermore, there is a significant risk of metachronous tumours developing in the oral cavity, and salvage or retreatment with either surgery or radiotherapy poses difficulties. Photodynamic therapy (PDT) offers the potential for improved functional and cosmetic outcomes, while achieving comparable tumour control. We conducted an open‐label, multicentre study to assess the efficacy and safety of meta‐tetrahydroxyphenylchlorin (mTHPC) in patients with early oral cancer. One hundred twenty‐one patients received intravenously administered mTHPC, followed 96 hr later by illumination of the tumour surface with 652 nm laser light. Of these patients, 114 were protocol compliant. A complete tumour response was achieved in 85% of protocol‐compliant patients (97 of 114 patients). A complete response was maintained in 85% of responders at 1 year and in 77% at 2 years. One‐ and 2‐year actuarial survival rates were 89% and 75%, respectively. In the opinion of the investigators, tumour clearance was accompanied by excellent cosmetic and functional results, without impact on the patients performance status. Mild‐to‐moderate pain at the treatment site, a recognised side effect of PDT in the oral cavity, was reported by 82% of patients but was manageable with appropriate analgesia. Mild‐to‐moderate skin photosensitivity reactions were reported for 13% of patients. mTHPC offers an effective alternative treatment for early oral squamous cell carcinoma. It is associated with excellent functional and cosmetic results and can be used in conjunction with other standard therapies.

The development of a prognostic score for patients with parotid carcinoma

Understanding of prognostic factors in parotid carcinoma has grown considerably. In particular, clinical tumor staging and histologic classification have been found to be prognostically important. Univariate and multivariate analyses have indicated that other variables, such as age, pain, skin invasion, and facial nerve impairment, are important predictors as well. In an actual patient, some of these factors are present and others are absent. However, a clinical tool incorporating this information, resulting in an individualized prognosis based on the combined effects of present adverse prognostic factors, has never been devised.

Does the combination of radiotherapy and debulking surgery favor survival in paranasal sinus carcinoma

PURPOSEnTo determine the contribution of debulking surgery on local control and survival in paranasal sinus tumors. As most patients present with locally advanced disease, the possibility of radical surgery is limited. Consequently, radiotherapy is often needed as monotherapy or as an adjunct to surgery.nnnMETHODS AND MATERIALSnBetween 1977 and 1996, 73 patients (50 male: 23 female) with a paranasal sinus carcinoma were treated. The histology distribution was as follows: squamous cell carcinoma, 55%; adenocarcinoma, 19%; adenoid cystic carcinoma, 11%; and undifferentiated carcinoma, 15%. The clinical T classification was (UICC/TNM 1997): T2 14%, T3 27%, and T4 59%. Pathological neck nodes were found in 11% of patients. Treatment consisted of surgery only in 3, chemotherapy only in 1, radiotherapy only in 18, both surgery and radiotherapy in 50 patients. One patient did not receive any treatment at all. Three patients had concurrent chemotherapy. Median follow-up was 66 months (range, 1-213 months).nnnRESULTSnFive-year local control (LC) was 65% with combination of radiotherapy and debulking surgery in comparison with 47% with radiotherapy alone, but this difference was not statistically significant (p = 0.58). However, combination treatment gave significantly better 5-year overall survival (OS) (60% vs. 9%; p = 0.001) and 5-year disease-free survival (DFS) (53% vs. 6%; p < 0. 0001). Cox-regression analysis showed that pathologic N status (p = 0.04), palliative intention of treatment (p = 0.018), clinical orbital invasion (p = 0.003), and orbital wall invasion (p = 0.003) were parameters significantly associated with poor local control. Total radiation dose of greater than 65 Gy (p = 0.05) and treatment consisting of radiotherapy alone (p = 0.002) were associated with worse overall survival; for disease-free survival clinical orbital invasion (p = 0.0005), age of greater than 65 years (p = 0.013) and pathologic T4 classification (p = 0.002) were significant factors for an unfavorable outcome. In 19 of 73 patients, 26 serious (mainly ophthalmological) complications were reported; in the majority of these, the visual tract was (partly) included in the treatment fields because of tumor extension. To analyze on which basis patients were selected for the combination therapy, a logistic regression was performed, concluding that clinical T4 classification (p = 0.05), radiological evidence of skull base invasion (p = 0.005), age of greater than 65 years (p = 0.026), radiological evidence of nasopharynx invasion (p = 0.02), clinical suspicion of palate invasion (p = 0.02), and radiological evidence of skin invasion (p = 0.009) were associated with choosing radiotherapy alone.nnnCONCLUSIONnDebulking surgery of paranasal sinus malignancies followed by high-dose radiotherapy to the involved sites was associated with better survival and (although not statistically significant) local control. Patient selection, based on clinical and radiological impression of tumor extension, was the main factor explaining these favorable results. We favor this combination regimen because the surgery gives quick relief of complaints and, at the same time, offers an excellent histologically proven staging method, enabling radiotherapy to be adjusted to the involved sites, thereby decreasing the risk of complications. This can all be achieved with a very low orbital exenteration rate.

Concomitant radio- and fluorescence-guided sentinel lymph node biopsy in squamous cell carcinoma of the oral cavity using ICG-(99m)Tc-nanocolloid.

PurposeFor oral cavity malignancies, sentinel lymph node (SLN) mapping is performed by injecting a radiocolloid around the primary tumour followed by lymphoscintigraphy. Surgically, SLNs can then be localized using a handheld gamma ray detection probe. The aim of this study was to evaluate the added value of intraoperative fluorescence imaging to the conventional radioguided procedure. For this we used indocyanine green (ICG)‐99mTc‐nanocolloid, a hybrid tracer that is both radioactive and fluorescent.MethodsFourteen patients with oral cavity squamous cell carcinoma were peritumourally injected with ICG-99mTc-nanocolloid. SLNs were preoperatively identified with lymphoscintigraphy followed by single photon emission computed tomography (SPECT)/CT for anatomical localization. During surgery, SLNs were detected with a handheld gamma ray detection probe and a handheld near-infrared fluorescence camera. Pre-incision and post-excision imaging with a portable gamma camera was performed to confirm complete removal of all SLNs.ResultsSLNs were preoperatively identified using the radioactive signature of ICG-99mTc-nanocolloid. Intraoperatively, 43 SLNs could be localized and excised with combined radio- and fluorescence guidance. Additionally, in four patients, an SLN located close to the primary injection site (in three patients this SLN was located in level I) could only be intraoperatively localized using fluorescence imaging. Pathological analysis of the SLNs revealed a metastasis in one patient.ConclusionCombined preoperative SLN identification and intraoperative radio- and fluorescence guidance during SLN biopsies for oral cavity cancer proved feasible using ICG-99mTc-nanocolloid. The addition of fluorescence imaging was shown to be of particular value when SLNs were located in close proximity to the primary tumour.

Nasopharyngeal carcinoma in Indonesia： epidemiology, incidence, signs, and symptoms at presentation

Among all head and neck (H&N) cancers, nasopharyngeal carcinoma (NPC) represents a distinct entity regarding epidemiology, clinical presentation, biological markers, carcinogenic risk factors, and prognostic factors. NPC is endemic in certain regions of the world, especially in Southeast Asia, and has a poor prognosis. In Indonesia, the recorded mean prevalence is 6.2/100 000, with 13 000 yearly new NPC cases, but otherwise little is documented on NPC in Indonesia. Here, we report on a group of 1121 NPC patients diagnosed and treated at Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia between 1996 and 2005. We studied NPC incidence among all H&N cancer cases (n=6000) observed in that period, focusing on age and gender distribution, the ethnic background of patients, and the disease etiology. We also analyzed most prevalent signs and symptoms and staging of NPC patients at first presentation. In this study population, NPC was the most frequent H&N cancer (28.4%), with a male-to-female ratio of 2.4, and was endemic in the Javanese population. Interestingly, NPC appeared to affect patients at a relatively young age (20% juvenile cases) without a bimodal age distribution. Mostly, NPC initiated in the fossa of Rosenmuller and spreaded intracranially or locally as a mass in the head. Occasionally, NPC developed at the submucosal level spreading outside the anatomic limits of the nasopharynx. At presentation, NPC associated with hearing problems, serous otitis media, tinnitus, nasal obstruction, anosmia, bleeding, difficulty in swallowing and dysphonia, and even eye symptoms with diplopia and pain. The initial diagnosis is difficult to make because early signs and symptoms of NPC are not specific to the disease. Early-age Epstein-Barr virus (EBV) infection combined with frequent exposure to environmental carcinogenic co-factors is suggested to cause NPC development. Undifferentiated NPC is the most frequent histological type and is closely associated with EBV. Expression of the EBV-encoded latent membrane protein 1(LMP1) Oncogene in biopsy material was compared between NPC patients of < 30 years old and those of ≥ 30 years old, matched for sex and tumor stage. Higher LMP1 expression in patients of <30 years old was observed, which was related to more locoregional progressivity. Increased medical awareness of prevailing early stage signs and symptoms coupled to use of EBV-related diagnostic tumor markers may lead to down-staging and timely treatment to improve survival of patients with this aggressive disease.

Development and Clinical Evaluation of a Second-generation Voice Prosthesis (Provox®2), Designed for Anterograde and Retrograde Insertion

Prosthetic voice restoration has considerably improved the results of vocal rehabilitation after total laryngectomy, and is presently the method of choice for many health-care providers treating laryngectomized patients. The Provox voice prosthesis, developed in the Netherlands Cancer Institute, is an indwelling device that has been applied in recent years with regular success. Its retrograde replacement method, using a disposable guide wire, assures reliable, atraumatic positioning of the prosthesis in the tracheoesophageal fistula. However, the method sometimes may be uncomfortable for the patient; therefore an adapted prosthesis and new replacement equipment were developed, which enable bidirectional insertion, i.e. not only in the traditional retrograde manner through the pharynx, but especially in an anterograde manner through the stoma. This second-generation voice prosthesis (Provox 2) was studied in a prospective clinical trial in 44 patients (33 experienced patients, seven first-time replacements and four primary insertions). The study demonstrated that the anterograde insertion with the Provox 2 system was applicable in all patients, making the voice prosthesis even easier to handle than with the traditional retrograde method. A stenosis of the pharyngoesophageal segment no longer interfered with the replacement. In addition, the patients judged the new method as being favourable, reporting significantly less discomfort during the replacement procedure (paired Students t-test: p < 0.0001). Furthermore, the adapted voice prosthesis could be removed from the tracheoesophageal fistula without excessive force (mean 7.9 N, range 6.0-14.0 N), more easily than the original Provox (mean 20.9 N, range 5.5-25.0 N). It can be concluded that this second-generation indwelling voice prosthesis (Provox 2) seems to be a further improvement in the application of this voice rehabilitation system, not only simplifying the replacement procedure, but also diminishing the discomfort for the patient.

Noninvasive diagnosis of nasopharyngeal carcinoma: nasopharyngeal brushings reveal high Epstein-Barr virus DNA load and carcinoma-specific viral BARF1 mRNA.

Nasopharyngeal carcinoma (NPC) is the most prevalent ENT‐tumour in Indonesia. We investigated the primary diagnostic value of Epstein‐Barr virus (EBV) DNA load and mRNA detection in noninvasive nasopharyngeal (NP) brushings, obtained prospectively from consecutive Indonesian ENT‐patients with suspected NPC (N = 106) and controls. A subsequent routine NP biopsy was taken for pathological examination and EBER‐RISH, yielding 85 confirmed NPC and 21 non‐NPC tumour patients. EBV DNA and human DNA load were quantified by real‐time PCR. NP brushings from NPC patients contained extremely high EBV DNA loads compared to the 88 non‐NPC controls (p < 0.0001). Using mean EBV DNA load in controls plus 3 SD as cut‐off value, specificity, sensitivity, positive and negative predictive values were 98, 90, 97 and 91%, respectively. Epstein‐Barr nuclear antigen 1 (EBNA1) and the carcinoma‐specific BARF1 mRNA were detected by nucleic acid sequence based amplification and found in 86 and 74% of NP brushings, confirming NPC tumour cell presence. EBV RNA positivity was even higher in fresh samples stored at −80°C until RNA expression analyses (88% for both EBNA1 and BARF1). EBV RNA‐negative NP brushings from proven NPC cases had the lowest EBV DNA loads, indicating erroneous sampling. No EBV mRNA was detected in NP brushings from healthy donors and non‐NPC patients. In conclusion, EBV DNA load measurement combined with detection of BARF1 mRNA in simple NP brushings allows noninvasive NPC diagnosis. It reflects carcinoma‐specific EBV involvement at the anatomical site of tumour development and reduces the need for invasive biopsies. This procedure may be useful for confirmatory diagnosis in large serological NPC screening programs and has potential as prognostic tool.

Is photodynamic therapy a good alternative to surgery and radiotherapy in the treatment of head and neck cancer

The mainstay treatments for head and neck carcinomas are surgery, radiotherapy and chemotherapy. These treatment options may be associated with considerable complications. Radical radiotherapy and chemotherapy can generally be employed only once, which presents difficulties in cases of recurrent disease or second primaries within the irradiated field. Salvage surgery at the same site is often difficult, due to progressive tissue loss. In this respect photodynamic therapy (PDT) seems to be a good alternative treatment option for small, localized tumors; with a good outcome and with excellent functional and cosmetic results. Selected patients with advanced cancer of the head and neck, who have exhausted other treatment options, can also achieve improvement in quality of life with PDT. The advantages of PDT compared with surgery or radiotherapy are reduced long-term morbidity and the fact that PDT does not compromise future treatment options for recurrent, residual or second primary disease.

Pretreatment probability model for predicting outcome after intraarterial chemoradiation for advanced head and neck carcinoma

Concurrent chemoradiation is being used increasingly to treat patients with advanced‐stage head and neck carcinoma. In the current study, a clinical nomogram was developed to predict local control and overall survival rates for individual patients who will undergo chemoradiation.

Stage as major long term outcome predictor in minor salivary gland carcinoma

The myriad of histologic types and anatomic sites of occurrence make minor salivary gland carcinomas the most heterogeneous group of carcinomas of the upper aerodigestive tract. Many publications addressing this group consider different subsections, making it hard to get a clear picture of long term treatment results and of modifying prognostic factors.