Georgios Koloutsos

Longitudinal Cohort Study of Risk Factors in Cancer Patients of Bisphosphonate-Related Osteonecrosis of the Jaw

PURPOSE The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0.94% to 18.6%. This cohort study aimed to calculate the incidence of and identify the risk factors for ONJ in patients with cancer treated with intravenous zoledronate, ibandronate, and pamidronate. PATIENTS AND METHODS Data analyzed included age, sex, smoking status, underlying disease, medical and dental history, bisphosphonates (BP) type, and doses administered. Relative risks, crude and adjusted odds ratios (aORs), and cumulative hazard ratios for ONJ development were calculated. RESULTS We included 1,621 patients who received 29,006 intravenous doses of BP, given monthly. Crude ONJ incidence was 8.5%, 3.1%, and 4.9% in patients with multiple myeloma, breast cancer, and prostate cancer, respectively. Patients with breast cancer demonstrated a reduced risk for ONJ development, which turned out to be nonsignificant after adjustment for other variables. Multivariate analysis demonstrated that use of dentures (aOR = 2.02; 95% CI, 1.03 to 3.96), history of dental extraction (aOR = 32.97; 95% CI, 18.02 to 60.31), having ever received zoledronate (aOR = 28.09; 95% CI, 5.74 to 137.43), and each zoledronate dose (aOR = 2.02; 95% CI, 1.15 to 3.56) were associated with increased risk for ONJ development. Smoking, periodontitis, and root canal treatment did not increase risk for ONJ in patients receiving BP. CONCLUSION The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.

Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study of Risk Factors in Breast Cancer Patients

PURPOSE Osteonecrosis of the jaws (ONJ) was initially described in 2001 in patients receiving intravenous bisphosphonate (BP) treatment. The objective of the present study was to determine whether routine dental procedures can be considered as possible risk factors for the development of ONJ in breast cancer patients receiving BP. PATIENTS AND METHODS Twenty breast cancer patients who developed ONJ receiving BP treatment were included in group A, whereas group B consisted of 40 matched controls (breast cancer patients who did not progress to ONJ receiving BP treatment). Routine dental care, smoking habits, history of tooth extraction, use of dentures, and root canal therapy were recorded. RESULTS Our results indicate that history of tooth extraction during zoledronic acid treatment (adjusted odds ratio [OR] = 16.4; 95% CI, 3.4 to 79.6) and the use of dentures (adjusted OR = 4.9; 95% CI, 1.2 to 20.1) increase the risk of developing ONJ. CONCLUSION The outcome of the present study suggests early referral by oncologists for dental evaluation for every patient to be treated with BP. These results raise the current American Society of Clinical Oncology Level of Evidence linking certain dental procedures with ONJ from V to III. Further studies are needed to assess other possible risk factors and also to highlight the etiopathogenesis mechanism of ONJ.

Treatment protocols of bisphosphonate-related osteonecrosis of the jaws.

To theEditor: We read with great interest the article by Wutzl et al, reporting awell-designed prospective study for the treatment of bisphosphonate-related osteonecrosis of the jaws (BRONJ) in a cohort of multiple myeloma, breast cancer, and other diseases in patients. The authors duly report patients’ underlying diseases and also dose schemas administered. However, they do not report any data from the previous dental history of these patients, ie, history of tooth extraction. Recently, we carried out a matched case–control study in patients with breast cancer. In this study, we reported that tooth extraction could pose up to 44 times higher risk for BRONJ development. We also found an almost 5-fold increased risk for BRONJ development among patients with breast cancer under zoledronic acid medication using dentures. The evidence provided from the latter study associated BRONJ with tooth extraction and use of dentures and updated the American Society of Clinical Oncology (ASCO) level of evidence from V to III. Wutzl et al report that 72.7% of their patients received zoledronic acid for the disease. We believe that dental history of the 58 patients is available to Wutzl et al and we look forward to reading these data in a forthcoming publication. Despite being well designed and original, the study by Wutzl et al also has an important limitation not addressed by the authors. Their followup period may be uniform for almost all patients included; however, we feel that 6 months may not be enough for a precise evaluation of the proposed treatment modalities. We also carry a prospective cohort of patients under treatment with biphosphonates, some of whom had progressed to BRONJ. Logically, we designed a separate prospective study to evaluate different treatment modalities for these patients. Preliminary results were published but the study is still ongoing, and the results will be published when it will be concluded. Nonetheless, we have witnessed relapse of BRONJ in surgically treated patients up to 14 months after surgery. We have also witnessed healing at the surgically treated site up to 8 months from surgery. Therefore, based on our partially unpublished data, we suggest that the therapeutic effect of the proposed modality may be exacerbated or enhanced if the follow-up period is extended to 18 months. The authors report having performed surgery in patients with stage 1 BRONJ as well. We concur with this modality, which we also employ. Another issue noted by Wutzl et al is discontinuing intravenous administration of biphosphonates or changing it to oral for those patients who were selected for surgery. The authors state that it is not clear whether the discontinuation had a positive effect on the outcome data. The protocol of the study we are conducting controls this effect, and we expect to have some results on this issue. Nevertheless, we feel that discontinuation of biphosphonates is unlikely to have a positive impact on the outcome of the treatment. Recent studies provide Head & Neck 31: 1112–1114, 2009 Published online 1 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.21148

Neck dissection in relation with disease-free, disease-specific, and overall survival of patients with squamous cell cancer of the oral cavity.

Purpose The aims of this study were to assess the accuracy of the presurgical TNM staging of patients with oral squamous cell carcinoma who underwent neck dissection, to explore the relation between the site of the primary tumor and the histopathologically determined neck metastasis, and to perform survival analysis in relation to the histopathologic neck status. Patients and Methods A retrospective chart review with prospective follow-up of oral squamous cell carcinoma patients who underwent neck dissection was performed. Presurgical clinical neck status (cN) and postsurgical histopathologic neck status (pN) were recorded. Sensitivity, specificity, and likelihood ratios were calculated. Kaplan-Meier survival analysis was performed. Results The patients clinically staged as cN+ have more than 2-fold odds of having a pN+ neck. Those staged as cN0 have 4 times less odds of a pN+ neck. The mean follow-up was 45.8 months. The median overall survival was 27 months (41 mo in the patients with pN0 and 19.5 mo in the patients with pN+). For the patients with pN0, the 1-year overall survival probability was 95%, falling to 90% at 2 years and 81.8% at 5 years. In the patients with pN+, the 1-year overall survival probability was 72.2%, falling to 44.4% at 2 years and 26.7% at 5 years. Disease-specific and disease-free survival exhibited similar trends. Conclusions No means of presurgical assessment either clinical or imaging was sufficiently sensitive and specific enough to predict the metastatic status of the neck. An approximately 50% decrease in the 5-year overall survival rate may be expected when regional metastasis is confirmed.

Branchial cyst carcinoma revisited: stem cells, dormancy and malignant transformation.

Purpose: Branchial cleft cysts are among the most common causes for a congenital neck mass. Branchial cleft cyst carcinoma (BCCC) is a type of cancer that arises from cells within these cysts. Despite the distinct criteria that have been reported for its diagnosis, BCCC remains a controversial entity. Clinical Report: We report a case of type I, first BCCC, on a 71-year-old white man. The diagnosis was based on the proposed criteria following lesion history and location, surgical excision, histology, and panendoscopy. Discussion: We argue for the first time the hypothesis that congenital branchial cysts and BCCC tumors may result from progenitor cell rests of the embryological branchial development. After a period of dormancy, these cells could eventually awake and proliferate, thus giving rise to branchial cleft cysts. With the acquirement of mutations due to genomic instability, some clones of these cells could transform to malignant stem cells, thus clinically manifesting as BCCC. Conclusions: The wide recognition of stem cells and their role in carcinogenesis provides a new context for the etiopathogenesis of controversial and rare entities such as the BCCC.