Oral Cavity Primaries Research Articles

Submandibular Gland-Sparing Technique Versus En-Bloc Level IB Dissection in Oral Cavity Cancers with N0 Neck Status: A Randomized Controlled Trial.

Metastases to the submandibular gland (SMG) from oral cavity primaries are very rare. Hence, a gland-preserving level IB dissection technique is a feasible option without compromising the lymph node yield (LNY). To assess the feasibility and noninferiority of the SMG-preserving dissection technique to the conventional en bloc removal of level IB in terms of LNY in patients with cN0 oral squamous cell carcinoma (OSCC) undergoing elective neck dissection. Parallel-design, single-center, open-label, randomized controlled trial. Tertiary care health care center-Department of Otorhinolaryngology-Head & Neck Surgery, AIIMS Rishikesh. Thirty-eight (n = 38) participants with 46 (n = 46) neck dissection specimens of OSCC were randomly allocated (1:1) into gland-preserving (n1 = 23) and en bloc (n2 = 23) dissection groups. Elective neck dissection comparing SMG-sparing level IB dissection technique versus en bloc level IB dissection. LNY, lymph node density, and level IB operative time in both groups were compared between groups (α < .05). Median LNY (P = .543) and lymph node density (P = 1.000) in level IB did not show significant differences between the groups. LNY in level IB by gland-preserving technique is also not inferior to the conventional en bloc dissection technique (mean difference = 0.217; 95% CI: [-0.597, 1.032]; P = .593). The mean level IB operative time is significantly longer in the gland-preserving group (P < .001). None of the examined SMGs were involved by the tumor. SMG-preserving technique is noninferior to the traditional technique of level IB clearance and can be used in elective neck dissections without compromising the LNY. Functional neck dissection has greatly evolved to decrease patient morbidity, and this method can be adopted in case-specific situations. The trial was registered in the Clinical Trials Registry-India (CTRI/2022/05/042344) on May 2, 2023, https://ctri.nic.in/.

Author’s reply to Krishnamurthy et al. and Thiagarajan

It was encouraging to note the bolstering responses from experts in the field to the recently published editorial on second primary versus recurrent tumor.[1] The editorial discussed the inconsistencies in the currently used sets of diagnostic criteria and their practical implications, focusing mainly on head-and-neck squamous cell carcinoma (HNSCC). I thank Krishnamurthy et al.[2] and Thiagarajan[3] for their letters, which not only shed light on a few more crucial observations relevant to the topic but also incited further deliberation on possible solutions to the problem at hand. In addition to the peculiar statistical and clinical issues highlighted in the editorial arising from the lack of a standardized definition of a second primary tumor and uniform criteria to distinguish it from recurrence (locally) or metastasis (distantly), there is also the question of how to determine the pathological status of the intervening mucosa. Does this accurate diagnosis mandate invasive pathological sampling of normal-looking intervening mucosa? As raised by Thiagarajan, what would be the diagnostic stand if the intervening mucosa showed dysplasia?[3] Regarding the risk of a second primary tumor, as conjectured by Krishnamurthy et al.,[2] some of the recent studies have reported an apparent protective effect of human papillomavirus (HPV) positivity in HNSCC, that contrasts with the significant increase in the risk of second primary tumors conferred by traditional risk factors like tobacco and alcohol.[4–6] This is not surprising, given the remarkable differences in the molecular mechanisms of carcinogenesis between HPV-positive and HPV-negative tobacco-related HNSCC.[7] Interestingly, in these studies, patients with oral cavity primaries and those with comorbidities were noted to have a significantly higher rate of second primary tumors, suggesting that these factors are also important determinants of the risk of developing second primary tumors in HNSCC.[4,5] As highlighted by Thiagarajan,[3] although the works of Warren and Gates from the 1930s remain the most cited criteria for defining the second primary tumor in the literature, several articles cite Theodore Billroth’s work from the 1880s as the origin of the three-point criteria.[4,5,8] However, the inability to access the original work of Billroth, and consequently, the lack of clarity about the context and components of the criteria described by him, could be some of the reasons for it not being widely adopted or cited. Nevertheless, as highlighted in the editorial,[1] despite the presence of sets of criteria endorsed by the International Association of Cancer Registries and the Surveillance, Epidemiology, and End Results program for a few decades now, researchers still prefer using the Warren and Gates criteria to define second primary tumors, probably for their simplicity and comprehensibility.[4,5] Interestingly, as discussed in both letters,[2,3] a group of researchers from The Netherlands proposed a novel and intriguing classification scheme in 2002 intending to solve the clinical predicament of distinguishing a second primary tumor from recurrent disease with the help of molecular characterization of the tumors.[9] However, not many have explored this approach, probably owing to issues with feasibility, technical challenges, and practical applicability of such a scheme in patient care, as subsequently pointed out by the experts from the International Head and Neck Scientific Group, which also included authors of the 2002 study from The Netherlands.[10] In other words, the practical utility of molecular diagnostics is yet to be streamlined and has a long way ahead. Even if made available in most large centers, standardization and universal adherence may still be challenging.[11] Thus, although molecular profiling is the future, with several added advantages that could aid in therapeutic decision-making until a sensitive and standardized set of molecular criteria are established for separating second primary tumors from recurrent and metastatic tumors, the most feasible solution currently is to standardize the existing clinical guidelines and ensure universal adherence across cancer registries and research groups. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Fascio-cutaneous and fascio-periosteal free flaps for treatment of intermediate stage osteoradionecrosis of the jaws

Osteoradionecrosis (ORN) of the jaw is a potentially devastating consequence of head and neck irradiation. Despite recent advances, there are patients who fail to respond to conventional therapies. Historically, free flaps were reserved for advanced cases requiring segmental resection and composite reconstruction, with early and intermediate disease treated more conservatively. We have adopted a more active surgical approach in selected intermediate cases. A retrospective review of patients with intermediate stage ORN who received debridement and either fascio-cutaneous or fascio-periosteal free flap reconstruction was performed. Demographic data, ORN severity, treatment, and outcomes are described. From 2019, 9 cases in 7 patients were identified. All cases were Notani grade II. There were 6 Epstein stage IIa and 3 Epstein stage IIIa. The mandible was the most common site (n=8). Of the 7 patients, 2 had oropharyngeal primaries treated with chemoradiation, and 5 had oral cavity primaries treated with surgery and adjuvant radiation therapy. Three patients had prior hyperbaric oxygen therapy, and 2 had pentoxifylline/tocopherol therapy. After debridement, the radial forearm, ulnar artery perforator, and antero-lateral thigh fascio-cutaneous free flaps were each used in 1 case and the temporoparietal fascio-periosteal free flap was used in 6 cases. There was no recurrence or progression of ORN at the site of surgery, but 2 patients developed additional sites of ORN. For patients with unresponsive intermediate ORN, debridement and soft tissue free flap reconstruction is an alternative to ongoing conservative management or composite resection and reconstruction.

To CT or not to CT: Questioning the Cost-Effectiveness of CT Thorax in Head and Neck Cancers

Computed tomography (CT) scan has been an integral part of the diagnostic workup for patients with head and neck squamous cell carcinoma. Our study was designed to find out the incidence of distant metastasis and second primary tumor and to correlate the cost-effectiveness of CT thorax in detecting the same. This study was conducted among 326 cancer patients who visited our center with curative intent in the year 2021, with lesions in various head and neck subsites. Data were collected based on their pathological TNM staging and the presence of distant metastasis as evident on their CT thorax imaging with various variables related to the disease. Incremental cost-effectiveness ratio (ICER) was calculated for detecting a single metastatic deposit and second primary tumor in terms of Indian currency and was correlated to each subsite and stage of disease at presentation. Out of these 326 patients, 281 patients were included in our study after considering the inclusion criteria, and among these 281 patients, 235 of them underwent CT thorax for metastatic workup. No patient was found to have a second primary. Metastases were found in 12 patients. The site of primary lesion and clinical tumor (cT) staging were found to be significantly influencing the incidence of metastasis on CT thorax. ICER was least for larynx, pharynx, and paranasal sinuses and was highest for oral cavity primaries and early-stage disease. As per our observations and results of ICER, CT thorax is indeed a valuable modality but should be used judiciously when it comes to initial diagnostic workup.

Predictors of early immunotherapy response in head and neck cancer: Per lesion analysis of a prospective randomized trial with nivolumab.

6041 Background: The capacity for radiation and checkpoint inhibitors to elicit clinical responses is impacted by tumor immunogenicity and the immune microenvironment. We sought to determine whether head and neck primary site and metastatic tumor location was associated with initial response in non-irradiated lesions. Methods: We evaluated response in 144 non-irradiated lesions from 59 patients with metastatic head and neck cancer enrolled on a phase II randomized controlled trial of nivolumab with stereotactic body radiotherapy (n=30) vs. nivolumab alone (n=29). Nivolumab was administered 3 mg/kg intravenously every 2 weeks. Radiated lesions were treated with 27 Gy / 3 fractions to a single lesion within 14 days of the first dose of nivolumab. Non-target lesion progression was defined ≥30% increase in the greatest axial diameter 8 weeks after enrollment. Fisher’s exact test with nested bootstrap resampling was used for univariate analysis. Logistic regression with a mixed random effects term was used for multivariate analysis. Results: Primary tumor site, metastatic tumor organ sites, and the unadjusted likelihood of progressive disease by site are listed in the table. On multivariate logistic regression controlling for PD-L1 status (p=0.66) and viral status (p=0.29), lymph node metastases (OR 0.79, p=0.0064) were associated with decreased risk of progression, while liver metastases (OR 1.39, p=0.014) and oral cavity primaries (OR 1.56, p=0.018) were associated with increased risk of progression at 8 weeks, using lung metastases and larynx/hypopharynx primaries as reference. Conclusions: Primary tumor subsite and metastasis location were predictors of response or stable disease following treatment with nivolumab. Metastases from oral cavity primaries and metastases to the liver were at increased risk of early progression. Clinical trial information: NCT02684253. [Table: see text]

Prognostic Role of p16 in Nonoropharyngeal Head and Neck Cancer.

Previous studies have reported conflicting information regarding the prognostic role of p16 in nonoropharyngeal head and neck squamous cell carcinoma (HNSCC). Using the US Veterans Affairs database, we analyzed 1448 patients with locoregionally advanced HNSCC and known p16 status diagnosed between 2005 and 2015 and treated with surgery, radiotherapy, or chemoradiotherapy. Tumor p16 status was determined through manual review of pathology reports of primary tumor specimens. Oropharyngeal (n = 1061) or nonoropharyngeal (n = 387; hypopharyngeal, laryngeal, or oral cavity) tumor site was determined from tumor registry data and manually reviewed for accuracy. We used multivariable Cox regression to analyze the effect of p16 status on overall survival (OS), cancer-specific survival (CSS), and competing mortality (CM) for oropharyngeal or nonoropharyngeal tumor sites. All statistical tests were two-sided. In multivariable models adjusting for treatment, stage, age, comorbidity, and body mass index, patients with p16-positive tumors had improved OS, CSS, and CM compared with patients with p16-negative tumors in both oropharyngeal (OS: hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.40 to 0.71, P < .001; CSS: HR = 0.50, 95% CI = 0.35 to 0.73, P < .001; CM: HR = 0.59, 95% CI = 0.38 to 0.93, P = .02) and nonoropharyngeal primary sites (OS: HR = 0.41, 95% CI = 0.25 to 0.69, P < .001; CSS: HR = 0.37, 95% CI = 0.18 to 0.77, P = .008; CM: HR = 0.46, 95% CI = 0.23 to 0.95, P = .04). The prognostic impact of p16 status did not statistically significantly differ by primary tumor site for OS, CSS, or CM (Pinteraction > .05). Our findings support the hypothesis that p16 has a similar prognostic role in both nonoropharyngeal and oropharyngeal cancer. Consideration should be given to increased testing for p16 in laryngeal, hypopharyngeal, and oral cavity primaries.

Prognostic value of the lymph node ratio in oropharyngeal carcinoma stratified for HPV-status.

Lymph node ratio (LNR) was shown to be a prognostic factor in laryngeal and oral cavity primaries. The purpose of this study was to investigate the impact of the lymph node ratio in oropharyngeal squamous cell carcinoma (OPSCC) with a high incidence of HPV-related disease. Therefore, the role of LNR was evaluated as an additional predictive parameter to the 8th edition of AJCC TNM staging system. From December 2009 to August 2015, patients diagnosed with primary oropharyngeal squamous cell carcinoma were prospectively enrolled. After tumor resection with uni- or bilateral neck dissection, patients with ≥ 1 nodal metastasis (pN+) were eligible for a retrospective LNR analysis. 137 patients underwent tumor resection with uni- or bilateral neck dissection. The proportion of HPV-associated disease was 42%. Most patients (n = 96; 70%) presented with involved neck nodes. In p16-positive OPSCC, the rate of pN + cases was significantly increased compared to p16-negative OPSCC (86% vs. 58%, p = 0.007). Patients with LNR ≤ 10% had a significant better overall survival (OS) and disease-specific survival (DSS). However, when stratified for p16-status, LNR ≤ 10% had a significant impact on OS only for HPV-associated tumors (p = 0.027), whereas LNR of ≤ 10% was not a significant predictor for better OS in p16-negative OPSCC (p = 0.143). The LNR with a cut-off value of 10% serves as an additional prognostic parameter in HPV-related OPSCC and may help to improve risk stratification in combination with the revised AJCC 8th edition TNM classification.

Risk factors for osteoradionecrosis in elderly patients with oral and pharyngeal cancer

Osteoradionecrosis (ORN) is a serious complication of radiation therapy used in the treatment of squamous cell carcinoma of the oral cavity and pharynx. The incidences reported in clinical series have varied significantly. In this study, we estimate the incidence of ORN and evaluate the variables associated with developing ORN using the SEER-Medicare database. Our analysis was limited to patients who were ≥66 years of age. ORN was identified using Medicare billing records. We estimated the incidence of ORN in the presence of mortality as a competing risk using the cumulative incidence function, controlling for available patient, disease, and treatment characteristics. Risk factors for ORN were identified using the competing risks regression model of Fine and Gray. Two hundred and twenty one of the 5,390 patients developed ORN, representing a crude incidence rate of 4.1 % (95 % CI, 3.6 to 4.7 %). At 1, 2, 5, and 10 years, the incidence of ORN was 1.4, 2.4, 4.1, and 5.9 %. Oral cavity primary (hazard ratio (HR) = 2.67, p < 0.001), multimodality treatment (HR = 1.39, p = 0.04), decreased age (HR = 0.59, p < 0.001), female gender (HR = 0.61, p < 0.001), and stage (HR = 0.43, p = 0.008) were associated with the development of ORN, but only oral cavity primary was not associated with a decreased risk of mortality, showing that mortality is a strong competing risk for ORN. The incidence of ORN continues to increase steadily up to 10 years from the time of diagnosis. Patients with oral cavity primaries are at highest risk in this population. Future research should be directed toward identifying factors that can reduce the incidence of ORN.

Correlation of Osteoradionecrosis and Dental Events With Dosimetric Parameters in Intensity-Modulated Radiation Therapy for Head-and-Neck Cancer

Osteoradionecrosis (ORN) is a known complication of radiation therapy to the head and neck. However, the incidence of this complication with intensity-modulated radiation therapy (IMRT) and dental sequelae with this technique have not been fully elucidated. From December 2000 to July 2007, 168 patients from our institution have been previously reported for IMRT of the oral cavity, nasopharynx, larynx/hypopharynx, sinus, and oropharynx. All patients underwent pretreatment dental evaluation, including panoramic radiographs, an aggressive fluoride regimen, and a mouthguard when indicated. The median maximum mandibular dose was 6,798 cGy, and the median mean mandibular dose was 3,845 cGy. Patient visits were retrospectively reviewed for the incidence of ORN, and dental records were reviewed for the development of dental events. Univariate analysis was then used to assess the effect of mandibular and parotid gland dosimetric parameters on dental endpoints. With a median clinic follow-up of 37.4 months (range, 0.8-89.6 months), 2 patients, both with oral cavity primaries, experienced ORN. Neither patient had preradiation dental extractions. The maximum mandibular dose and mean mandibular dose of the 2 patients were 7,183 and 6,828 cGy and 5812 and 5335 cGy, respectively. In all, 17% of the patients (n= 29) experienced a dental event. A mean parotid dose of >26 Gy was predictive of a subsequent dental caries, whereas a maximum mandibular dose >70 Gy and a mean mandibular dose >40 Gy were correlated with dental extractions after IMRT. ORN is rare after head-and-neck IMRT, but is more common with oral cavity primaries. Our results suggest different mechanisms for radiation-induced caries versus extractions.

The Importance of Dexamethasone in Reducing Post-Operative Morbidity from a Tonsillectomy

The Importance of Dexamethasone in Reducing Post-Operative Morbidity from a Tonsillectomy

Osteoradionecrosis (ORN) of the Mandible in Head/Neck Cancer Treated with Intensity Modulated Radiation Therapy (IMRT)

Retrospective review of the incidence and patterns of ORN in head/neck cancer patients treated with IMRT at a single institution. We combined our institutional databases of head/neck cancer patients who underwent IMRT from 9/99 to 5/07 (n = 218). The sites were: nasopharynx (n = 25), paranasal sinuses (n = 35), oral cavity (n = 36), oropharynx (n = 41), larynx/hypopharynx (n = 31), and thyroid gland (n = 50). The T-stages were: T1, 9% (n = 19); T2, 28% (n = 61); T3, 19% (n = 42); T4, 41% (n = 89). Seven patients were not staged. Fifty-four percent of patients (n = 118) underwent surgery prior to RT and 57% (n = 125) had chemotherapy as a component of their initial treatment. Six patients (3%) had mandibular invasion prior to treatment. All patients underwent a comprehensive dental examination at our institution and were given instructions on post-RT dental care/fluoride treatment. Patients that were expected to receive a significant dose to the oral cavity were also fitted with a mouth guard prior to treatment. Pre-RT extractions were performed in 15% of patients (n = 33). The median prescription dose was 69.96 Gy. The median Dmax, mean dose, D05, and D95 doses were 66.89 Gy (range, 24.71-77.69 Gy); 37.46 Gy (range, 3.36-65.30 Gy), 60.09 Gy (range, 16.76-73.32 Gy), and 15.99 Gy (range, .29-56.85 Gy), respectively. The mean mandibular volume receiving IMRT was 73 cc (range, 8-163 cc). Median doses to the left and right parotid gland were 25.61 Gy (range, .90-65.95 Gy) and 25.54 Gy (range, .53-59.07 Gy), respectively. With a median follow-up of 28 months (range, 1-101 months), 2 patients, both with oral cavity primaries, (stages T2N2 and T2N1) experienced ORN. The first patient had ORN 31 months after IMRT. He underwent a sequestrectomy and had healed well at last follow-up. The second patient had ORN 32 months after IMRT. He underwent surgical debridement and also healed fully at last follow-up. In addition to surgery, these patients also underwent post-operative concurrent chemoradiotherapy. Neither patient had mandibular invasion prior to treatment. The mandibular and parotid parameters in these 2 patients were: Dmax, 68.28/71.83 Gy, mean dose 53.35/58.12 Gy, D05 64.64/70.17 Gy, D95 14.98/28.30 Gy, volume 66.8/87 cc, left parotid 25.99/24.73 Gy, and right parotid 23.95/25.30 Gy, respectively. ORN is rare after treatment of head/neck cancer with IMRT. However, the incidence was 6% in oral cavity cancer. Due to the delayed onset of this complication more patients may experience ORN with longer follow-up. Patients that experienced ORN had mandibular parameters that were higher than the median values. All patients should be followed with rigorous dental care and mandibular dose constraints should be applied.

Use of External Beam Radiotherapy Is Associated With Reduced Incidence of Second Primary Head and Neck Cancer: A SEER Database Analysis

Patients with head and neck cancer have a significant risk of developing a second primary cancer of the head and neck. We hypothesized that treatment with external beam radiotherapy (RT) might reduce this risk, because RT can eradicate occult foci of second head and neck cancer (HNCA). The data of patients with Surveillance, Epidemiology, and End Results Historic Stage A localized squamous cell carcinoma of the oral cavity, larynx, and pharynx were queried using the Surveillance, Epidemiology, and End Results database. For patients treated with or without RT, the incidence of second HNCA was determined and compared using the log-rank method. Cox proportional hazards analysis was performed for each site, evaluating the influence of covariates on the risk of second HNCA. Between 1973 and 1997, 27,985 patients were entered with localized HNCA. Of these patients, 44% had received RT and 56% had not. The 15-year incidence of second HNCA was 7.7% with RT vs. 10.5% without RT (hazard ratio 0.71, p <0.0001). The effect of RT was more profound in patients diagnosed between 1988 and 1997 (hazard ratio 0.53, p <0.0001) and those with pharynx primaries (hazard ratio 0.47, p <0.0001). On multivariate analysis, RT was associated with a reduced risk of second HNCA for pharynx (p <0.0001) and larynx (p = 0.04) tumors. For oral cavity primaries, RT was associated with an increased risk of second HNCA in patients treated before 1988 (p <0.001), but had no influence on patients treated between 1988 and 1997 (p = 0.91). For localized HNCA, RT is associated with a reduced incidence of second HNCA. These observations are consistent with the eradication of microscopic foci of second HNCA with external beam RT.

2361: The Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy (PORT) and Pathologic Risk Groups in Patients With Head and Neck Cancer (HNC)

2361: The Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy (PORT) and Pathologic Risk Groups in Patients With Head and Neck Cancer (HNC)

Is Extended Selective Supraomohyoid Neck Dissection Indicated for Treatment of Oral Cancer with Clinically Negative Neck?

Oral cavity tumors may develop occult metastases to the cervical lymph nodes. Current imaging techniques and routine histopathologic methods may fail to detect lymph node micrometastases, but the surgeon has to electively dissect a neck at risk of developing clinical disease. Supraomohyoid neck dissection has been the elective surgery for treating a clinically negative neck in patients with oral cavity primaries. A literature review revealed that level IV nodes can be significantly affected by occult disease with and without metastases in level I-III lymph nodes. This means that level IV nodes have to be included in the supraomohyoid neck dissection, resulting in a more extensive surgical procedure to ensure a margin of oncological safety.

Tumor regression and other prognosticators in advanced head and neck cancers: a sequel to the RTOG methotrexate study

The randomized Radiation Therapy Oncology Group (RTOG) Methotrexate trial in advanced squamous cancers of the head and neck has reported no control or survival benefits when the chemotherapy adjuvant was administered to patients just prior to definitive irradiation. The required data collection and outcome reporting among 146 patients bearing oral cavity primaries and 354 patients with oropharyngeal cancers has allowed a multi-variate approach seeking answers to many unresolved questions. As anticipated, the ability to control these squamous cancers is largely a function of size (T & N stage) with a superior clearance among T3-4 primaries of the oropharynx (66 %) contrasted to identically staged oral cavity tumors (48 %). Adjusted median survival is more than doubled to 26.6 months or 19.8 months among oral cavity and oropharynx patients respectively, when compared to the 8 month median survival when neither primary nor cervical nodes are controlled. Lymph node deposits also impact upon survival, especially among oropharynx patients where the 17.6 month adjusted median survival among NO patients declines to 11.0 months when the primaries are associated with N3 nodes. Surprisingly, the ability to control nodel deposits of all sizes (N 1, N2, or N3) is superior among oropharynx patients when compared with identical oral cavity metastases (e.g. 71.4 % adjusted clearance in N3 oropharyngeal deposits versus 46.1 % in N3 nodes secondary to oral cavity primaries). Adjustments for maldistribution of advanced N-stages in association with T-4 primary stage eliminated an apparent T-stage effect upon nodal clearance within both anatomic regions. Finally, the association of T and N-stage upon distant metastases was investigated, with the surprising conclusion that neither initial T nor N-stage exerts any apparent influence on the observed 10–12% occurrence. The interrelationship of these various prognostic variables is explored using the Cox and logistic models.