Comparing the clinical outcomes of initial surgery and primary definitive radiotherapy with a dosage of 6600 cGy or higher in cT1-2N0M0 oral cavity squamous cell carcinoma: A nationwide cohort study.

BACKGROUND: To compare the clinical outcomes of two treatment modalities, initial surgery and primary definitive radiotherapy (RT), in Taiwanese patients diagnosed with cT1-2N0M0 oral cavity squamous cell carcinoma (OCSCC). METHODS: Between 2011 and 2019, we analyzed data for 13,542 cT1-2N0M0 patients who underwent initial surgery (n = 13,542) or definitive RT with a dosage of at least 6600 cGy (n = 145) for the treatment of OCSCC. To account for baseline differences, we employed propensity score (PS) matching, resulting in two well-balanced study groups (initial surgery, n = 580; definitive RT, n = 145). RESULTS: Before PS matching, the 5-year disease-specific survival (DSS) rates were 88% for the surgery group and 58% for the RT group. After PS matching, the 5-year DSS rates of the two groups were 86% and 58%, respectively. Similarly, the 5-year overall survival (OS) rates before PS matching were 80% for the surgery group and 36% for the RT group, whereas after PS matching, they were 73% and 36%, respectively. All these differences were statistically significant (p < 0.0001). A multivariable analysis identified treatment with RT, older age, stage II tumors, and a higher burden of comorbidities as independent risk factors for both DSS and OS. We also examined the 5-year outcomes for various subgroups (margin ≥5 mm, margin <5 mm, positive margins, RT combined with chemotherapy, and RT alone) as follows: DSS, 89%/88%/79%/63%/51%, respectively, p < 0.0001; OS, 82%/79%/68%/39%/32%, respectively, p < 0.0001. CONCLUSIONS: In Taiwanese patients with cT1-2N0M0 OCSCC, a remarkably low proportion (1.1%) completed definitive RT. A significant survival disparity of 30% was observed between patients who underwent initial surgery and those who received definitive RT. Interestingly, even patients from the surgical group with positive surgical margins exhibited a significantly superior survival compared to those in the definitive RT group.

Should sub-millimeter margins be deemed positive in oral cavity squamous cell carcinoma?

BACKGROUND: While several studies have indicated that a margin status of < 1 mm should be classified as a positive margin in oral cavity squamous cell carcinoma (OCSCC), there is a lack of extensive cohort studies comparing the clinical outcomes between patients with positive margins and margins < 1 mm. METHODS: Between 2011 and 2020, we identified 18,416 Taiwanese OCSCC patients who underwent tumor resection and neck dissection. Of these, 311 had margins < 1 mm and 1013 had positive margins. To compare patients with margins < 1 mm and those with positive margins, a propensity score (PS)-matched analysis (n = 253 in each group) was conducted. RESULTS: The group with margins < 1 mm displayed a notably higher prevalence of several variables: 1) tongue subsite, 2) younger age, 3) smaller depth of invasion), 4) early tumor stage, and 5) treatment with surgery alone. Patients with margins < 1 mm demonstrated significantly better disease-specific survival (DSS) and overall survival (OS) rates compared to those with positive margins (74 % versus 53 %, 65 % versus 43 %, both p < 0.0001). Multivariable analysis further confirmed that positive margins were an independent predictor of worse 5-year DSS (hazard ratio [HR] = 1.38, p = 0.0103) and OS (HR = 1.28, p = 0.0222). In the PS-matched cohort, the 5-year outcomes for patients with margins < 1 mm compared to positive margins were as follows: DSS, 71 % versus 59 %, respectively (p = 0.0127) and OS, 60 % versus 48 %, respectively (p = 0.0398). CONCLUSIONS: OCSCC patients with a margin status < 1 mm exhibited distinct clinicopathological characteristics and a more favorable prognosis compared to those with positive resection margins.

Is elective neck dissection justified in cT2N0M0 oral cavity cancer defined according to the AJCC eighth edition staging system?

BACKGROUND: The current NCCN guidelines recommend considering elective neck dissection (END) for early-stage oral cavity squamous cell carcinoma (OCSCC) with a depth of invasion (DOI) exceeding 3 mm. However, this DOI threshold, determined by evaluating the occult lymph node metastatic rate, lacks robust supporting evidence regarding its impact on patient outcomes. In this nationwide study, we sought to explore the specific indications for END in patients diagnosed with OCSCC at stage cT2N0M0, as defined by the AJCC Eighth Edition staging criteria. METHODS: We examined 4723 patients with cT2N0M0 OCSCC, of which 3744 underwent END and 979 were monitored through neck observation (NO). RESULTS: Patients who underwent END had better 5-year outcomes compared to those in the NO group. The END group had higher rates of neck control (95% vs. 84%, p < 0.0001), disease-specific survival (DSS; 87% vs. 84%, p = 0.0259), and overall survival (OS; 79% vs. 73%, p = 0.0002). Multivariable analysis identified NO, DOI ≥5.0 mm, and moderate-to-poor tumor differentiation as independent risk factors for 5-year neck control, DSS, and OS. Based on these prognostic variables, three distinct outcome subgroups were identified within the NO group. These included a low-risk subgroup (DOI <5 mm plus well-differentiated tumor), an intermediate-risk subgroup (DOI ≥5.0 mm or moderately differentiated tumor), and a high-risk subgroup (poorly differentiated tumor or DOI ≥5.0 mm plus moderately differentiated tumor). Notably, the 5-year survival outcomes (neck control/DSS/OS) for the low-risk subgroup within the NO group (97%/95%/85%, n = 251) were not inferior to those of the END group (95%/87%/79%). CONCLUSIONS: By implementing risk stratification within the NO group, we found that 26% (251/979) of low-risk patients achieved outcomes similar to those in the END group. Therefore, when making decisions regarding the implementation of END in patients with cT2N0M0 OCSCC, factors such as DOI and tumor differentiation should be taken into account.

Quantitative Measurement of Perineural Invasion for Prognosis Analysis of Oral Cavity Cancer Treated by Radical Surgery With or Without Adjuvant Therapy.

Objectives: Perineural invasion (PNI) was quantitatively analyzed in oral squamous cell carcinoma (OSCC) specimens obtained by radical surgery to correlate with survival outcomes. Methods: This is a retrospective study that reviewed the Cancer registry data between 2009 and 2015. Inclusion criteria were oral cavity cancer, treatment by radical surgery, presence of PNI, and available pathologic samples for S100 staining. Patients with M1 disease and those with synchronous or metachronous cancer during staging work-up were excluded. All pathologic samples were reviewed to confirm PNI status and processed by immunohistochemical staining for S100 to quantify PNI. Pathologic information and staging results were also reviewed, and clinical outcomes were analyzed. Results: The retrospective study included 92 patients; 63 had intratumoral PNI (IPNI) and 29 had extratumoral PNI (EPNI). The average number of PNI foci (APNI) was higher in the EPNI group than in the IPNI group (6.7 vs 3.8, t-test 2-tail significance = 0.021). The 3-year overall survival (OS) and time-to-recurrence (TTR) rates of all patients were 82.5% and 81.2%, respectively. Univariate analysis showed that pathological T4 or N2-3 stage correlated with poor OS, whereas APNI ≥4 correlated with poor TTR. In multivariate analysis, only the pathological N2-3 stage was significantly correlated with poor OS, whereas only APNI ≥ 4 was an independent factor of poor TTR. The 3-year TTR rates were 92.4% and 65.6% for diseases with APNI < 4 and ≥ 4, respectively (P = .008). Conclusions: In patients with OSCC with PNI, a greater amount of PNI identified by S100 staining indicated a poorer TTR regardless of stage and other prognostic factors. Quantification of PNI by S100 immunohistochemistry is a potential method for prognosis prediction.

Fucoidan enhances the effect of chemotherapeutic drug against drug-resistant lung cancer cells.

Development of adjuvant chemotherapy drugs against drug-resistant lung cancer cells is necessary. The use of non-toxic adjuvant natural product combined with chemotherapy drugs will be an important treatment mode in the future. The purpose of the study investigates that fucoidan enhances chemotherapy drug poisoning drug-resistant lung cancer cell. Drug-resistant lung cancer cells are established in the study. Cell culture, MTT assay, wound healing assay, gelatin zymography assay, DNA fragmentation assay, apoptosis assay, reverse transcription polymerase chain reaction (RT-PCR) western blot analysis was adopted. The results showed that fucoidan synergized with doxorubicin increased efficacy of poisoning drug-resistant lung cancer cells and enhanced the ability of doxorubicin to inhibit the migration of drug-resistant lung cancer cells. It was observed that fucoidan synergized with doxorubicin induced the increase of apoptosis and inhibited expression of MMP-9, LC3, Beclin-1 and ß-catenin in drug-resistant lung cancer cells. Fucoidan synergized with doxorubicin significantly inhibited proliferation, migration and metastasis of drug-resistant lung cancer cells. Fucoidan strengthened doxorubicin to induce apoptosis and autophagy of drug-resistant lung cancer cells. This study confirms that the combined use of fucoidan and chemotherapeutic drugs can effectively poison drug-resistant lung cancer cells.

Indications for elective neck dissection in cT1N0M0 oral cavity cancer according to the AJCC eight edition: A nationwide study.

OBJECTIVES: According to the NCCN guidelines, there is weak evidence to support the use of elective neck dissection (END) in early-stage oral cavity squamous cell carcinoma (OCSCC). We sought to examine the indications for END in patients with cT1N0M0 OCSCC defined according to the AJCC Staging Manual, Eight Edition. METHODS: Of the 3886 patients diagnosed with cT1N0M0 included in the study, 2065 underwent END and 1821 neck observation. RESULTS: The 5-year outcomes for patients who received END versus neck observation before and after propensity score matching (n = 1406 each) were as follows: neck control, 96 %/90 % (before matching), p < 0.0001; 96 %/90 % (after matching), p < 0.0001; disease-specific survival (DSS), 93 %/92 % (before matching), p = 0.0227; 93 %/92 % (after matching), p = 0.1436. Multivariable analyses revealed that neck observation, depth of invasion (DOI) > 2.5 mm, and poor differentiation were independent risk factors for 5-year outcomes. Upon the application of a scoring system ranging from 0 (no risk factor) to 3 (presence of the three risk factors), the following 5-year rates were observed: neck control, 98 %/95 %/84 %/85 %; DSS, 96 %/93 %/88 %/85 %; and overall survival, 90 %/86 %/79 %/59 %, respectively (all p < 0.0001). The survival outcomes of patients with scores of 0 and 1 were similar. The occult metastasis rates in the entire study cohort, DOI > 2.5 mm, and poor differentiation were 6.8 %/9.2 %/17.1 %, respectively. CONCLUSION: Because all patients who received neck observation had a score of 1 or higher, END should be performed when a DOI > 2.5 mm or poorly differentiated tumors are present. Under these circumstances, 48.6 % (1888/3886) of cT1N0M0 patients may avoid END without compromising oncological outcomes.

Early relapse is an adverse prognostic factor for survival outcomes in patients with oral cavity squamous cell carcinoma: results from a nationwide registry study.

BACKGROUND: The prognostic significance of the relapse interval in patients with resected oral cavity squamous cell carcinoma (OCSCC) is a matter of ongoing debate. In this large-scale, registry-based, nationwide study, we examined whether the time interval between surgery and the first disease relapse may affect survival outcomes in Taiwanese patients with OCSCC. METHODS: Data made available by the Taiwan Health Promotion Administration as of 2004 were obtained. The study cohort consisted of patients who were included in the registry between 2011 and 2017. Disease staging was performed according to the American Joint Committee on Cancer (AJCC) Staging Manual, Eight Edition. We retrospectively reviewed the clinical records of 13,789 patients with OCSCC who received surgical treatment. A total of 2327 (16.9%) patients experienced a first disease relapse. The optimal cutoff value for the relapse interval was 330 days when both 5-year disease-specific survival (DSS) and overall survival (OS) (≤ 330/>330 days, n = 1630/697) were taken into account. In addition, we undertook a propensity score (PS)-matched analysis of patients (n = 654 each) with early (≤ 330 days) versus late (> 330 days) relapse. RESULTS: The median follow-up time in the entire study cohort was 702 days (433 and 2001 days in the early and late relapse groups, respectively). Compared with patients who experienced late relapse, those with early relapse showed a higher prevalence of the following adverse prognostic factors: pT4, pN3, pStage IV, poor differentiation, depth of invasion ≥ 10 mm, and extra-nodal extension. Multivariable analysis revealed that early relapse was an independent adverse prognostic factor for both 5-year DSS and OS (average hazard ratios [AHRs]: 3.24 and 3.91, respectively). In the PS-matched cohort, patients who experienced early relapse showed less favorable 5-year DSS: 58% versus 30%, p < 0.0001 (AHR: 3.10 [2.69 - 3.57]) and OS: 49% versus 22%, p < 0.0001 (AHR: 3.32 [2.89 - 3.81]). CONCLUSION: After adjustment for potential confounders and PS matching, early relapse was an adverse prognostic factor for survival outcomes in patients with OCSCC. Our findings may have significant implications for risk stratification.

Optimizing margin status for improving prognosis in patients with oral cavity squamous cell carcinoma: A retrospective study from the two highest-volume Taiwanese hospitals.

Background: In the treatment of oral cavity squamous cell carcinoma (OCSCC), surgical quality measures which are expected to affect outcomes, including the achievement of a clear margin, are surgeon-dependent but might not be invariably associated with hospital volume. Our objective was to explore surgical margin variations and survival differences of OCSCC between two highest-volume hospitals in Taiwan. Materials and methods: A total of 2009 and 1019 patients with OCSCC who were treated at the two highest-volume Taiwanese hospitals (termed Hospital 1 and Hospital 2, respectively) were included. We examined how a pathological margin <5 mm impacted patient outcomes before and after propensity score (PS) matching. Results: The prevalence of margins <5 mm was markedly lower in Hospital 1 than in Hospital 2 (34.5%/65.2%, p<0.0001). Compared with Hospital 2, tumor severity was higher in Hospital 1. On univariable analysis, being treated in Hospital 2 (versus Hospital 1; hazard ratio [HR] for 5-year disease-specific survival [DSS] = 1.34, p=0.0002; HR for 5-year overall survival [OS] = 1.17, p=0.0271) and margins <5 mm (versus ≥5 mm; HR for 5-year DSS = 1.63, p<0.0001; HR for 5-year OS = 1.48, p<0.0001) were identified as adverse factors. The associations of treatment in Hospital 2 and margins <5 mm with less favorable outcomes remained significant after adjustment for potential confounders in multivariable analyses, as well as in the PS-matched cohort. The 5-year survival differences between patients operated in Hospital 1 and Hospital 2 were even more pronounced in the PS-matched cohort (before PS matching: DSS, 79%/74%, p=0.0002; OS, 71%/68%, p=0.0269; after PS matching: DSS, 84%/72%, p<0.0001; OS, 75%/66%, p<0.0001). In the entire cohort, the rate of adjuvant therapy was found to be lower in patients with margins ≥5 mm than in those with margins <5 mm (42.7%/57.0%, p<0.0001). Conclusions: Within the two highest-volume hospitals in Taiwan, patients with OCSCC with a clear margin status (≥5 mm) achieved more favorable outcomes. These results have clinical implications and show how initiatives aimed at improving the margin quality can translate in better outcomes. A clear margin status can reduce the need for adjuvant therapy, ultimately improving quality of life.

Towards an Improved Pathological Node Classification for Prognostic Stratification of Patients With Oral Cavity Squamous Cell Carcinoma: Results From a Nationwide Registry Study.

Background: To assess the prognostic significance of different nodal parameters [i.e., number of pathologically positive nodes, log odds of positive lymph nodes, lymph node ratio (LNR), and extra-nodal extension (ENE)] in Taiwanese patients with oral cavity squamous cell carcinoma (OCSCC), and to devise an optimized pN classification system for predicting survival in OCSCC. Methods: A total of 4287 Taiwanese patients with first primary OCSCC and nodal metastases were enrolled. Cox proportional hazards regression analysis with the spline method was applied to identify the optimal cut-off values for LNR, log odds of positive lymph nodes, and number of pathologically positive nodes. Results: On multivariable analysis, we identified a LNR ≥0.078/0.079, the presence of at least three pathologically positive nodes, and ENE as independent prognosticators for 5-year disease-specific survival (DSS) and overall survival (OS) rates. We therefore devised a four-point prognostic scoring system according to the presence or absence of each variable. The 5-year DSS and OS rates of patients with scores of 0-3 were 70%/62%/50%/36% (p <0.0001) and 61%/52%/40%25%, respectively (p <0.0001). On analyzing the AJCC 2017 pN classification, patients with pN3a displayed better survival rates than those with pN2 disease. The 5-year DSS and OS rates of patients with pN1/pN2/pN3a/pN3b disease were 72%/60%/67%/43% (p <0.0001) and 63%/51%/67%/33%, respectively (p <0.0001). Conclusions: Three nodal parameters (i.e., a LNR ≥0.078/0.079, the presence of at least three pathologically positive nodes, and ENE) assessed in combination provided a better prognostic stratification than the traditional AJCC pN classification.

Factors affecting patients with concurrent deep neck infection and aspiration pneumonia.

BACKGROUND: Deep neck infection (DNI) is a life-threatening condition of the deep neck spaces with potential to obstruct the airway. Aspiration pneumonia (AP), which results from aspiration of colonized oropharyngeal or upper gastrointestinal contents, is a respiratory infection that affects the lungs, wherein the air sacs are filled with purulent fluid. The cooccurrence of these two diseases can cause severe damage to the respiratory system, leading to morbidity and mortality. However, the risk factors for concurrent DNI and AP have not yet been investigated. This study aimed to address this issue. METHODS: A total of 561 DNI patients were enrolled in this study between June 2016 and December 2021. Among these patients, 26 had concurrent DNI and AP at the time of diagnosis. Relevant clinical variables were assessed. RESULTS: In the univariate analysis, age > 60 years (OR = 3.593, 95% CI: 1.534-8.414, p = 0.002), C-reactive protein (OR = 1.005, 95% CI: 1.001-1.008, p = 0.003), involvement of ≥3 spaces (OR = 4.969, 95% CI: 2.051-12.03, p < 0.001), and retropharyngeal space involvement (OR = 4.546, 95% CI: 1.878-11.00, p < 0.001) were significant risk factors for concurrent DNI and AP. In the multivariate analysis, age > 60 years (OR = 2.766, 95% CI: 1.142-6.696, p = 0.024) and retropharyngeal space involvement (OR = 3.006, 95% CI: 1.175-7.693, p = 0.021) were independent risk factors for concurrent DNI and AP. The group with concurrent DNI and AP had longer hospital stays (p < 0.001) and lower rates of incision and drainage (I&D) open surgery (p = 0.020) than the group with DNI alone. There were no significant differences in pathogens (p > 0.05) between the groups. CONCLUSIONS: Both DNI and AP can independently compromise the airway, and the concurrence of these two conditions makes airway protection more difficult. Age > 60 years and retropharyngeal space involvement were independent risk factors for the concurrence of DNI and AP. The group with concurrent DNI and AP had longer hospital stays and lower rates of I&D open surgery than the group with DNI alone. There were no differences in DNI pathogens according to concurrent AP status.

Clinical outcomes of patients with pT4a and pT4b oral cavity squamous cell carcinoma who had undergone surgery: Results from a Taiwanese registry-based, nationwide cohort study.

OBJECTIVES: While the NCCN guidelines maintain that T4b oral cavity squamous cell carcinoma (OCSCC) should undergo either non-surgical treatments or clinical trials, promising outcomes of T4b OCSCC having surgical excision have been reported. We analyzed and compared the clinical outcomes of Taiwanese patients with pT4a and pT4b OCSCC who had undergone surgical treatment. METHODS: From 2011 to 2017, a total of 4031 and 355 patients with first primary pT4a and pT4b OCSCC were identified. A propensity score (PS)-matched analysis of patients (n = 351 each) for pT4a and pT4b tumors was also performed. RESULTS: The 5-year disease-specific and overall survival (DSS/OS) rates were more favorable in patients with pT4a than in those with pT4b OCSCC (64%/55%, p < 0.0001; 55%/43%, p < 0.0001, respectively). Compared with pT4a, those with pT4b tumors had a higher burden of the following risk factors: buccal/retromolar/hard palate subsite, male sex, depth ≥ 10 mm, and positive margins. Before PS matching, multivariable analyses revealed that pT4b tumors (versus pT4a) were an adverse prognosticator for both 5-year DSS and OS (hazard ratios: 1.32 and 1.39, respectively). However, in the PS-matched cohort, no significant differences in 5-year DSS and OS rates were observed between pT4a and pT4b OCSCC (57%/56%, p = 0.4024; 48%/44%, p = 0.1807, respectively) CONCLUSIONS: No significant outcome differences were evident between pT4b and pT4a OCSCC after PS matching. The most plausible hypothesis for the observed survival difference between T4a and T4b tumors is that it was driven by positive margins. We suggest that T4b OCSCC should undergo initial surgical excision if adequate resection is possible.

Improved prognostic stratification of patients with pN3b oral cavity cancer based on maximum standardized uptake value of metastatic nodes, lymph node ratio, and level of cervical nodal metastases.

OBJECTIVES: The prognosis of pN3b oral cavity squamous cell carcinoma (OCSCC) remains heterogeneous. We sought to improve the prognostic stratification of patients with pN3b OCSCC through a combined analysis of FDG-PET parameters and clinicopathological risk factors (RFs). METHODS: From 2001 to 2019, complete data on maximum standardized uptake values derived from FDG-PET of neck metastatic nodes (SUV-nodal-max) and clinicopathological RFs were available for 257 patients with pN3b disease. RESULTS: Using the 5-year disease-free survival (DFS) as the outcome of interest, the optimal cutoff points for SUV-nodal-max and lymph node ratio (LNR) were 15.9 and 0.17, respectively. The 5-year DFS rates/(number of cases) for patients with pN3b disease were as follows: SUV-nodal-max < 15.9 versus ≥ 15.9, 49%(226)/21%(31), p = 0.000003; LNR < 0.17 versus ≥ 0.17, 49%(230)/17%(27), p = 0.000117; absence versus presence of neck level IV/V metastases, 49%(230)/15%(27), p = 0.000004. Multivariable analyses revealed that SUV-nodal-max ≥ 15.9, LNR ≥ 0.17, and level IV/V metastases were independent prognosticators for 5-year distant metastases (DM), DFS, disease-specific survival (DSS), and overall survival (OS) rates. Based on these variables, we devised a scoring system that identified three distinct prognostic subgroups at low (score 0, n = 190), intermediate (score 1, n = 51), and high (scores 2-3, n = 16) risk. The 5-year rates of patients with pN3b disease deemed to be at low/intermediate/high risk were as follows: DM, 31%/52%/89%; DFS, 54%/26%/0%; DSS, 59%/36%/8%; OS, 42%/31%/6%, respectively; all p < 0.001. CONCLUSIONS: A scoring system based on SUV-nodal-max, LNR, and level IV/V metastases improves the prognostic stratification of OCSCC patients with pN3b disease.

cN+pN0 disease does not portend a less favorable prognosis compared with cN0pN0 in patients with resected oral cavity squamous cell carcinoma.

BACKGROUND: We compared the clinical outcomes of patients with oral cavity squamous cell carcinoma (OCSCC) with cN+pN0 versus cN0pN0 disease. METHODS: A total of 1309 OCSCC patients with pN0 disease were included. Of them, 1019 and 290 cases had cN0pN0 and cN+pN0 disease, respectively. For comparison purposes, we also examined 799 patients with pN+disease (cN0pN+/cN+pN+, n = 239/560). Subgroup analysis was performed in a propensity score-matched cohort with cN0pN0 and cN+pN0 disease (n = 284 each). RESULTS: Compared with cN0pN0, patients with cN+pN0 had a higher prevalence of the following variables: betel chewing, pT3-4, depth ≥10 mm, perineural invasion, and treatment with surgery and adjuvant therapy. The prognosis of patients with cN+pN0 (mean: 52 nodes) and cN0pN0 (mean: 39 nodes) disease was similar both in the original cohort and after propensity score matching. However, the 5-year outcomes were more favorable for cN+pN0/cN0pN0 compared with cN0pN+/cN+pN+ (local control, 88%/88%/83%/81%; neck control, 94%/93%/82%/76%; distant metastases, 4%/3%/13%/31%; disease-free survival, 84%/83%/68%/52%; disease-specific survival, 92%/92%/77%/57%; overall survival, 81%/82%/59%/42%; all p values <0.001; cN+pN0 versus cN0pN0, all p values >0.05). cN+pN0 disease (vs. cN0pN0) was not significantly associated with local control, neck control, distant metastases, and survivals either in univariable or multivariable analyses. CONCLUSIONS: Despite a higher risk factor burden, the prognosis of patients with cN+pN0 disease did not differ from that of cases with cN0pN0. The higher nodal yield and the more frequent use of adjuvant therapy in cN+pN0 disease may explain the lack of significant differences in terms of neck control compared with cN0pN0 disease.

Poor tumor differentiation is an independent adverse prognostic variable in patients with locally advanced oral cavity cancer--Comparison with pathological risk factors according to the NCCN guidelines.

METHODS: We sought to compare the prognostic impact of tumor differentiation with respect to adverse risk factors (RFs) identified by the National Comprehensive Cancer Network (NCCN) guidelines--including extranodal extension (ENE), positive/close margins, perineural invasion, lymphatic invasion, and vascular invasion--in patients with locally advanced oral cavity squamous cell carcinoma (OCSCC). RESULTS: Between 1996 and 2018, 1179 consecutive patients with first primary pT3-4 OCSCC were included. A three-level grading system was adopted--in which the final classification was assigned according to the most prevalent tumor grade. We identified 382/669/128 patients with well/moderately/poorly differentiated tumors, respectively. Compared with well/moderately differentiated tumors, poorly differentiated OCSCC had a higher prevalence of the following variables: female sex (4%/6%/11%), ENE, (14%/36%/61%), positive margins (0.5%/2%/4%), close margins (10%/14%/22%), perineural invasion (22%/50%/63%), lymphatic invasion (2%/9%/17%), vascular invasion (1%/4%/10%), and adjuvant therapy (64%/80%/87%). The 5-year rates of patients with well/moderately/poorly differentiated OCSCC were as follows: local control (LC, 85%/82%/84%, p = 0.439), neck control (NC, 91%/83%/70%, p < 0.001), distant metastases (DM, 6%/18%/40%, p < 0.001), disease-free survival (DFS, 78%/63%/46%, p < 0.001), disease-specific survival (DSS, 85%/71%/49%, p < 0.001), and overall survival (OS, 68%/55%/39%, p < 0.001). Multivariable analysis identified the following variables as independent prognosticators for 5-year outcomes: ENE (LC/NC/DM/DFS/DSS/OS), poorly differentiated tumors (NC/DM/DFS/DSS/OS), positive margins (LC/DFS), lymphatic invasion (DFS/DSS/OS), perineural invasion (DM), and age ≥65 years (OS). CONCLUSIONS: In addition to ENE, poor tumor differentiation was identified as the second most relevant adverse RF for patients with pT3-4 OCSCC. We suggest that the NCCN guidelines should include poor tumor differentiation as an adverse RF to refine and tailor clinical management.

Prognostic stratification of patients with AJCC 2018 pStage IVB oral cavity cancer: Should pT4b and pN3 disease be reclassified?

OBJECTIVES: pStage IVB oral cavity squamous cell carcinoma (OCSCC) is defined as either pT4b or pN3 disease. We sought to devise an improved prognostic stratification of this patient group. METHODS: Between December 2003 and January 2018, we retrospectively reviewed the clinical records of 1331 consecutive patients with OCSCC who received tumor excision and neck dissection. The number of patients with pT4a/pT4b, pT1N3b/pT2N3b/pT3N3b/pT4N3b, and pStage IVA/IVB was 370/83, 3/49/42/142, and 332/295, respectively. RESULTS: The 5-year rates of disease-free survival (DFS) and disease-specific survival (DSS) for patients with pT4a/pT4b disease were 64%/63% (p = 0.973) and 72%/69% (p = 0.672), respectively. The 5-year DFS and DSS rates for patients with pT1N3b/pT2N3b/pT3N3b/pT4N3b disease were 67%/65%/40%/42% (p < 0.001; pT1-2N3b versus pT3-4N3b, p = 0.002) and 100%/68%/45%/49% (p < 0.001; pT1-2N3b versus pT3-4N3b, p = 0.002), respectively. We devised a new definition for pStage IV by considering patients with pT4bN0-2 and pT1-2N3b diseases as pStage-IVA. The number of patients with pStage IVA/IVB (pT3-4N3b) was 443/184. The 5-year rates of AJCC pStage IVA/IVB and the newly proposed pStage IVA/IVB (pT3-4N3b) were as follows: DFS, 74%/52% and 72%/42%; DSS, 83%/58% and 81%/47%; respectively, all p value < 0.001. CONCLUSIONS: The clinical outcomes of pT4b and pT4a OCSCC are similar. However, patients with pT3-4N3b disease have a less favorable 5-year prognosis compared with cases with pT1-2N3b. In light of the unfavorable outcomes, pT3-4N3b disease should continue to be classified as pStage IVB. Conversely, pT4bN0-2 and pT1-2N3b diseases portend a less adverse prognosis and should therefore be downstaged to pStage IVA.

Clinical outcomes of Taiwanese patients with resected squamous cell carcinoma of the upper and lower gum.

OBJECTIVES: This large-scale cohort study was designed to compare the clinical outcomes of Taiwanese patients with squamous cell carcinoma (SCC) of the upper versus lower gum. METHODS: Between 2004 and 2017, we identified 4244 patients with first primary SCC of the gum (694 upper gum; 3550 lower gum) who were treated with surgery either with or without adjuvant therapy. Of them, 1990 patients (329 upper gum; 1661 lower gum) enrolled from 2011 to 2017 had a higher number of histopathological variables and entered subgroup analyses. Five-year disease-specific survival (DSS) and overall survival (OS) rates served as outcome measures. RESULTS: The 5-year DSS and OS rates of patients with upper gum SCC were lower than those of cases with lower gum SCC (65%/74%, p < 0.0001; and 55%/65%, respectively, p < 0.0001). Compared with lower gum SCC, upper gum SCC had a higher prevalence of the following variables: female sex, age ≥ 65 years, pNx (without neck dissection), no-betel chewing (2011-2017), no-smoking (2011-2017), and margin status ≤ 4 mm (positive and close margins, 2011-2017). On multivariable analysis, gum subsite (upper versus lower), age (≥65 versus < 65 years), pT (T3 - 4 versus T1 - 2), pN (N1 - 3 versus N0/Nx), depth (≥10 mm versus < 10 mm, 2011-2017), ENE (present versus absent, 2011-2017), and margins (≤4 mm versus > 4 mm 2011-2017, only DSS) were identified as independent adverse prognostic factors for 5-year DSS and OS. CONCLUSIONS: Compared to lower gum SCC, upper gum SCC had less favorable 5-year outcomes. Wide resection margins are recommended to improve prognosis of upper gum SCC.

A combined analysis of maximum standardized uptake value on FDG-PET, genetic markers, and clinicopathological risk factors in the prognostic stratification of patients with resected oral cavity squamous cell carcinoma.

OBJECTIVE: Clinical outcomes of patients with resected oral cavity squamous cell carcinoma (OCSCC) chiefly depend on the presence of specific clinicopathological risk factors (RFs). Here, we performed a combined analysis of FDG-PET, genetic markers, and clinicopathological RFs in an effort to improve prognostic stratification. METHODS: We retrospectively reviewed the clinical records of 2036 consecutive patients with first primary OCSCC who underwent surgery between 1996 and 2016. Of them, 345 underwent ultra-deep targeted sequencing (UDTS, between 1996 and 2011) and 168 whole exome sequencing (WES, between 2007 and 2016). Preoperative FDG-PET imaging was performed in 1135 patients from 2001 to 2016. Complete data on FDG-PET, genetic markers, and clinicopathological RFs were available for 327 patients. RESULTS: Using log-ranked tests based on 5-year disease-free survival (DFS), the optimal cutoff points for maximum standardized uptake values (SUV-max) of the primary tumor and neck metastatic nodes were 22.8 and 9.7, respectively. The 5-year DFS rates were as follows: SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7 (n = 77) versus SUVtumor-max < 22.8 and SUVnodal-max < 9.7 (n = 250), 32%/62%, P < 0.001; positive UDTS or WES gene panel (n = 64) versus negative (n = 263), 25%/62%, P < 0.001; pN3b (n = 165) versus pN1-2 (n = 162), 42%/68%, P < 0.001. On multivariate analyses, SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7, a positive UDTS/WES gene panel, and pN3b disease were identified as independent prognosticators for 5-year outcomes. Based on these variables, we devised a scoring system that identified four distinct prognostic groups. The 5-year rates for patients with a score from 0 to 3 were as follows: loco-regional control, 80%/67%/47%/24% (P < 0.001); distant metastases, 13%/23%/55%/92% (P < 0.001); DFS, 74%/58%/28%/7% (P < 0.001); and disease-specific survival, 80%/64%/35%/7% (P < 0.001) respectively. CONCLUSIONS: The combined assessment of tumor and nodal SUV-max, genetic markers, and pathological node status may refine the prognostic stratification of OCSCC patients.

Tumor Depth of Invasion (Tumor > 4 cm/Depth > 10 mm and Depth > 20 mm) and Through Cortex/Skin Invasion are Both Valid Criteria for Classifying Tumors as pT4a in AJCC 2018 Oral Cavity Cancer Staging System.

BACKGROUND: According to the AJCC third to seventh edition staging manuals (1988-2010), the presence of through cortex and/or skin invasion in oral cavity squamous cell carcinoma (OCSCC) identifies T4a tumors. The AJCC eighth edition (2018) introduced a depth of invasion (DOI) > 20 mm as a criterion for pT4a. Subsequently, a revision maintained that tumors > 4 cm with a DOI > 10 mm should be classified as pT4a. We sought to analyze the prognostic impact of the three distinct criteria identifying pT4a disease. METHODS: We examined 667 consecutive patients with pT3-4 buccal/gum/hard palate/retromolar SCC who underwent surgery between 1996 and 2016. pT1/pT2 (n = 108/359) disease were included for comparison purposes. RESULTS: The 5-year outcomes of patients with pT1/pT2/without (n = 406)/with tumor > 4 cm/DOI > 10 mm (n = 261), pT1/pT2/DOI ≤ 20 mm (n = 510)/> 20 mm (n = 157), and pT1/pT2/without (n = 305)/with through cortex/skin invasion (n = 362) were as follows: disease-specific survival (DSS), 98%/89%/79%/65%, p < 0.001, 98%/89%/78%/59%, p < 0.001, and 98%/89%79%/69%, p < 0.001; overall survival (OS), 90%/79%/63%/51%, p < 0.001, 90%/79%/63%/42%, p < 0.001, and 90%/79%/65%/52%, p < 0.001. In pT3-4 disease, a tumor > 4 cm/DOI > 10 mm was an independent adverse prognosticator for 5-year DSS rate, DOI > 20 mm was an independent adverse prognosticator for 5-year DSS and OS rates, whereas through cortex/skin invasion independently predicted 5-year OS rates. CONCLUSIONS: All of the three criteria (tumor > 4 cm/DOI > 10 mm, DOI > 20 mm, and through cortex/skin invasion) identify high-risk patients, which should be reflected in further revisions of pT4a classification in OCSCC.

Prognostic significance of combined pretreatment lymphocyte counts and body mass index in patients with head and neck cancer treated with radiation therapy.

We aimed to investigate the prognostic significance of combined pretreatment lymphocyte counts (LCs) and body mass index (BMI) in patients with head and neck cancer (HNC) treated with radiation therapy (RT). Nine hundred and twelve patients with HNC who were treated with RT were retrospectively reviewed. Survival was analyzed by stratifying the patients according to pretreatment LCs and BMI. Patients with low pretreatment LCs and BMI were characterized by a more advanced T stage, fewer nasopharyngeal subsites, less smoking and drinking, and fewer comorbidities. Patients with low pretreatment LCs and BMI had a significantly poorer overall and distant metastasis-free survival than those with high pretreatment LCs and BMI. No significant differences were observed in terms of local or regional recurrence-free survival. Combined pretreatment LCs and BMI may be more effective at predicting overall and distant metastasis-free survival in patients with HNC treated with RT.

Incidence and Outcomes of Patients With Oral Cavity Squamous Cell Carcinoma and Fourth Primary Tumors: A Long-term Follow-up Study in a Betel Quid Chewing Endemic Area.

The aim of this study was to explore the incidence and outcomes of patients with oral cavity squamous cell carcinoma (OSCC) and fourth primary tumors (PTs) in a betel-chewing endemic area.We retrospectively examined the records of 1836 OSCC patients who underwent radical tumor resection between 1996 and 2014. The outcome measures included the incidence and number of multiple PTs, the main risk factors, and their associations with overall survival (OS).Of the 1836 patients, 1400 (76.3%) had a single PT, 344 (18.7%) a second PT, 67 (3.6%) a third PT, and 25 (1.4%) a fourth PT. Univariate analyses (log-rank test) identified the following factors as significantly associated with a fourth PT: simultaneous first and second PTs, betel quid chewing, buccal subsite, and pT3-4 status. After allowance for the potential confounding effect of other risk factors, all of these factors retained their independent prognostic significance in stepwise multivariate analyses, the only exception being betel chewing. The incidences of second, third, and fourth PTs at 5 and 10 years were 20.2%/34.6%, 4.0%/8.6%, and 1.0%/2.3%, respectively. The 5 and 10-year OS rates (calculated from the diagnosis of each PTs) for patients with a single, second, third, and fourth PTs were 68%/61%, 43%/37%, 45%/39%%, and 30%/30%, respectively (P < 0.0001). Among patients with a fourth PT, those who underwent radical surgery showed a significantly higher 3-year OS than those who did not (57% vs 13%; P = 0.0442).Fourth PTs are rarely observed in OSCC patients in a betel quid-chewing endemic area. Long-term survival rates of patients treated with radical surgery seems acceptable, being 4-fold higher than their counterparts.