Abstract
Background
Operable stage IV gingivobuccal complex cancer is classified as Stage IVA and IVB. Among patients with Stage IVA disease, different subgroups with likely different prognoses are combined. Patients with advanced nodal status tend to have a poorer prognosis. We divided these patients into four groups: group I (T4aN0), group II (T4aN1-2), group III (T1-3N2) constituting stage IVA category, and group IV (TanyN3) representing stage IVB. This study assesses if these patients can be prognostically subgrouped based on nodal status.
Methods
It is a prospective observational study done at a tertiary care center from July 2017 to June 2020. This study aims to analyze survival outcomes in these subgroups using Kaplan Meir, univariate and multivariate analysis.
Results
The study enrolled 113 patients of operable gingivobuccal complex stage IVA cancer with a median follow up of 26 months, disease-free survival (DFS) was 74% for group 1, while it was 55%, 26% and 32.2% for group 2, group 3 and group 4 respectively. Patients with T4N3 disease had DFS of just 15%. Patients in group 3 and 4 had the worst outcomes in terms of DFS and Overall Survival(OS) with HR-3.7 and 3.3 and 3.3 and 3.8 respectively (p value-0.001).
Conclusion
The nodal status is the most important prognostic factor affecting DFS and OS. Patients with small primary but advanced nodal stage do poorly than patients with advanced primary and node-negative disease. There is a need for subgrouping patients with Stage IVA tumors based on nodal status for better prognostication.
Keywords: Gingivobuccal, Nodal status, Stage IV, Subgrouping, Survival
Introduction
Squamous cell carcinoma of the gingivobuccal complex is predominantly a problem in a country like India where tobacco chewing is the main culprit for these cancers [1, 2]. The gingivobuccal complex includes the buccal mucosa, lower gingivobuccal sulcus, lower gingiva, and retromolar trigone. These cancers mostly present in the advanced stages requiring morbid surgeries [1, 2].
AJCC 8th edition recognizes buccal mucosa, lower alveolus and retromolar trigone as separate sites while the classification of gingivobuccal sulcus tumors is done with buccal mucosa or lower alveolus depending on the epicenter of the disease [3].
As per AJCC 8th edition, the Stage IV cancers are divided into Stage IVA and stage IVB [3]. Based on the nodal status, stage IVA can be further stratified into three groups. These include cancers with advanced primary i.e. T4 and either N0 or N1–N2 nodes or cancers with early (T1–T2) or intermediate primary (T3) and N2 nodes. Stage IVB includes very advanced cancers that involve masticator space, prevertebral space, or patients with a very advanced nodal disease (N3) either by size > 6 cm or because of multiple nodes with one of them having perinodal extension [3]. Only selected patients are eligible for upfront surgery among these Stage IVB patients.
Patients with Stage IVA constitute these different groups of patients with likely different prognoses based on nodal status [4]. It is expected that patients with small or intermediate primary tumors but advanced nodal status (T1-T2N2-3 and T3N2-3) are likely to do worse than patients with advanced primary and negative nodes (T4aN0) [4]. We divided our patients of upfront operable stage IV gingivobuccal cancers into four subgroups-group I- T4aN0, group II-T4N1-2, group III-T1-3N2, group IV- TanyN3. This study was undertaken to assess survival analysis in these subgroups of patients.
Materials and Methods
The study was conducted in Prince Aly Khan Hospital, Mumbai, a tertiary care center for head and neck cancer. The patients were recruited between July 2017 and May 2018. The sample size was calculated using the proportion of relative precision with the DFS rate taken as 60% at the end of 2 years according to previous studies. Sample size calculated as 113.
All patients with previously untreated operable stage IV gingivobuccal complex cancers were included in the study. Patients were staged according to AJCC 8th edition [3]. The judgment of operability was made based on clinical examination, cross-sectional imaging, and if need be examination under anesthesia. Patients with fixed neck node disease or with the involvement of high ITF (cT4b) and patients who were offered neoadjuvant treatment were not included in the study. Patients who had multifocal disease and those who were treated previously with any of the three modalities (surgery, radiation, or chemotherapy) were excluded from the study.
Detailed clinical history, examination of head and neck, and metastatic workup was done. As per the Institution protocol, Wide excision of the lesion along with or without mandibulectomy and elective modified radical or radical neck dissection. Appropriate reconstruction was done for all the cases. After surgery, histopathological analysis of the resected specimen was recorded as part of data collection for all the cases. Adjuvant treatment was given in the form of radiation therapy or chemoradiation therapy. Adjuvant chemoradiation was given to patients with perinodal extension or margin positive disease. Patients were followed up every 3 months in the first year and then every 4 months in the second year and every 6 months in the third year after surgery and adjuvant treatment. During the follow-up, patients were examined clinically as well as using appropriate investigations as and when needed to see the recurrence at the primary site, neck and distant organs as per the institution's protocol.
Patients were stratified into four groups based on nodal disease as stated above. This study aims to find out the difference in DFS, OS, and recurrence rate in these subgroups and thus impact of nodal status in these subgroups.
Statistical Methods
Data was descriptively reported using mean, median and IQR depending on the normality of the data for continuous variables and in frequencies and percentage for categorical variables. The Kaplan Meier analysis was run using the log-rank test to test the difference in survival distributions between the categories. Variables with a p value of less than 0.05 were considered for multivariate cox regression analysis with backward LR. In the final model, variables with a p value of less than 0.05 were considered statistically significant.
DFS was calculated in months from the date of surgery to the date of first observed recurrence of disease (local, regional or locoregional) or metastatic disease or second primary. Overall survival is calculated in months from the date of surgery to the death due to any cause.
Two-year disease-free survival (DFS) and 2-year overall survival (OS) percentage with the 95% confidence interval were reported.
The locoregional recurrence rate was calculated as the percentage of patients who developed local, regional, or both recurrences after surgery upon total patients in the group in the study period. Data were analyzed using RStudio software version 1.1.442 and IBM SPSS 25.
Results
In our study, 113 patients fulfilling the inclusion criteria were initially recruited. Out of these, 5 patients were lost to follow up. 4 patients died during treatment due to treatment-related morbidity. 104 patients were taken for the final oncological analysis. The median follow up was 26 months (range-1–35 months). Out of these 104 patients, 4 patients died due to causes unrelated to the disease during their follow up course. There were 26 local and regional recurrences, 5-s primaries in the oral cavity, 15 distant metastasis observed during the study follow up. One patient who developed local recurrence was operated and is disease-free at present. Local and regional recurrence rate was 25% with the median time to recurrence of 9 months. The 2-year DFS and OS was 52.5% and 53.3% respectively for the whole group.
Most of the patients were male (86.5%) with a male to female ratio of 6:1. The majority of the patients underwent Segmental Mandibulectomy (67%) followed by Bite composite resection (16.8%). 13.2% of cases underwent wide excision of the buccal mucosa. Marginal mandibulectomy was done in 2.7% cases. (Table 1).
Table 1.
Distribution of surgical treatment (n = 113)
| Surgery | Number of patients | % |
|---|---|---|
| Wide excision buccal mucosa | 15 | 13.2% |
| Marginal mandibulectomy | 3 | 2.7% |
| Mandibulectomy | 76 | 67.2% |
| Bite composite resection | 19 | 16.8% |
The majority of the defects were reconstructed using pectoralis major myocutaneous flaps (48.7%) followed by submental flaps (25.7%) and free microvascular flaps (9.7%). Primary closure was done in 9.7% cases while local rotation flap and nasolabial flap was utilized in 5% and 1% cases.
Local and regional recurrence rate was 15.7% while 2-year DFS was 74% in group I i.e. patients with advanced primary and node-negative tumors (T4aN0). The recurrence rate was 22.2% and DFS was 55% in group II (T4N1-2) while group III i.e. patients with early or intermediate primary with N2 disease (T1-3N2) had a recurrence rate of 47.3% and DFS of 26.3%. Group IV which included patients with advanced neck node disease and any primary (T1-4N3) had local and regional recurrence rate of 22.5% while DFS was 32.2%. On further analysis, the patients with T4N3 had a local and regional recurrence rate of 30.7% and DFS of just 15.2%. The group distribution & their follow-ups are presented in Table 2.
Table 2.
Disease free survival (DFS) of different groups (n = 104)
| AJCC stage group | Groups | T and N Stage | Number of patients | NED | Recurrence | 2nd Primary | Distant mets | DOOC | Recurrence % | DFS % |
|---|---|---|---|---|---|---|---|---|---|---|
| Stage IVA | Group I | T4N0 | 38 | 28 | 6 | 2 | 2 | - | 15.7% | 74% |
| Group II | T4N1-2 | 16 | 10 | 4 | 2 | - | - | 22.2% | 55% | |
| Group III | T1-3N2 | 19 | 5 | 9 | 1 | 4 | - | 47.3% | 26.3% | |
| Stage IVB | Group IV | T1-4N3 | 31 | 12 | 7 | 1 | 7 | 4 | 22.5% | 32.2% |
NED No evidence of disease, DOOC Died of other cause
We analyzed the DFS and OS in these groups based on Kaplan Meire analysis (Figs. 1, 2) and univariate and multivariate analysis. We found that the patients with group III and group IV had worse DFS with a hazard ratio of 3.7–3.6 respectively (p value-0.001) and overall survival with a hazard ratio of 3.3–3.8 (p value- 0.004 and 0.001 respectively) (Table 3).
Fig. 1.
Kaplan Meir survival curve for disease free survival (DFS) for various groups
Fig. 2.
Kaplan Meire curve for overall survival (OS) for various groups
Table 3.
Multivariate analysis of disease free survival (DFS) & overall survival (OS) for various groups
| Disease free survival(DFS) | n | Events | 2 years survival | 95% LCL | 95% UCL | Exp(B) | Lower@(95% CI) | Upper@(95% CI) | Significance |
|---|---|---|---|---|---|---|---|---|---|
| Groups = Group I | 38 | 10 | 0.73 | 0.6 | 0.889 | ||||
| Groups = Group2 | 16 | 6 | 0.625 | 0.428 | 0.914 | 1.444 | 0.525 | 3.973 | 0.477 |
| Groups = Group3 | 19 | 14 | 0.316 | 0.163 | 0.612 | 3.744 | 1.660 | 8.447 | 0.001 |
| Groups = Group4 | 31 | 20 | 0.355 | 0.221 | 0.57 | 3.636 | 1.697 | 7.789 | 0.001 |
| Overall survival(OS) | n | Events | 2 years survival | 95% LCL | 95% UCL | Exp(B) | Lower | Upper | Significance |
| Groups = Group I | 38 | 10 | 72.7% | 59.6% | 88.8% | ||||
| Groups = Group II | 16 | 6 | 68.8% | 49.4% | 95.7% | 1.445 | 0.525 | 3.979 | 0.476 |
| Groups = Group III | 19 | 13 | 31.6% | 16.3% | 61.2% | 3.320 | 1.453 | 7.587 | 0.004 |
| Groups = Group IV | 31 | 20 | 35.5% | 22.1% | 57.0% | 3.814 | 1.781 | 8.168 | 0.001 |
LCL Lower confidence limit, UCL Upper confidence limit
The pathological nodal stage was divided as per AJCC 8th edition. 36.5% of patients had N0 disease, 8.6% of cases had N1 disease, 2% of cases had N2a disease, 23% of cases had N2b disease, 30% of cases had N3b disease. The pathological nodal stage (pN) was found to be a significant prognostic factor on Kaplan Meire analysis for DFS and OS with p value-0.003 and 0.002 (Figs. 3, 4). In both the univariate and multivariate analysis for Cox regression (Table 4), the nodal disease was found to be a significant prognostic factor for DFS and overall survival with a hazard rate of 3.1 and 2.9 (p value-0.018 and 0.032) respectively on multivariate analysis.
Fig. 3.
Kaplan Meire survival curve for disease free survival (DFS) for various nodal stage
Fig. 4.
Kaplan Meire survival curve for overall survival (OS) for various nodal stage
Table 4.
Multivariate analysis for disease free survival (DFS) and overall survival (OS) based on nodal stage
| (a) Multivariate analysis for DFS | ||||
|---|---|---|---|---|
| No (ref) | HR | 95% CI for HR | p value | |
| N1 | 1.480 | 0.456 | 4.805 | 0.514 |
| N2 | 3.186 | 1.219 | 8.322 | 0.018 |
| N3 | 4.250 | 0.367 | 49.199 | 0.247 |
| (b) Multivariate analysis for OS | ||||
|---|---|---|---|---|
| No (ref) | HR | 95% CI for HR | p value | |
| N1 | 1.505 | 0.462 | 4.897 | 0.497 |
| N2 | 2.910 | 1.099 | 7.708 | 0.032 |
| N3 | 3.569 | 0.301 | 42.322 | 0.313 |
HR Hazard ratio
Discussion
In India, most of the gingivobuccal complex cancers present at an advanced stage [1, 2]. As an oncologist, one needs to prognosticate these patients in terms of survival and recurrence rate. These advanced gingivobuccal complex cancers have been divided into Stage IVA and IVB by AJCC staging [3].
Although clubbed together in AJCC staging, patients in stage IVA can be divided into three groups (group I- T4aN0, group II-T4N1-2, group III-T1-3N2) as stated previously. Patients with operable upfront stage IVB cancers with advanced N3B nodal status were assigned group IV. We did not include patients with T4b tumors in the study.
In these subgroups of operable stage IV GBC cancers, some patients will have a long disease-free and overall survival while others will have quick locoregional or distant failures [1, 2, 4].
In our study, the local and regional recurrence rate was 25% with a median follow up of 26 months in the whole group of Stage IV operable gingivobuccal complex cancers. The median time to recurrence was 9 months. 2 years disease-free survival (DFS) was 52.5% and overall survival (OS) was 53.3%. This is comparable to various studies [2, 5–7]including MSKCC-PMH data where 2 years OS was found to be 51% and highlights the aggressive nature of the disease in these advanced gingivobuccal complex cancer patients [3].
AJCC/UICC staging has undergone several modifications in the past three decades based on suggestions by several independent studies including the incorporation of depth and extracapsular extension in the staging system [3, 8, 9]. Despite the incorporation of these changes, AJCC staging does not give meaningful information about the prognosis of patients in certain stage groups [4, 8]. For instance, the subset of stage IVA patients can be divided based on nodal staging into three prognostic groups as highlighted in the study. A retrospective study from Taiwan by Liao et al. highlighted the difference in prognosis between T4aN0 patients and T4N1-2. In their series, patients with the T4aN0 category had a similar outcome as stage III disease [4]. Similarly, a study by Mair et al. tried to divide stage IVA and stage IVB tumors based on the involvement of primary tumor extent in the form of masticator space involvement [10]. In our study, we tried to divide stage IV patients based on nodal status.
In our study, Group I which comprised of patients with node-negative disease had the best outcome amongst all the subgroups with a 2-year DFS rate of 74% and local and regional recurrence rate of 15.7%. In comparison, patients with small to intermediate primary with N2 nodes (group III) fared poorly with a 2-year local and regional recurrence rate of 47% and DFS of 26% respectively. We found the difference in DFS and OS between these two subsets of patients highly significant based on a hazard ratio of 3.7–3.3 for DFS and OS respectively (p value-0.001 and 0.004 respectively). This points out that although these two subsets of patients belong to AJCC stage IVA, they have a huge difference in prognosis in terms of DFS, OS, and local and regional recurrence rates.
AJCC 8th edition incorporated extracapsular extension as part of nodal staging based on several reports highlighting its prognostic value and poorer outcomes in patients with the extracapsular extension [1–3, 11–13]. In our study, patients with advanced node disease (N3b) irrespective of their primary tumor stage had a 2-year DFS of 32.2% which compared to patients in group I had a hazard ratio of 3.6–3.8 respectively for DFS and OS (p value-0.001). Among patients with N3b nodal status, patients with the T4aN3b stage had the worst outcome with a 2-year DFS of just 15.2%. This underscores the importance of nodal status and extracapsular extension in these subsets of advanced gingivobuccal complex cancers.
The role of nodal status as the most important prognostic factor in oral malignancies is not new. There have been multiple studies that showed lymph node metastasis as a predictor for poor locoregional control [1, 2, 14]. A retrospective study of 642 advanced gingivobuccal cancer patients from a high volume tertiary care center in India showed lymph node metastasis as one of the most significant predictors for locoregional control in Stage III and IV gingivobuccal cancers [1]. Similarly in our study, we found nodal status to be a significant factor for DFS and OS on multivariate analysis with HR of 3.1 and 2.9 respectively (p value-0.018 and 0.032). Our study highlighted the role of nodal status in stratifying these operable Stage IV gingivobuccal complex cancer patients further into prognostic subgroups.
Although nodal status is the most important prognostic factor, there are other pathological factors which are not yet part of TNM staging that might also influence the prognosis. These include the worst pattern of invasion [15–17], pattern of bony invasion [18], and Lymphovascular and perineural invasion [19, 20].
Various prediction models and nomograms based on clinical and pathological factors have been evaluated to prognosticate the head and neck malignancy patients as well as to assess the need for multimodality treatment, but none of them are utilized routinely for prognostication and decision making in the clinic [21–23].
As an oncologist, one needs to think about the possible solutions for the high failure rates in these patients. Based on the combined analysis of the EORTC-RTOG trial, it was recommended to give adjuvant chemoradiation to patients with perinodal extension and margin positive disease [24]. Patients with multiple neck node involvement without perinodal extension are still treated with adjuvant radiation alone. A recent National Cancer Database study showed that there was a survival benefit to use chemoradiation in patients with multiple node-positive disease [25]. Although the objective of our study was not to see the difference due to adjuvant treatment, we hypothesize that these three groups of patients in Stage IVA with different prognosis as stated in the study probably need different adjuvant treatment. Patients in group III with multiple positive nodes may be benefitted from adjuvant chemoradiation owing to high failure rates.
In the future, we believe that by stratifying the patients of operable stage IV into these groups and developing better nomograms that include various clinical and pathological factors including the ones highlighted here, we may be able to better prognosticate these patients and probably tailor the adjuvant treatment accordingly. Secondly, patients with T4aN3b group have very poor outcomes despite undergoing surgery and multimodality treatment as shown in our study.
This study is limited by small sample size and the number of patients in each group. A study with larger sample size and more number of patients in each group might have provided better statistical value to the issue addressed. Secondly, our study did not include T4b patients who are part of the stage IVB stage group.
To conclude, the nodal stage is still the most important prognostic factor for DFS and overall survival in operable stage IV gingivobuccal complex cancers. Patients with small primary and higher nodal stage tend to fare poorly compared to patients with advanced primary and node-negative disease. The study highlights the need for subgrouping stage IVA patients into different prognostic groups based on nodal status. Patients with advanced nodal disease (N3b) tend to fare worse with poor DFS and higher locoregional and distant recurrences.
Availability of Data and Material
Yes.
Acknowledgement
We like to thank Dr. Prathmesh Pai, Dr. Roshni Chinoy & Dr. Rajesh Mundhe for their valuable inputs for drafting the manuscript.
Author Contribution
SJ: Contribution—designing the study, standardizing the case selection and analysis and interpretation of data, writing the manuscript. SP, RK: Contribution—designing the study, standardizing the case selection, writing the manuscript. SM: Contribution—analysis and interpretation of data. SK: Contribution—data collection, analysis and interpretation of data. AD: Contribution—analysis and interpretation of data and writing the manuscript.
Funding
No source of funding.
Compliance with Ethical Standards
Conflicts of Interest
The author declare that they have no conflict of interest.
Consent to Participate
Consent was obtained from all the patients in the language they best understood before enrollement into the study.
Consent for Publication
Yes.
Ethical Approval
Approval of the Ethical Committee of Prince Aly Khan Hospital was obtained before the start of the study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
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