Abstract
Introduction: Patients with OSCC in India (oral squamous cell carcinoma) presents at a later stage with approximately 28% presenting at stage III and 64% at stage IV disease. In this retrospective study we have reviewed the treatment modalities rendered and outcomes associated for the management of locally advanced oral squamous cell carcinoma in our Institute. We evaluated the survival data and the factors effecting survival. Methods: Kaplan Meir method was used to evaluate OS and DFS rate and log rank test was used to compare the survival amongst groups. Cox regression analysis (univariate and multivariate) was used to evaluate the hazard ratio to find out the possible factors influencing risk of death and disease. Results: The median OS and DFS in our study were 32 and 24 months respectively. On a subset analysis of only T4b patients who underwent either upfront surgery or induction chemotherapy followed by surgery there was no significant difference in OS and DFS. All patients with TURD had partial response after induction chemotherapy and were subjected to surgical resection followed by adjuvant therapy. Conclusion: Extracapsular spread, bone involvement, skin infiltration, treatments, surgical margins and Lymph node size are the prime predictors of survival.Upfront surgery remains the standard of care for resectable LAOSCC. Induction chemotherapy might improve the resectability in technically unresectable OSCC. There is no difference in survival between concurrent chemoradiation, sequential chemoradiation and radical radiotherapy in the management of unresectable disease.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12070-023-04168-4.
Keywords: Oral cancer, Locally advanced, Radiotherapy, Chemoradiation
Introduction
Patients with OSCC in India (oral squamous cell carcinoma) presents at a later stage with approximately 28% presenting at stage III and 64% at stage IV disease [1]. In accordance with the AJCC 8th edition stage III and stage IV constitutes locally advanced oral squamous cell carcinoma (LAOSCC) without distant metastasis. T4a disease is classified as moderately advanced disease and T4b as very advanced disease in addition to disease with depth of invasion > 1 cm are classified as T3 and locally advanced disease [2]. The 5 year Overall survival in advanced disease is less than 50% [3, 4]. Locally advanced OSCC can be classified into resectable, unresectable and technically unresectable disease based on its behavior and the ability of the surgeon to achieve negative margin [5]. T4b primaries are generally considered to be unresectable and are associated with a poor overall prognosis with locoreginal control rated and disease free survival of around 30% with non surgical therapies. However, recent studies have shown that in a subset of T4b patients who underwent surgical resection had excellent loco regional control and disease free survival [6, 7]. The standard treatment for locally advanced OSCC is surgery with negative/ clear margins followed by adjuvant radiotherapy or chemoradiation [8]. The NCCN (National Comprehensive Cancer Network) lists certain special situations associated with poor outcome or difficulty in achieving tumor free margins. These are; Involvement of the pterygoid muscles, particularly when associated with severe trismus or pterygopalatine fossa involvement with cranial neuropathy, gross extension of the tumor to the skull base, direct extension to the superior nasopharynx deep extension into the Eustachian tube and lateral nasopharyngeal walls, invasion (encasement) of the common or internal carotid artery, direct extension of the neck disease to involve external skin, direct extension to mediastinal structures, prevertebral fascia, or cervical vertebrae and presence of subdermal metastases. These conditions make a disease unresectable [8–10]. The term technically unresectable disease has been used recently to describe a subset of locally advanced disease specifically within the oral cavity which responded well to induction chemotherapy to improve its resectability. These include; Buccal mucosa primary with diffuse margins and peritumoral edema extending to or above the level of zygomatic arch and without any satellite nodules, primary oral tongue tumors extending upto or below the level of hyoid bone, extension of oral tongue tumors in the valeculla, tumor extension into infratemporal fossa (supra notch tumors) and excessive skin infiltration [11].
In this retrospective study we have reviewed the treatment modalities rendered and outcomes associated for the management of locally advanced oral squamous cell carcinoma in our Institute. We evaluated the survival data and the factors effecting survival.
Patients and Methods
The following retrospective study was conducted in an Institute of National Importance in India. Records were obtained of patients who were diagnosed and treated for oral cavity squamous cell carcinoma from the records directory from January 2010-May 2023. Ethical clearance was obtained from the Institute’s Ethical committee. From the initial patient records only patients who were in stage III and stage IV oral carcinomas without distant metastasis without any prior treatment were selected for evaluation. The entire cohort of patients was re classified according to the 8th edition of TNM AJCC staging [12]. Patients with less than 3 years follow up, patients who received induction therapies and poor performance status were excluded from the study.
Data was also collected on pre operative planning. For the initial staging; physical examination, biopsy and imaging (CT and/ or MRI and OPG) were done to assess the primary tumor and CT/MRI/USG with or without FNAC was done to evaluate and stage the neck. The data records of the patients were also stratified in accordance with the resectability guidelines according to NCCN and Vijay Patil et al. [8, 11]. The study population was divided into three groups based on these guidelines; resectable, unresectable and technically unresectable diseases. For resectable disease upfront full thickness wide local excision was done with 1 cm margins all around with marginal or segmental mandibulectomy as dictated. Marginal mandibulectomy was done in cases with limited perisoteal invasion, limited superficial bony erosion and tumor abutting the mandible and segmental mandibulectomy was done in cases with gross cortical and medullary involvement, gross paramandibular involvement and edentulous mandibles. The maxilla was also addressed in accordance with standard surgical principles. Adjuvant therapy was given in accordance with the NCCN, RTOG #9501 (Radiation Therapy Oncology Group) and EORTC #22,931(European Organization for Research and Treatment of Cancer) guidelines [8, 13]. Adjuvant radiotherapy was given in all the cases and chemo radiation was given in the presence of positive margin or extracapsular spread. For margin analysis the Royal College of pathologists guidelines were followed. Margin < 1 mm was considered as positive, 1-5 mm as close and > 5 mm as negative.
In a subset of patients induction chemotherapy was used prior to definitive surgery or non surgical therapy. This data was subset was reclassified into either unresectable or technically unresectable groups. Records where induction chemotherapy was used for resectable locally advanced disease was excluded from the study. Induction chemotherapy regimen consisted of triplet regimen of cisplatin, docetaxel and 5 Flurouracial in 3 week conventional regimen (TPF). The response to neo adjuvant therapy was done in accordance with the RECIST 1.1 criteria [14]. Non responders were either subjected to chemoradiation or palliative therapy. Partial and complete responders were either subjected to surgical therapy or concurrent chemoradiation as a part of sequential chemoradiation in our Institute. A subset of unresectable patients also received radical therapy with conventional fractionation schedule. In the chemoradiation group a small number of patients were subjected to altered fractionation mainly hyperfractionation and accelerated fractionation schedules. Due to the small cohort of patients separate evaluation of radio therapeutic regimens was not done in this study. The endpoint assessment of the study was overall survival (OS) and disease free survival (DFS). Overall survival was defined from the date of diagnosis till death due to any cause. Disease free survival was defined from the date of diagnosis till the date of first recurrence. The secondary.
Data Analysis
The statistical analysis was performed using IBM SPSS software, version 22.0 (IBM, Armonk, NY, USA). Kaplan Meir method was used to evaluate OS and DFS rate and log rank test was used to compare the survival amongst groups. Cox regression analysis (univariate and multivariate) was used to evaluate the hazard ratio to find out the possible factors influencing risk of death and disease. A p value of < 0.05 was considered statistically significant at 95% confidence interval.
Results
A total of 196 patient records were evaluated from 10 year medical records directory who presented and were treated with locally advanced oral squamous cell carcinoma. Patients were divided into three broad categories based on disease presentation into resectable, unresectable and technically unresectable disease. Patients were also segregated in accordance with the treatments received into upfront surgery (Group A), radical radiotherapy (Group B), concurrent chemoradiation (Group C), sequential chemoradiation/ Induction chemotherapy- concurrent chemoradiation –adjuvant therapy (Group D) and induction chemotherapy-surgery-adjuvant therapy (Group E). Upfront surgery was used for all resectable disease, CTRT, sequential chemoradation and radical RT were the treatments used for unresectable disease and induction chemotherapy-surgery-adjuvant therapy was primarily used for technically unresectable disease. The mean age of the patients in our study was 48.63 ± 7.34 years. The M:F ratio in our study 1:0.4. The median follow up for our patients was 40 months (25–72).
The median overall survival in our study was 32 months (27–36) and the median DFS was 24 months (19–28). The 3 year OS and DFS were 43.4% and 36.2% respectively. The projected 5 year overall survival was 20.5% and DFS was 19.8% [Figures 1 and 2]. A total of 103 patients received upfront surgery, 13 patients received radical RT, 47 patients received concurrent chemoradiation, 24 patients received sequential chemoradiation and 9 patients received neo adjuvant chemotherapy followed by surgery and adjuvant therapy. Majority of the tumors were poorly differentiated, 56.6% of tumors had aggressive pattern of invasion, extracapsular spread was present in 36.7% of patients, positive margin was present in 18.7% of patients, bone involvement was present in 78.1% of patients and skin infiltration was present in 40.8% of patients. Most of the patients had lymph node size in the range of 3–4 cm with 17.9% of patients having lymph nodes > 5 cm [Table 1].
Fig. 1.
Kaplan Meier estimator of Overall survival
Fig. 2.
Kaplan Meier estimator of Disease Free survival
Table 1.
Comparison of survival amongst predictive factors using Log Rank Test
| DFS (%) | OS (%) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Category | Frequency | Percent | 1 YEAR | 3 YEAR | 5 YEAR | p value | 1 YEAR | 3 YEAR | 5 YEAR | p value |
| Resectable | 103 | 52.6 | 85.4 | 33.1 | 16.3 | 95 | 44 | 14 | ||
| Unresectable | 84 | 42.9 | 85.6 | 39.1 | 22.5 | 0.957 | 94 | 42 | 28 | 0.877 |
| TURD | 9 | 4.6 | 100.0 | 37.5 | 37.5 | 100 | 44 | 44 | ||
| Treatment | ||||||||||
| Group A/ Upfront surgery | 103 | 52.6 | 96.3 | 51.7 | 29.8 | 100 | 59.7 | 35.4 | ||
| Group B/ Radical RT | 13 | 6.6 | 47.1 | 7.4 | 7.4 | 82.4 | 11.8 | 5.9 | ||
| Group C/ CTRT | 47 | 24 | 81.3 | 29.3 | 17 | < 0.001 | 93.7 | 40.6 | 25.5 | < 0.001 |
| Group D/ IC-CTRT | 24 | 12.2 | 87.3 | 26 | 13.9 | 90.3 | 38.8 | 8.1 | ||
| Group E/ IC- surgery-adjuvant therapy | 9 | 4.6 | 88.2 | 31.4 | 15.7 | 94.1 | 27.5 | 27.5 | ||
| Grading | ||||||||||
| Well | 58 | 29.6 | 89.7 | 60.9 | 39 | 98.2 | 67.8 | 54.4 | ||
| Moderate | 84 | 42.9 | 88 | 35.6 | 19.5 | 0.001 | 97.6 | 38.9 | 18.6 | |
| Poor | 54 | 27.6 | 79.6 | 14.6 | 6.1 | 87 | 27.2 | 4.5 | < 0.001 | |
| POI | ||||||||||
| Cohesive | 85 | 43.4 | 90.6 | 46.2 | 36 | 97.6 | 56.7 | 41.4 | ||
| Aggressive | 111 | 56.6 | 82.8 | 29.2 | 11.9 | 0.001 | 92.7 | 33.8 | 10.8 | 0.004 |
| ECS | ||||||||||
| Absent | 124 | 63.3 | 91.1 | 46.3 | 27.5 | 95.9 | 51.8 | 29.5 | ||
| Present | 72 | 36.7 | 77.8 | 20.7 | 9.2 | < 0.001 | 93.1 | 30.1 | 0 | 0.003 |
| PNI | ||||||||||
| Absent | 129 | 65.8 | 89.1 | 46.2 | 27 | 95.3 | 49.3 | 23.8 | ||
| Present | 67 | 34.2 | 80.6 | 17.5 | 7.5 | < 0.001 | 94 | 32.5 | 16.4 | 0.02 |
| MARGIN | ||||||||||
| Negative | 67 | 59.8 | 91.4 | 60 | 45 | 94.3 | 61.4 | 28.1 | ||
| Close | 24 | 21.4 | 78.1 | 37.7 | 12.9 | < 0.001 | 93.8 | 54.2 | 16.7 | < 0.001 |
| Positive | 21 | 18.7 | 83.6 | 10.3 | 6.9 | 93.8 | 22.2 | 6.2 | ||
| LVI | ||||||||||
| Absent | 119 | 60.7 | 89.9 | 49.1 | 29.3 | 95.8 | 54.3 | 24.7 | ||
| Present | 77 | 39.3 | 80.4 | 16.8 | 7.7 | < 0.001 | 93.4 | 26.7 | 20.7 | 0.001 |
| Bone involvement | ||||||||||
| Absent | 43 | 21.9 | 95 | 60.3 | 29.1 | 100 | 70.4 | 24.2 | ||
| Present | 153 | 78.1 | 83.9 | 30.3 | 17.6 | 0.002 | 93.5 | 37.4 | 19.3 | 0.003 |
| SKIN INFILTRATION | ||||||||||
| Absent | 116 | 59.2 | 89.7 | 41 | 20.9 | 98.1 | 53.6 | 34.2 | ||
| Present | 80 | 40.8 | 81.9 | 29.8 | 16.7 | 0.031 | 89.8 | 32.3 | 16.1 | 0.02 |
| LN SIZE (cm) | ||||||||||
| ≤ 3 | 49 | 25 | 98 | 56.8 | 34.3 | 100.0 | 64.5 | 43.2 | ||
| 3.1-4.0 | 87 | 44.4 | 88.4 | 41.3 | 24.6 | < 0.001 | 96.4 | 45.3 | 18.2 | < 0.001 |
| 4.1-5.0 | 25 | 12.8 | 68 | 25.8 | 6.9 | 91.7 | 35.8 | 21.4 | ||
| > 5 | 35 | 17.9 | 76.5 | 4.2 | 4.2 | 85.7 | 16.5 | 5.5 | ||
| Site | ||||||||||
| BM | 59 | 89.8 | 34.7 | 18.2 | 96.6 | 40.9 | 37.2 | |||
| FOM | 43 | 78.7 | 32.5 | 23.7 | 90.5 | 42 | 27.8 | |||
| HP | 4 | 100 | 50 | 50 | 0.378 | 100 | 37.5 | 37.5 | 0.539 | |
| Tongue | 37 | 86.5 | 49.9 | 25.4 | 91.9 | 52.3 | 26.2 | |||
| Mandible GB- Sulcus | 46 | 87 | 28 | 12.4 | 97.8 | 34.5 | 12.2 | |||
| RMT | 7 | 85.7 | 37 | 37 | 100 | 71.4 | 10 | |||
TURD: technically unresectable disease, RT: radiotherapy, CTRT: chemo radiotherapy, IC: induction chemotherapy, POI: pattern of invasion, ECS: extracapsular spread, LVI: lympho vascular invasion, PNI: perineural invasion, LN: lymph node, GB: gingivo buccal, RMT: retromolar trigone, DFS: disease free survival, OS: overall survival. BM: buccal mucosa, FOM: floor of mouth, HP: hard palate
Tables 2 and 3 describes the mean and median survival amongst the various variables in our study. The median DFS and OS of patients who underwent upfront surgery were 49 months and 37 months respectively. The median DFS and OS in patients with ECS were 19 months and 28 months respectively. The overall survival in patients with resectable, unresectable and TURD was 31, 32 and 29 months respectively. The overall survival in patients with positive margins was 24 months compared to 39 months and 59 months in patients with close and negative margins respectively.
Table 2.
Mean and median DFS amongst groups
| DFS | ||||||||
|---|---|---|---|---|---|---|---|---|
| Treatment | Mean (months) | Median (months) | ||||||
| Estimate | Std. Error | 95% Confidence Interval | Estimate | Std. Error | 95% Confidence Interval | |||
| Lower Bound | Upper Bound | Lower Bound | Upper Bound | |||||
| Group A | 44.111 | 2.084 | 40.027 | 48.195 | 49.000 | 8.069 | 33.184 | 64.816 |
| Group B | 23.353 | 2.697 | 18.067 | 28.639 | 22.000 | 4.735 | 12.720 | 31.280 |
| Group C | 34.902 | 2.587 | 29.832 | 39.972 | 28.000 | 1.617 | 24.830 | 31.170 |
| Group D | 32.418 | 3.045 | 26.449 | 38.387 | 26.000 | 5.206 | 15.797 | 36.203 |
| Group E | 33.837 | 4.210 | 25.584 | 42.089 | 29.000 | 1.574 | 25.915 | 32.085 |
| Category | ||||||||
| Resectable | 31.172 | 1.970 | 27.311 | 35.034 | 25.000 | 2.665 | 19.776 | 30.224 |
| Unresectable | 32.254 | 2.259 | 27.826 | 36.683 | 23.000 | 2.778 | 17.555 | 28.445 |
| TURD | 28.000 | 4.416 | 19.345 | 36.655 | 19.000 | 1.414 | 16.228 | 21.772 |
| Grading | ||||||||
| Well | 41.490 | 2.793 | 36.016 | 46.964 | 53.000 | 10.103 | 33.198 | 72.802 |
| Moderate | 31.477 | 2.231 | 27.105 | 35.849 | 21.000 | 1.447 | 18.164 | 23.836 |
| Poor | 23.068 | 1.971 | 19.204 | 26.932 | 19.000 | 0.718 | 17.592 | 20.408 |
| POI | ||||||||
| Cohesive | 37.402 | 2.331 | 32.833 | 41.971 | 33.000 | 5.542 | 22.138 | 43.862 |
| Aggressive | 27.957 | 1.783 | 24.462 | 31.453 | 20.000 | 1.359 | 17.337 | 22.663 |
| ECS | ||||||||
| Absent | 36.299 | 1.916 | 32.543 | 40.056 | 32.000 | 6.476 | 19.308 | 44.692 |
| Present | 24.632 | 1.883 | 20.941 | 28.323 | 19.000 | 1.254 | 16.543 | 21.457 |
| PNI | ||||||||
| Absent | 35.781 | 1.877 | 32.102 | 39.460 | 30.000 | 5.128 | 19.950 | 40.050 |
| Present | 24.117 | 1.831 | 20.528 | 27.706 | 19.000 | 0.986 | 17.068 | 20.932 |
| MARGIN | ||||||||
| Negative | 42.090 | 3.483 | 35.264 | 48.916 | 53.000 | 0.834 | 51.786 | 54.216 |
| Close | 32.455 | 3.534 | 25.529 | 39.381 | 32.000 | 6.790 | 18.691 | 45.309 |
| Positive | 21.273 | 1.638 | 18.063 | 24.482 | 17.000 | 0.970 | 15.098 | 18.902 |
| LVI | ||||||||
| Absent | 37.297 | 1.951 | 33.472 | 41.121 | 33.000 | 7.043 | 19.197 | 46.803 |
| Present | 23.366 | 1.671 | 20.092 | 26.640 | 19.000 | 1.041 | 16.960 | 21.040 |
| Bone involvement | ||||||||
| Absent | 41.200 | 2.986 | 35.348 | 47.051 | 49.000 | 7.242 | 34.806 | 63.194 |
| Present | 29.330 | 1.580 | 26.234 | 32.427 | 21.000 | 1.309 | 18.435 | 23.565 |
| SKIN INFILTRATION | ||||||||
| Absent | 33.875 | 1.855 | 30.239 | 37.511 | 30.000 | 2.437 | 25.224 | 34.776 |
| Present | 28.443 | 2.153 | 24.224 | 32.662 | 19.000 | 1.029 | 16.984 | 21.016 |
| LN SIZE (cm) | ||||||||
| ≤ 3 | 40.207 | 2.925 | 34.474 | 45.940 | 44.000 | 10.354 | 23.706 | 64.294 |
| 3.1-4.0 | 34.187 | 2.261 | 29.756 | 38.618 | 27.000 | 3.534 | 20.074 | 33.926 |
| 4.1-5.0 | 25.938 | 3.401 | 19.273 | 32.604 | 23.000 | 5.834 | 11.566 | 34.434 |
| > 5 | 18.130 | 1.238 | 15.704 | 20.556 | 19.000 | 1.147 | 16.752 | 21.248 |
| Site | ||||||||
| BM | 31.693 | 2.544 | 26.707 | 36.679 | 27.000 | 2.766 | 21.579 | 32.421 |
| FOM | 29.925 | 3.143 | 23.765 | 36.085 | 20.000 | 3.057 | 14.007 | 25.993 |
| HP | 32.750 | 6.426 | 20.155 | 45.345 | 26.000 | . | . | . |
| Tongue | 36.307 | 3.615 | 29.222 | 43.392 | 36.000 | 12.931 | 10.655 | 61.345 |
| Sulcus | 27.919 | 2.693 | 22.640 | 33.197 | 20.000 | 1.423 | 17.212 | 22.788 |
| RMT | 36.536 | 7.118 | 22.584 | 50.487 | 31.000 | 6.096 | 19.051 | 42.949 |
Table 3.
Mean and median OS amongst groups
| Mean and Median for Overall Survival. | ||||||||
|---|---|---|---|---|---|---|---|---|
| Treatment | Mean | Median | ||||||
| Estimate | Std. Error | 95% Confidence Interval | Estimate | Std. Error | 95% Confidence Interval | |||
| Lower Bound | Upper Bound | Lower Bound | Upper Bound | |||||
| Group A | 38.679 | 2.306 | 34.160 | 43.199 | 37.000 | 11.464 | 14.531 | 59.469 |
| Group B | 18.324 | 3.048 | 12.349 | 24.298 | 12.000 | 4.116 | 3.933 | 20.067 |
| Group C | 26.914 | 2.503 | 22.008 | 31.821 | 21.000 | 1.873 | 17.330 | 24.670 |
| Group D | 28.328 | 3.239 | 21.980 | 34.677 | 20.000 | 1.064 | 17.914 | 22.086 |
| Group E | 30.052 | 4.464 | 21.304 | 38.801 | 27.000 | 6.383 | 14.489 | 39.511 |
| Category | ||||||||
| Resectable | 36.773 | 1.881 | 33.086 | 40.460 | 31.000 | 3.260 | 24.610 | 37.390 |
| Unresectable | 37.427 | 2.087 | 33.335 | 41.518 | 32.000 | 2.435 | 27.227 | 36.773 |
| TURD | 37.313 | 6.001 | 25.550 | 49.075 | 29.000 | 5.155 | 18.897 | 39.103 |
| Grading | ||||||||
| Well | 47.267 | 2.412 | 42.541 | 51.994 | . | . | . | . |
| Moderate | 36.320 | 2.118 | 32.168 | 40.472 | 28.000 | 2.473 | 23.152 | 32.848 |
| Poor | 29.162 | 1.976 | 25.290 | 33.035 | 25.000 | 1.556 | 21.951 | 28.049 |
| POI | ||||||||
| Cohesive | 41.771 | 2.106 | 37.643 | 45.900 | 44.000 | 5.724 | 32.781 | 55.219 |
| Aggressive | 33.997 | 1.749 | 30.569 | 37.424 | 29.000 | 2.151 | 24.784 | 33.216 |
| ECS | ||||||||
| Absent | 40.286 | 1.762 | 36.833 | 43.738 | 39.000 | 5.708 | 27.812 | 50.188 |
| Present | 32.230 | 2.040 | 28.232 | 36.228 | 28.000 | 1.432 | 25.193 | 30.807 |
| PNI | ||||||||
| Absent | 39.485 | 1.723 | 36.108 | 42.862 | 36.000 | 5.250 | 25.710 | 46.290 |
| Present | 33.024 | 2.140 | 28.831 | 37.218 | 27.000 | 1.450 | 24.158 | 29.842 |
| MARGIN | ||||||||
| Negative | 45.023 | 3.314 | 38.528 | 51.518 | 59.000 | 10.926 | 37.585 | 80.415 |
| Close | 38.854 | 3.443 | 32.107 | 45.602 | 39.000 | 7.544 | 24.214 | 53.786 |
| Positive | 27.868 | 1.866 | 24.210 | 31.525 | 24.000 | 0.855 | 22.323 | 25.677 |
| LVI | ||||||||
| Absent | 40.895 | 1.744 | 37.477 | 44.313 | 44.000 | 4.866 | 34.462 | 53.538 |
| Present | 31.031 | 1.901 | 27.306 | 34.756 | 26.000 | 1.703 | 22.663 | 29.337 |
| Bone involvement | ||||||||
| Absent | 46.866 | 2.927 | 41.128 | 52.603 | 52.000 | 3.430 | 45.278 | 58.722 |
| Present | 35.024 | 1.488 | 32.108 | 37.940 | 29.000 | 1.723 | 25.622 | 32.378 |
| SKIN INFILTRATION | ||||||||
| Absent | 39.996 | 1.786 | 36.496 | 43.496 | 39.000 | 5.982 | 27.275 | 50.725 |
| Present | 33.764 | 2.012 | 29.822 | 37.707 | 27.000 | 2.162 | 22.763 | 31.237 |
| LN SIZE (cm) | ||||||||
| ≤ 3 | 45.215 | 2.640 | 40.041 | 50.389 | 57.000 | 11.538 | 34.385 | 79.615 |
| 3.1-4.0 | 38.388 | 2.027 | 34.415 | 42.361 | 33.000 | 4.421 | 24.336 | 41.664 |
| 4.1-5.0 | 33.130 | 4.054 | 25.185 | 41.076 | 28.000 | 6.945 | 14.387 | 41.613 |
| > 5 | 26.327 | 2.050 | 22.308 | 30.346 | 26.000 | 2.074 | 21.936 | 30.064 |
| Site | ||||||||
| BM | 38.303 | 2.574 | 33.259 | 43.348 | 32.000 | 1.882 | 28.310 | 35.690 |
| FOM | 35.369 | 3.039 | 29.412 | 41.326 | 29.000 | 5.005 | 19.190 | 38.810 |
| HP | 35.625 | 4.850 | 26.120 | 45.130 | 36.000 | 11.456 | 13.545 | 58.455 |
| Tongue | 40.256 | 3.163 | 34.056 | 46.456 | 44.000 | 12.027 | 20.427 | 67.573 |
| Sulcus | 33.609 | 2.594 | 28.524 | 38.694 | 26.000 | 2.567 | 20.968 | 31.032 |
| RMT | 43.857 | 6.210 | 31.686 | 56.028 | 47.000 | 7.326 | 32.642 | 61.358 |
Univariate regression: The primary site of the lesion did not influence OS and DFS. There was also no significant difference in survival between resectable, unresectable and TURD. Patients who received radical radiotherapy, concurrent chemoradiation and sequential chemoradiation had significantly poor survival compared to upfront surgery. There was no significant difference in survival for patients who received induction chemotherapy prior to surgery compared to upfront surgery. The OS and DFS in patients with well differentiated tumors were significantly better compared to moderate and poorly differentiated tumors. Aggressive tumors had significantly lower OS and DFS compared to cohesive tumors. Presence of ECS, LVI, PNI, bone involvement and skin infiltration significantly reduced OS and DFS. Positive margin was significantly associated with poor OS and DFS compared to negative and close margins. However there was no difference in survival in patients who had close and negative margins. Lymph node size > 3 cm significantly reduced OS and DFS in our cohort of patients. [Table 4]
Table 4.
Univariate regression analysis of predictive factors with OS and DFS.
| Site | Odds ratio | 95% Confidence Interval: Lower | 95% CI: Upper |
p value |
|---|---|---|---|---|
| BM | Reference | |||
| FOM | 1.288 | 0.751 | 2.209 | 0.359 |
| HP | 0.845 | 0.201 | 3.554 | 0.819 |
| Tongue | 0.943 | 0.530 | 1.677 | 0.842 |
| Sulcus | 1.464 | 0.881 | 2.432 | 0.141 |
| RMT | 0.930 | 0.358 | 2.418 | 0.882 |
| Category | ||||
| Resectable | Reference | |||
| Unresectable | 0.943 | 0.646 | 1.379 | 0.764 |
| TURD | 0.792 | 0.288 | 2.183 | 0.653 |
| Treatment | ||||
| Group A | Reference | |||
| Group B | 4.117 | 2.252 | 7.526 | < 0.001 |
| Group C | 1.908 | 1.160 | 3.138 | 0.011 |
| Group D | 2.321 | 1.371 | 3.928 | 0.002 |
| Group E | 1.705 | 0.813 | 3.576 | 0.158 |
| Grading | ||||
| Well | Reference | |||
| Moderate | 2.374 | 1.381 | 4.083 | 0.002 |
| Poor | 3.836 | 2.209 | 6.660 | < 0.001 |
| POI | ||||
| Cohesive | Ref | |||
| Aggressive | 1.743 | 1.178 | 2.580 | 0.005 |
| ECS | ||||
| Absent | Reference | |||
| Present | 1.736 | 1.193 | 2.527 | 0.004 |
| PNI | ||||
| Absent | Reference | |||
| Present | 1.557 | 1.064 | 2.276 | 0.023 |
| MARGIN | ||||
| Negative | Reference | |||
| Close | 1.678 | 0.821 | 3.426 | 0.156 |
| Positive | 3.489 | 1.815 | 6.708 | < 0.001 |
| LVI | ||||
| Absent | Reference | |||
| Present | 1.912 | 1.311 | 2.790 | 0.001 |
| Bone involvement | ||||
| Absent | Reference | |||
| Present | 2.293 | 1.285 | 4.089 | 0.005 |
| SKIN INFILTRATION | ||||
| Absent | Reference | |||
| Present | 1.546 | 1.064 | 2.246 | 0.022 |
| LN SIZE (cm) | ||||
| ≤ 3 | Reference | |||
| 3.1-4.0 | 1.776 | 1.025 | 3.079 | 0.041 |
| 4.1-5.0 | 2.264 | 1.130 | 4.539 | 0.021 |
| > 5 | 4.567 | 2.478 | 8.416 | < 0.001 |
Multivariate regression: Extracapsular spread, bone involvement, skin infiltration, treatments, surgical margin and lymph node size were significant predictors for OS and DFS. [Table 5] The median OS and DFS in patients with positive margin were 24 months and 17 months respectively vs. 59 months and 53 months in patients with negative margin. Lymph node size > 3 cm significantly influenced survival. The Odds ratio for LN size > 5 cm influencing survival was 5.932 (95% CI: 1.920-18.326). The median OS and DFS in patients with skin infiltration were 27 months and 19 months respectively vs. 39 months and 30 months in patients without skin involvement. The DFS and OS in patients with bone involvement were 21 months and 29 months compared to 49 months and 52 months in patients without bone involvement.
Table 5.
Multivariate regression analysis of predictive factors for survival
| OR | 95.0% CI for OR | p value | ||
|---|---|---|---|---|
| Lower | Upper | |||
| Category | 0.970 | 0.849 | 1.109 | 0.657 |
| Site | 0.950 | 0.812 | 1.112 | 0.524 |
| POI | 0.975 | 0.603 | 1.578 | 0.919 |
| ECS | 2.595 | 1.441 | 4.670 | 0.001 |
| PNI | 0.554 | 0.183 | 1.684 | 0.298 |
| LVI | 2.476 | 0.784 | 7.818 | 0.122 |
| Grading | 1.417 | 0.979 | 2.051 | 0.065 |
| Bone involvement | 3.337 | 1.572 | 7.082 | 0.002 |
| Treatment | 1.205 | 1.010 | 1.436 | 0.038 |
| MARGIN | 1.864 | 1.266 | 2.745 | 0.002 |
| LN size | 1.383 | 1.138 | 1.681 | 0.001 |
| SKIN INFILTRATION | 1.971 | 1.069 | 3.635 | 0.030 |
On a subset analysis of only T4b patients who underwent either upfront surgery or induction chemotherapy followed by surgery there was no significant difference in OS and DFS. All patients with TURD had partial response after induction chemotherapy and were subjected to surgical resection followed by adjuvant therapy.
Discussion
Key results
The essence of the study was to evaluate the outcome of various treatment modalities and factors which might impact OS and DFS in locally advanced oral squamous cell carcinomas without distant metastasis. The median OS and DFS in our study were 32 and 24 months respectively. Extracapsular spread, bone involvement, skin infiltration, treatments, surgical margins and Lymph node size being the prime predictors of survival.
Limitations
Only a small cohort of patients received induction chemotherapy before surgery. Comparison with upfront surgery might require further clinical trials.
Different fractionation schedules and their impact on survival were not assessed.
In our institute immunotherapy is currently not the first line of treatment for unresectable head and neck carcinomas. Hence their efficacy in comparison to cytotoxic chemotherapy was not assessed.
Since it was a retrospective analysis separate evaluation of supra notch and infra notch advanced cancers and their impact could not be assessed.
Larger cohort of patients with clinical trials is necessary for definitive comment about the efficacy of each treatment modality on survival.
Interpretation: LAOSCC warrants multimodal therapy with surgery being the mainstay of treatment when patients are considered to be operable. As previously discussed LAOSCC should be categorically divided broadly into two groups; resectable and unresectable while the later being subdivided into a third group namely technically unresectable disease. The management of LAOSCC hence includes consideration of the extent of the tumor.
Resectable LAOSCC
Surgery is the mainstay of treatment for resectable disease. The NCDB (National Cancer Database) study of Spiotto et al [15] showed that surgery + RT had a 3 year OS of 49.7% compared with 36% for concurrent chemoradiation. The study by Sher et al. showed that surgery + RT had superior progression free survival and locoregional control compared with concurrent chemoradiation [16]. In the retrospective study by Gore et al. CTRT was associated with 16.6 fold risk of disease specific death and 10 fold higher risk for overall death compared to surgery + RT [17]. Addition of induction chemotherapy to surgery has also been tested without being effective in improving survival. Two studies by Licitra et al. and Zhong et al. showed no benefits in survival with addition of induction chemotherapy to surgery. In the study by Licitra et al. 55% survival was observed in both the arms (induction arm vs. upfront surgery). Nevertheless; patients in the induction arm required less mandibulectomy compared to the upfront surgery arm (31% vs. 52%). However, induction chemotherapy would identify a subset of patients who had complete response leading to favorable final outcomes [18, 19]. The systematic review by Marta et al. [20] found OS benefit only in a subset of patients with cN2 disease in favor of induction chemotherapy. Studies have also shown that selected T4b OSCC can have a favorable outcome with primary surgery [21, 22]. The study by Liao et al. from Chang Gung Memorial Hospital has showed that supra notch T4b tumors were associated with a significant poor OS, DFS, neck control and local control. There was also a trend for poor outcome in posteriorly located masticator space tumors and involving > 3components, however; the results were not significant. The study by Kumar et al. also showed that infra notch tumors with < 3 masticator space component involvements had comparable outcome with T4a tumors.
Unresectable LAOSCC: The Intergroup trial by Adelstein et al. showed that addition of cisplatin to conventional RT improved survival compared to RT alone (37% vs. 23%) although with more toxicities. Two retrospective studies by Foster et al. and Scher et al. showed their results on definitive CTRT. In the study by Sher et al. the 5 year OS, locoregional control (LRC) and disease control (DC) were 15%, 37% and 70% respectively. Conversely the results from Foster et al. showed 63.2%, 58.7%, 78.6% and 87.2% respectively for OS, PFS (progression free survival), LRC and DC. Definitive and conclusive results are lacking in the utility of induction chemotherapy followed by concurrent chemoradiation (sequential chemoradiation) in LAOSCC. PARDIGM, DeCIDE and the trials by Hitt et al. failed to show any survival benefit by addition of induction chemotherapy [25–31]. The Italian study group by Ghi et al. showed a benefit of adding induction chemotherapy to CTRT in terms of PFS and OS [32]. The updated 2021 MACH-NC meta analysis by Lacas et al. showed an absolute 5 year benefit of 6.5% limited to concomitant chemoradiotherapy. Induction chemotherapy did not improve overall survival [33]. The MARCH meta analysis by Lacas et al. showed that hyperfractionated radiotherapy with concurrent chemoradiotherapy as the standard of care for locally advanced Head and Neck Squamous Cell Carcinomas [34]. The combined results of MACH-NC and MARCH by Petit et al. [35] showed benefit of hyperfractionated concurrent chemoradiation or TPF induction chemotherapy followed by platinum based concurrent chemoradiation over chemoradiaotherapy alone in Head and Neck cancers. In our study there was no significant difference in survival between concurrent chemoradiation, sequential chemoradiation, radical radiotherapy in the management of unresectable OSCC [p value:- B vs. C: 0.055, C vs. D: 0.0659, D vs. E: 0.433].
Technically Unresectable LAOSCC: Patil et al. in their two consecutive studies [11, 23] have proved the benefit of induction chemotherapy in these subset of patients. In the 2013 study the overall survival was 8 months in the non surgical group following induction chemotherapy. In the study by Joshi et al. there was a significant improvement in OS in patients who underwent surgery following induction chemotherapy vs. induction chemotherapy followed by non surgical treatments (18 vs. 6.5 months) [24]. Hence induction chemotherapy is a valuable treatment option for down staging the disease and improving respectability and survival. However; these results are only applicable to oral cavity cancers. In our study there was no significant difference in survival for T4b tumors treated either with upfront surgery or induction chemotherapy followed by surgery and adjuvant therapy; p value: 0.054.
Conclusion
Based on the results from the study and previous literature upfront surgery remains the standard of care for resectable LAOSCC. Induction chemotherapy might improve the resectability in technically unresectable OSCC. There is no difference in survival between concurrent chemoradiation, sequential chemoradiation and radical radiotherapy in the management of unresectable disease. Extracapsular spread, bone and skin involvement, surgical margins, treatments and lymph node size are the prime predictors for survival.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Acknowledgements
None.
Author Contribution
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [RATHINDRA NATH BERA]. The first draft of the manuscript was written by RICHIK TRIPATHI AND RITUSHA MISHRA]. All authors read and approved the final manuscript.
Funding
None.
Data Availability
Data sets can be accessed via mail to the corresponding author.
Declarations
Ethical Approval
Obtained (Dean/2021/EC/2697).
Consent to Participate
Informed and written consent was obtained from all patients during initial treatment.
Consent to Publish
All authors give full consent to publish.
Conflict of Interest
none declared.
Footnotes
Publisher’s Note
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data sets can be accessed via mail to the corresponding author.