Head and neck cancer (HNC) is the seventh most common cancer globally. In India it is the second most common cancer and the third common cause of cancer deaths. Head and neck cancer (HNC) constitutes around 30% of all the cancers because of the widespread tobacco use across India . About 30 to 40% patients with head and neck squamous cell carcinoma present with stage I and II (early stage) disease. These patients are treated with either primary surgery or definitive radiation therapy2. Around 60% of these cancers are diagnosed at an advanced stage and are treated by combined modality approaches (surgery, radiation and or chemotherapy) to optimise the chance of long term locoregional control. In an effort to improve the cure rates and functional outcomes, chemotherapy has been integrated into various multimodality approaches as a part of organ preservation. Hence induction chemotherapy (addition of chemotherapy prior to definitive surgery and or RT), concurrent chemoradiotherapy and sequential therapy (induction chemotherapy followed by concurrent chemoradiotherapy) are now used in different situations. Selected patients are treated by concurrent chemoradiation. But the results of chemo radiation or radiation alone are not promising3. By giving induction chemotherapy and assessing the response, we can tailor the treatment intent of this group of patients and filter those patients who would otherwise undergo morbid surgeries with poor functional outcomes. The results of the randomised phase III trials, European TPF regimen (protocol TAX 323/EORTC 24971) and the American TPF regimen (TAX 324) showed a superior response rate with TPF chemotherapy regimen. But oral cavity tumours constituted only 15% in these trials4,5. The role of Neoadjuvant chemotherapy in technically unresectable oral cavity SCC was studied by Patil et al and reported R0 resection rates of 66.21% with three drug and 40.34% with two drug6. At our centre, selected inoperable and borderline operable patients (patients with good performance status, younger age and good social support who will tolerate triplet drug regimen) are given 3 cycles of induction chemotherapy and are reassessed for radical treatment. Those patients with less than partial response would continue to receive treatment in the form of radiation (radical/palliative) or chemotherapy(palliative). Patients with more than partial response as per RECIST criteria version 1.1 would be treated with surgery followed by adjuvant radiation+/- chemotherapy. We plan to conduct a prospective study to assess the effect of induction chemotherapy on outcomes in patients with stage IV B gingivobuccal complex tumours.

This is a Prospective observational study done between 1st January 2021- 30th June 2022. After getting approval from Instituitional review board (01/2021/11) and human ethics committee (17/2021), patients with borderline operable stage IV B disease of gingivobuccal complex both were recruited for the study. Inclusion criteria: 1. Patients between age group 18- 65 years. 2. ECOG PS 0-1. 3. Biopsy proven HNSCC. 4. Stage IVB disease of gingivobuccal complex 5. Adequate hematological, renal and cardiac function so as to tolerate chemotherapy. 6. No synchronous or metachronous malignancy. METHODS All the patients underwent a baseline workup which included complete hemogram, renal function, creatinine clearance, liver function, chest X ray. Contrast enhanced Computed Tomography scan of head and neck was done for all patients to assess the extent of disease. Baseline cardiology evaluation was done prior to chemotherapy. Dental evaluation and nutritional assessment was done prior to treatment. Histopathology review of slides and blocks were done at RCC for all patients who underwent biopsy elsewhere. TREATMENT All patients were staged according to AJCC TNM staging 8th edition. The patients underwent either 1. Induction chemotherapy Surgery adjuvant chemoradiation 2. Induction chemotherapy Surgery adjuvant radiation 3. Induction chemotherapy Radical chemoradiation 4. Induction chemotherapy Palliative radiation 5. Induction chemotherapy Palliative chemotherapy/Best supportive care CHEMOTHERAPY Chemotherapy regimen included 1.TPF Regimen x 3 cycles(Neoadjuvant) Cisplatin 75 mg/m2 D1, Docetaxel 75 mg/m2 D1 and 5 flurouracil 750 mg/m2 D1-D4 as infusion. 2. Methotrexate(Post neoadjuvant as palliation) Inj methotrexate 40 mg/m2 iv D1 2 weeks apart 3.Concurrent chemotherapy regimen was three weekly cisplatin 80 -100 mg/m2. SURGERY All patients underwent wide excision of the lesion with adequate margins and modified radical neck dissection (level I-IV) with reconstruction. Negative margins were attained for all patients and adequate margins were confirmed per operatively with frozen section. RADIATION All the patients who underwent surgery received adjuvant chemoradiation/ radiation. Adjuvant RT dose was 60Gy/30#, at 2Gy per fraction, 1 fraction per day, treated 5 days a week. Patient who underwent radical chemoradiation received 66Gy/30 fractions along with concurrent cisplatin. All patients were treated with 3DCRT or IMRT. Simultaneous integrated boost (SIB) schedule of 66, 60 and 54Gy in 30 fractions was delivered to high, intermediate and low risk CTV in patients treated with IMRT. RESPONSE ASSESMENT AFTER RADICAL TREATMENT The first follow up was done after 2months. Patients were assessed clinically for residual disease or recurrence. Locoregional control was assessed at 12 weeks post treatment. Subsequent followup as per the instituitional protocol was planned every 3 months in the first year of completion of treatment, every 4 months in the second year, and every 6 months till 5 years and then annually. Toxicity Reporting Acute chemotherapy toxicities were assessed using CTCAE version 5.0. and radiation toxicities were evaluated using RTOG criteria. STATISTICAL ANALYSIS Patient and tumour characteristics were analysed using descriptive statistics such as mean, median, frequency, and percentages.Survival curves were generated using Kaplan –Meier method.Statistical significance of survival curves were assessed using log rank –test. Prognostic factors were assessed using Cox- proportional regression model.

Patient characteristics Fifteen patients were included in the study and the study population was followed up for 6 months. The age of the patients ranged from 26 to 54 years (median age 43 years). There were 3 females and 12 male patients. Most of the patients had an ECOG performance status ranging from 0 to 1. Majority of the patients in the study population had one or more habits (80%). Table:2 Baseline patient characteristics Characteristics N(%) Age <40 years 7 (46.6%) >40 years 8 (53.3%) Gender Male 12 (80%) Female 3 (20%) Habits Smoking 6 (40%) Chewing 12 (80%) Alcohol 9 (60%) Comorbidities Diabetes 2 (13.3%) Hypertension 2 (13.3%) Cardiovasular 1 (6.6%) ECOG PS 0 12 (80%) 1 3 (20%) Tumour characteristics The most common T stage was T4b (80%) and N stage was N3b (46.6%). Majority of the patients had gingivobuccal complex tumours (66%) followed by retromolar trigone (33%). Table:3 Tumour characteristics Variables N (%) T stage T4b N3b 6 (40%) T4a 3 (20%) T4b 12 (80%) Nodal staging N1 5 (33.3%) N2 3 (20%) N3b 7 (46.6%) Subsite Gingivobuccal Complex 10 (66%) Retromolar Trigone 5 (33.3%) Treatment Characteristics Fifteen patients with stage IV B disease were included in the study. Eleven patients received neoadjuvant chemotherapy with three cycles of TPF, one patient developed disease progression after first cycle and two patients developed grade IV neutropenia after first cycle and further chemotherapy with TPF was deferred. A delay in chemotherapy was found in three patients, the reasons being low creatinine clearance (6.6%) and covid-19 infection (13.3%). The duration of delay ranged from 2 to 21 days . After three cycles, nine out of fifteen patients attained partial response and six patients underwent surgery within 4 weeks from the completion of chemotherapy. One patient received radical chemoradiation as the disease was not operable. Two patients defaulted radical treatment and received palliative chemotherapy at the time of progression. One patient who underwent surgery achieved pathological complete response. After surgery, one patient received concurrent chemoradiation in view of extracapsular nodal disease (66Gy/33#with concurrent cisplatin). All others received adjuvant radiation to a dose of 60Gy/30#. No treatment interruptions were found during radiation. Table :4 Treatment characteristics Variables N (%) Chemotherapy Response Complete Response 1 (6.6%) Partial response 8 (53%) Stable disease 5 (33.3%) Progression 1 (6.6%) Surgery Yes 6 (40%) No 9 (60%) Intent of Treatment Radical 7 (46.6%) Palliative 8 (53.3%) Treatment Modality NACT f/b Surgery f/b adjuvant RT 5 (33.3%) NACT f/b Surgery f/b adjuvant CTRT 1 (6.6%) NACT f/b Radical CTRT 1 (6.6%) NACT f/b Palliative RT 1 (6.6%) NACT f/b Palliative Chemotherapy 6 (40%) NACT f/b Best supportive care 1(6.6%) Radiotherapy Dose(7) 60Gy/30# 4 (57.14%) 66Gy/30# 3 (42.8%) Progression after radical treatment(7) Yes 3 (42.85%) No 4 (57.14%) f/b :Followed by Factors affecting the rates of resectability Odds of having unresectable disease was found to be high in patients having comorbidities and Retromolar trigone primaries with a p value of 0.274 ,odds ratio 3.5 CI 0.372 -32.971. However it was not statistically significant and this may be due to small sample size. Toxicity Acute toxicities of radiation was evaluated weekly by the physicians. Mucositis started developing by the end of second week in most patients. Grade III mucositis mostly developed at the end of fourth week. Table: 6 Mucositis and skin reaction with radiation Mucoitis at 4 weeks Number of patients(%) Grade I 2 (28.5%) Grade II 4 57.14%) Grade III 1 (14.2%) Mucositis at week 6 Grade II 2 (28.5%) Grade III 5 (71.4%) Radiation induced Dermatitis Radiation dermatitis at week 4 N (%) Grade I 7 (100%) Grade II Radiation Dermatitis at week 6 Grade I 2 (28.5%) Grade II 5 (71.4%) Locoregional Control at 6 months Of the fifteen patients, seven patients were radically treated. One patient developed disease recurrence during adjuvant radiation and was referred for best supportive care. Two patients developed locoregional recurrence within two months of completion of treatment and was offered palliative chemotherapy. Table: 7 Locoregional control at 6 months Locoregional control at 6 months N (%) Complete Response 4 (57.14%) Progression 3 (42.85%) Figure:4 Pie diagram on locoregional control at 6 months

The 5-year survival of patients with locally advanced Stage IV B (T4b/N3b) oral cavity lesions is only 15 to 20 %7. Most of these patients are treated with palliative intent. However, patients with good performance status and organ function can be considered for neoadjuvant chemotherapy followed by tailored treatment according to their response. Induction chemotherapy before surgery may convert a borderline resectable or unresectable disease into technically resectable disease and this might improve survival outcomes in a selected group of patients8. Three drug induction is proved to be superior to two drug regimen in terms of response rates and outcomes9. A few retrospective studies have reported response rates and resectability after induction chemotherapy in gingivobuccal complex tumours. There are no prospective randomised trials addressing this issue. To the best of our knowledge this is the first attempt to prospectively study and evaluate the response rates and resectability with three drug induction regimen for T4b/N3b gingivobuccal complex tumours. The median age of our study population is 43 years (26 to 54 years) which is comparable to many published series10. In a retrospective study, Joshi et al reported partial response in 28%, stable disease in 49% and progressive disease in 23% of patients after two cycles of induction chemotherapy with 3 drug regimen11. In a similar retrospective study, Patil et al reported an overall response rate of 50% with the three drug regimen6. In our study the response rate attained after three cycles of induction chemotherapy was 60%. Being a prospective study, the inclusion criteria was stringent and patients with good performance status and organ function were included. The compliance to treatment was better and this might be the reason for good response rates observed in this study. Primary surgery may not be feasible for all T4b or N3b disease. The prognosis of such unresectable stage IVA or IVB tumours treated with a non surgical approach is poor with median survival ranging from 2 to 12 months. The outcomes are improved if R0 surgical resection is achieved. Study by Liao et al. reported a 5-year survival of 45% in T4b stage oral cancers after surgery7. The main goal of induction chemotherapy in unresectable and borderline resectable tumors is to convert it into technically resectable tumors. A retrospective study from India with 80 patients reported resectability rate of 23.8% in patients with unresectable T4a disease after two drug induction chemotherapy8. About 30% of patients with unresectable T4b disease underwent R0 resection after three drug induction chemotherapy in the study by Joshi et al12. Patil et al analysed patients with T4a or T4b tumors and a resectability rate of 43% has been reported with the three drug induction regimen6. In the present study, 40% of patients attained R0 resection after 3 cycles of TPF. This is comparable to other published series with three drug induction regimens. The role of induction chemotherapy before concurrent chemoradiation is not clear as various trials failed to prove the benefit of induction chemotherapy in this setting13,14. In our study, the patient who received radical concurrent chemoradiation after neoadjuvant chemotherapy attained complete response and is on follow up with no evidence of active disease clinically and radiologically15. Our patients tolerated the chemotherapy regimen with manageable toxicities. Two patients developed febrile neutropenia (13.3%) and further chemotherapy was deferred for them. Similar rates of febrile neutropenia was reported by Joshi et al (12.72%) and Rudresha et al(18%). Acute toxicities with radiation were also manageable. Grade III mucositis appeared by week 4 in 14.2% and grade II radiation dermatitis appeared in 71.4% patients at the end of 6 weeks. All patients were managed symptomatically and no treatment interruption during radiation was observed. As reported from the retrospective study by Patil et al, after a median follow up of 28 months, the locoregional control at 24 months was 20.6%. Patients who underwent surgery attained a locoregional control rate of 32% at 2 years in that study. Here we report an overall locoregional control rate of 26.6% at 6 months and we also noticed an improvement in locoregional control for those who underwent surgery as compared to non-surgical patients. Our study has many limitations. The sample size was small as the accrual was slow due to covid 19 pandemic. Our study is limited to one site of oral cavity as other sites like tongue might have variable prognosis.

The prognosis of stage IV B disease is dismal. However, a subset of patients with good PS, organ functioning and social support may be offered neoadjuvant chemotherapy with triplet regimen (TPF) followed by radical treatment according to the response to chemotherapy. A prospective trial with large sample size is warranted to evaluate the efficacy of triple drug regimen in unresectable and borderline resectable gingivobuccal complex tumours.

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