This study was a prospective type. A total of 44 cases with advanced squamous cell carcinoma of head and neck were studied during the period of October 2011 to September 2013 in the Department of Otorhinolaryngology – Head and Neck Surgery, KMC Hospital, Attavara and Government Wenlock Hospital, Mangalore, India.

Inclusion criteria: (i) Age > 30, <80 years; (ii) Sex – both male and female; (iii) Newly diagnosed patients & previously untreated cases; (iv) Advanced stage 3 & 4 head and neck cancers including oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, nose & paranasal sinuses, metastasis of unknown origin; (v) Biopsy confirmed Squamous cell carcinoma of head & neck; (vi) Patients who were willing to get admitted and receive chemotherapy.

Patients with previous history of any major surgery within a period of one year, presence of major co-morbid illness (Infective and immunosuppressive diseases like TB, HIV, uncontrolled diabetes, uncontrolled HTN, chronic renal disease at the time of diagnosis), Unscheduled hospitalization in-between, Squamous cell Carcinoma of cutaneous, salivary gland, esophageal origin were excluded from the study.

Each patient included in the study was evaluated thoroughly by detailed history, detailed head & neck as well as systemic examination. With the help of Karnofsky score [7] patient’s general condition was evaluated. The relevant investigations that included a complete blood picture, ESR, RFT (urea & creatinine), LFT (AST, ALP), serum electrolytes, chest X ray, ECG, ultra sound neck and abdomen and CT scan of the head and neck was routinely done in all patients. An FNAC was done in all palpable lymph nodes in head & neck. Necessary endoscopic examinations including sinuscopy, nasopharyngoscopy, direct laryngoscopy, 70 degree telelaryngoscopy, esophagoscopy were done considering the site of malignancy.

All the 44 patients were evaluated by a multidisciplinary team that included medical oncologist, head and neck surgeons, radiologists, and pathologists so as to confirm the eligibility, staging and treatment planning. Patients were assigned a clinical stage according to the criteria of the American joint committee on cancer. Tumour unresectability/advanceness/inoperability was assessed at this stage based on the following criteria [8]:

A histopathological confirmation by taking biopsy was made in all cases prior to start of chemotherapy. Based on the American Joint Commission on Cancer guidelines for grading tumours a histopathological grading was done as described in [Table/Fig-1]:

Induction chemotherapy: The regimen followed was use of pre-medication drugs followed by chemotherapeutic drug. Pre-medication drugs: Inj. Dexamethasone of 4-8mg; Inj. Rantac 50mg; Inj. Emeset 8mg in 100 ml NS over ½ hour.

Chemotherapy was started within a period of 3 weeks of study entry as an in-patient basis after confirming the normalcy of baseline investigations. Adequate hydration was maintained and patients were monitored for toxicity (medical interview, physical examination and complete blood counts) during their hospital stay. The same chemotherapeutic regimen was repeated at 3 week interval for a total of 3 cycles.

Following parameters was evaluated at the time of diagnosis & after completion of 3 cycles of chemotherapy within a period of not more than 3 weeks: (i) History and clinical examination: symptoms, signs, tumour size/extent, lymph node size; (ii) CT scan/USG quantification of tumour/nodal Size; (iii) Relevant Laboratory investigations: Hb%, CBC, RFT, LFT; Electrolytes (iv) Adverse effects.

CT and clinical response grading was done accordingly [Table/Fig-2].

Adverse events during the chemotherapy were evaluated based on common toxicity criteria (edition CTCAE version 4) developed by National cancer institute. For each adverse event, grades are assigned and defined using a scale from 0 to 5 (mild – death related to adverse event). After the completion of chemotherapy patient was assessed for response and based on the increase/decrease of the growth further treatment with radiotherapy or surgery or palliative chemotherapy or combined modality was persuaded.

The sample size was calculated with an 85% power (ß = .2) and a two-sided significance level of α = .05. Patient characteristics, toxicity, and response rates in the two treatment arms were compared using the Student’s t-test for continuous variables and the χ² test for categorical variables.

Fifty five patients diagnosed with advanced SCCHN during the period of October 2011 to September 2013 was enrolled in our study. All the patients in the study group received 3 cycles of induction chemotherapy with Cisplatin and 5-FU only after considering the patients general condition, biopsy report, and eligible criteria.

Eleven patients were excluded from our study because three had poor Karnofsky performance score (<50). Four patients interrupted therapy after one or two cycles of induction and were considered as invaluable for assessing response. Two patients were hospitalized in-between for the treatment of cardiac illness; hence their chemo treatment was delayed. Two were lost to follow up during the induction therapy. As all these were considered as protocol violation these patient were excluded in the study.

In our study maximum number of patients was seen in the age group of 51-70 years. With a mean age of incidence equals to 60. Patients whose karnofsky status was <50 were excluded from study as general condition of the patient withholds the start of chemotherapy. Among the 44 patients, 14 were female, and 30 were male patients. Males were predominated in all sites of malignancy. A 47.7% patients had Karnofsky score of 70, implying majority of patients were capable to care for self but unable to do or perform daily activity.

As described in the [Table/Fig-3], majority of patients (61.4%) presented to us in stage IV malignancy followed by (38.6%) stage III. Oral cavity and laryngeal tumours constituted up to 27.3%, oropharynx 20.5%, hypopharyngeal 15.9%, PNS and MUO constituted 2% of the head and neck cancers included in our study. The histological differentiation was described as moderately differentiated in 22 cases (50%), poorly differentiated in 15(34.1%) and well differentiated in 7 cases (15.9%).

Efficacy of the treatment regimen: When compared to females, 42.9% having a stable and 28.6% partial response to chemotherapy; 53.3% male patients showed a stable response with 33.3% showing partial response. Even though male patients showed a better response, overall there was no significant response change to chemotherapy with respect to gender (p=0.489).

Out of 17 stage III patients, 10 showed a stable response (58.8%), 5 partial response and 2 treatment failure (11.8%). And in case of 27 patients who had stage IV malignancy, 12 had stable response (44%), 9 had partial response (33.3%) and 5 patients (18.5%) had treatment failure. There found to be no difference in overall response to chemotherapy with reference to stage of the malignancy (p=0.84).

Analysis of response to various histopathological differentiation of malignancy showed partial response of 57.1% in case of moderately differentiated tumours, 14.3% in poorly differentiated tumours, and 28.6% in well differentiated squamous cell carcinomas. A stable response was seen in 45.5% of moderately differentiated, 73.3% of poorly differentiated and 14.3% of well-differentiated tumours. Treatment failure was majority seen well-differentiated tumours constituting 28.6% followed by moderately differentiated (13.6%) and poorly differentiated tumours (13.3%). Overall less response to chemotherapy was seen in cases of well differentiated squamous tumours.

Primary tumour response evaluation to induction therapy showed a highly significant response in controlling the progression the tumour (p=0.00) with 22 cases showing a stable response (52.4%), 12 cases having a partial response (28.6%), and 1 case had a complete response (2.4%). Nodal response evaluation for chemotherapy also showed a significant reduction in the size or the bulk (p=0.00). Out of 39 nodal positive patients, 22 cases (50%) had stable response, 14 cases (31.8%) had partial response and 1 had complete disappearance of the node.

Overall response evaluation after three completed cycles of chemotherapy showed 31.8% achieving partial response, 50% stable response, 15.9% failure to respond and only 2.3% of patients having a complete response. Partial response was best achieved in cases of oropharyngeal (28.6%) followed by laryngeal and oral cavity malignancies (21.4%). 31.8% achieved stable response in oral cavity malignancies followed by 27.3% in case of oropharyngeal cancers. With the p-value of 0.99 there was no statistical significant overall response (considering both the primary site and the lymph node status) to induction chemotherapy.

Adverse effects grading: Majority of our patients experienced moderate (47.6%) and mild (42.1) adverse reactions related to induction chemotherapeutic agents. No severe nor death related adverse event was seen during chemotherapy. Nonspecific/unlikely/unrelated symptoms were also included during study. Even though 50% of patients had nonspecific symptoms, major adverse events related to chemotherapeutic drugs noted were disturbed haematological parameters followed by asthenia and anorexia. Some toxicity related to chemotherapeutic agents was encountered in all patients but only few were consistent with all the 3 cycles of chemotherapy as shown below in [Table/Fig-4,5].

The non-surgical management of squamous cell carcinoma of head & neck has always been an area of constant interest in medical research. Over the years, multiple varied clinical trials involving small to large population as study group, from single drug regimen phase I & II studies to multidrug regimen phase III trials and from single modality to multimodal/ combined treatment regimens have evolved eventually. Incorporation of chemotherapy has proved beneficial in oncology, beginning from untreated solid tumours to the recurrent, unresectable metastatic tumours. The rationale for use of induction chemotherapy was based on the increased responsiveness to chemotherapy seen in the previously untreated patient and the possibility that chemotherapy-induced tumour shrinkage might improve local control [10,11].

In a trial designed to determine whether intensive induction chemotherapy administered before loco-regional treatment would improve survival of patients by Paccagnella A et al., with previously untreated, advanced nonmetastatic (stages III and IV) SCCHN showed there were no significant differences in loco-regional failure or in disease-free or overall survival between the patients receiving initial chemotherapy (Cisplatin and infusional fluorouracil with 5 day regimen course for 3 cycles) followed by loco-regional treatment and loco-regional treatment alone strategies, although the development of distant metastases was reduced in the former group. They also showed for operable patients, the only benefit from chemotherapy was a significant reduction in the incidence of distant metastases and for inoperable patients, chemotherapy improved local control, decreased the incidence of distant metastases, and improved the complete remission rate and overall survival [2].

In our study at a median follow up of 3 months, PF showed an individual decrease in the tumour and the nodal burden, but overall response of induction agents in controlling the malignancy was insignificant. Thus, the PF regimen has showed shrinkage in tumour and nodal burden, the % of complete response i.e. complete regression of the tumour is very low. Primary tumour response to induction therapy showed effective response in controlling the progression of the tumour in 22 cases showing a stable response (52.4%), with 12 cases having a partial response (28.6%), and 1 case of complete response (2.4%). The lymph Node response for chemotherapy also showed a significant reduction in the size or the bulk. Out of 39 nodal positive patients, 22 cases (50%) had stable response, 14 cases (31.8%) had partial response and 1 had complete disappearance of the node. To obtain an overall response for each patient, the response at the primary tumour and the regional nodes were combined, and the lesser response was taken as the overall response. Similar studies conducted by Charlotte et al., which showed no impact of histopathological differentiation of the tumour [12], our study showed better response of induction therapy in poor and moderately differentiated tumours and more failure rate in cases of well differentiated tumours.

We analysed the option of induction chemotherapy in advanced tumours where treatment options are limited and found that laryngeal carcinoma is one of the most common such malignancy. An analysis of the only phase 3 study which has compared induction chemotherapy, chemoradiotherapy and radiotherapy alone reported that PF induction chemotherapy was equivalent to Cisplatin based chemoradiotherapy and both were significantly better than radiotherapy alone in terms of 5 year survival with an intact larynx [13].

Study by Vermorken et al., where TPF induction regimen i.e addition of docetaxel to Cisplatin and 5-FU was compared with PF followed by radiotherapy alone in patients with unresectable tumours demonstrated TPF improved a better survival rate with an acceptable toxicity profile when compared to PF. Recent similar studies by Schrijvers et al., Hadad et al., have showed the superior response of induction chemotherapy with taxol group of chemotherapeutic agent (docetaxel/paclitaxel) along with Cisplatin and 5 fluorouracil in controlling the tumour progression, prolonged survival rate, increased disease free period; our study was confined only to conventional standard chemotherapeutic agents involving Cisplatin and 5-Fluorouracil because of financial instability of the patients and lack of availability of taxel compounds in the government hospital [6,14,15].

The overall major toxicity observed in our study was nonspecific adverse effects including diarrhea, constipation, myalgia, loss of taste, excessive sweating and weight loss constituting 50% among the cases. The usage of pre-medication drugs: Inj. Dexamethasone of 4-8mg; Inj. Rantac 50mg; Inj. Emeset 8mg in 100 ml NS over ½ hr may have resulted in fewer incidences of nausea and vomiting. The specific significant side effect noted in females was anaemia (p=0.00) and thrombocytopenia (p=0.021) and in males it was leucopenia. Other toxic effects likes asthenia was predominant in both the groups. Despite of use of premedication agent’s nausea and vomiting was noted in 20.5% of patients. Based on the common toxicity criteria manual, 47.6% of patients developed moderate and 42.1% developed mild adverse reactions related to induction chemotherapeutic agents. Only 9.5% of patients experienced severe and undesirable adverse reactions necessitating the requirement of active treatment. Neither severe nor death related adverse event was seen during the course of chemotherapy. This may indicate the dose related toxicity of Cisplatin and 5-FU is negligible if the patient’s general condition is adequate for starting chemotherapy along with necessary use of premedication agents.

With the use of cisplatin and 5-FU as induction chemotherapy agents in advanced and inoperable squamous cell carcinoma of head and neck, a distinct benefit was seen in stabilizing the tumour from progression. But achieving a significant complete response to the same is of faint possibility. An alternate multidrug regimen or multimodality treatment would be ideal to gain the optimum results from induction agents. Toxicity related to chemotherapy usually is transient at therapeutic doses, and can be controlled by adequate prophylactic measures.