A Prospective Randomised Comparative Study Between Weekly Cisplatin Versus Three Weekly Cisplatin with Radiotherapy in Unresectable Locally Advanced Head and Neck Cancer

Abstract

To compare the efficacy, compliance and the complications of weekly cisplatin 40 mg/m2 against the three weekly cisplatin 100 mg/m2 with EBRT(external beam radiotherapy) in unresectable locally advanced head and neck squamous cell carcinoma(LAHNSCC) Study design was Prospective randomized and comparative.85 Patients with histologically proven stage III–IVA LAHNSCC presenting from December 2017 to May 2019 were assigned to concurrent three weekly cisplatin 100 mg/m2 (arm 1) and weekly cisplatin 40 mg/m2 (arm 2) with EBRT. There were 41 patients were in arm 1 and 44 patients in arm 2. Statistical analysis was done using SPSS version 2.0. At 4 week of completion of treatment, response was assessed using RECIST(1.1) criteria.In Arm 1,61% patients and in arm 2 55% patients achieved complete response but the difference was statistically non- significant (p = 0.756).Median follow up was 12 months after which 49% patients in arm 1 and 38% in arm 2 had complete response whereas 12% patients in arm 1 and 15.5% patients in arm 2 had locoregional relapse. There was no statistically significant difference between the two arms in terms of mucositis, nausea,vomiting, dysphagia, acute skin reaction and ototoxicity. Leukopenia (p = 0.003),thrombocytopenia (p = 0.04) and acute renal toxicity (p  = 0.004) was significantly more in three weekly arm. As compared to three weekly cisplatin, weekly cisplatin with radiotherapy is an acceptable approach in a limited resource setting due to good patient compliance where a large number of patients are treated on outpatient basis.

Introduction

Head and neck cancer is the term used to describe a number of different malignant tumours that develop in the oral cavity, pharynx, larynx, nose and sinuses.

Worldwide, head and neck cancer accounts for more than 650,000 cases and 330,000 deaths annually and over 2,00,000 cases of head and neck cancers occur each year in India and approximately 50–60% of patients present with locally advanced head neck carcinoma [1].

Therapy for locally advanced HNSCC has the major goals of eradicating locoregional disease, treating distant micro-metastases, preserving organ function, and minimizing toxicities [2].

Recent meta-analysis of chemotherapy in head and neck cancer (MACH-NC) reveals an absolute survival benefit of 4.5% for chemo-irradiation (neoadjuvant, concurrent, adjuvant chemoradiation) in HNSCC, and 6.5% for concurrent chemoradiation over RT alone. The benefit of the addition of chemotherapy to locoregional treatment is consistent in all tumour locations of HNSCC. [3].

Concurrent cisplatin-based chemoradiation is currently the most widely used regimen for advanced head and neck cancer, which provides a significant improvement in 5 year overall survival (OS) compared with radiotherapy alone. A 100 mg/m² dose of cisplatin administered once every three weeks is the preferred therapeutic regimen as category 1 in NCCN Guideline of head and neck cancers (Version 1.2019), achieving 71% complete response (CR) rate and 34% 4 year survival [4, 5].

But its high emetic potential, nephrotoxicity and haematological toxicity demand further efforts towards improving its therapeutic and toxicity profiles.

At our institute more than 75% of the patients had locally advanced/advanced disease at the time they reported to us.

Non-surgical management with EBRT and concurrent cisplatin is the best available option since surgery is not always possible due to several reasons like advanced disease at presentation, low performance status, lack of awareness and unwillingness to surgery. Our study was aimed to further compare the efficacy, compliance and the complications of weekly cisplatin 40 mg/m2 with EBRT against the standard three weekly cisplatin 100 mg/m2 with EBRT in locally advanced squamous cell head and neck carcinoma patients in our scenario.

Methods

This prospective randomized comparative study was approved by the Ethical Committee of the Institution. Patient data consisted of those with locally advanced squamous cell carcinoma head and neck receiving definitive chemoradiotherapy in our department from December 2017 to May 2019. A total of 85 patients who were willing to give informed consent and fulfilling the specified inclusion and exclusion criteria were enrolled for the study.

Inclusion Criteria included patients who were > 18 years and < 75 years in age who had histopathologically proven head and neck squamous cell carcinoma. The disease was in locally advanced disease stage (III & IVA). Eastern Cooperative Oncology Group (ECOG) Performance status of the patients was 0–2.All were treatment naive except for biopsy. Signed study specific informed consent was given by the patient before randomization.

Patients who were excluded from the study were those with uncontrolled comorbidity, already receiving treatment in the form of chemotherapy or radiation or surgery and ECOG performance status more than 2. Pregnant and lactating women were kept out of the study. Patients with known hypersensitivity to cisplatin, distant metastasis or other synchronous malignancies were also excluded.

All patients were evaluated including history and physical examination, ENT examination complete blood count, renal function and liver function tests. Preventive dentistry and biopsy of the primary tumour was mandatory for all patients. Radiological investigations included CECT face and neck, chest radiography, ultrasound abdomen. All the patients were staged according to TNM staging system (AJCC 8th edition).

After pre-treatment evaluation and staging, patients were randomized into two arms by sequential randomization according to their first visit in our department.

As per Radiotherapy protocol, all the patients were treated with conventional External Beam Radiotherapy (EBRT) for a total dose of 70 Gy in 35fraction, with a protocol of 2 Gy per fraction and 5 days a week with shrinking field technique.

For concurrent chemotherapy,patients were randomised in two arms. In arm 1, concurrent three weekly Cisplatin (100 mg/m²) was given intravenously on day 1, 22, and 43 of the radiotherapy and in arm 2 concurrent weekly cisplatin (40 mg/m²) was given intravenously on days 1, 8, 15, 22, 29, 36, and 43 of the radiotherapy. Routine hydration and standard anti-emetic prophylaxis was given before and after chemotherapy as per institutional guidelines.

All patients were reviewed once weekly in the OPD to assess treatment-induced toxicity. These included acute in-field toxicity (mucositis and acute skin reaction), gastro intestinal toxicity (nausea, vomiting), haematological toxicity (haemoglobin, total leucocyte count, and platelet count) ototoxicity, and acute renal toxicity. Toxicity was graded according to the NCI—CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03. Acute toxicity was defined as toxicity that was noted during RT.

Response evaluation was performed after 4th week of completion of chemo-radiotherapy. Then patients were kept on follow up monthly till 12 months by physical examination, ENT examination, and CECT face and neck. Additional investigations were performed whenever necessary. Clinical and radiological responses were evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

Results

After taking permission from institutional ethical committee, 85 patients were enrolled in the study. Patients were randomised into two arms. Patients in Arm 1 received concurrent three weekly cisplatin 100 mg/m2 with while patients in arm 2 received weekly cisplatin 40 mg/m2 with definitive radiotherapy.

The treatment arms were reasonably comparable in terms of baseline characteristics including age, sex, performance status, primary site, stage and tumour differentiation (Table 1).

Table 2.

Acute toxicities

Toxicity	Arm 1 (cisplatin100 mg/m2)	Arm 2 (cisplatin 40 mg/m2)	P value
Nausea grade 2	20(49%)	17(39%)	0.458
Vomiting grade 2	20(49%)	11(25%)	0.150
Acute skin reaction grade 2	19(46%)	12(27%)	0.679
Dysphagia grade 3	23(56%)	19(43%)	0.449
Mucositis grade ¾	28(68%)	25(57%)	0.714
Anaemia grade 2	26(63%)	25(57%)	0.824
Leukopenia	38(93%)	28(64%)	0.003 (significant)
Thrombocytopenia	17(41%)	10(23%)	0.04 (significant)
Ototoxicity	8(19.5%)	7(15.9%)	0.77
Acute renal toxicity	34(83%)	16(36%)	0.004 (significant)

Table 1.

Baseline characteristics of patients treated with chemoradiotherapy using 100 mg/m2 or 40 mg/m2 cisplatin for head and neck squamous cell carcinoma

Characterstics	Arm 1(N = 41) Cisplatin 100 mg/m2	Arm 2 (N = 44) Cisplatin 40 mg/m2
Median age	53.9 (30–75)	54.9 (30–75)
Male, No. (%)	34 (83%)	39 (89%)
Female, No.(%)	7(17%)	5(11%)
Rural: Urban	24:17	26:18
Performance status:
ECOG 0	5(12%)	3(7%)
ECOG 1	15 (37%)	17 (39%)
ECOG 2	21 (51%)	24 (54%)
Addiction in any form	39(95%)	44(100%)
Tobacco chewing	22(54%)	31(70%)
Betel nuts	22(54%)	29(66%)
Smoking status:	30(73%)	32(73%)
Alcohol	18(44)	18(41%)
Both alcohol & smoking	18(44%)	18(41%)
Tumour site
Oral cavity	16	20
Oropharynx	11	10
Hypopharynx	3	3
Larynx	11	11
Stage at diagnosis, No. (%)
III	15	20
IVA	26	24
T stage
T1/T2	13	8
T3/4	28	36
N stage
N0	3	10
N1	13	13
N2	25	21

Locoregional Response

At 4th week of completion of treatment, response was assessed using the RECIST criteria.In three weekly cisplatin arm(Arm 1) 61% patient achieved complete response, 32% patients had partial response and 7% had progressive disease. In weekly cisplatin arm (Arm 2) 55% of the patients achieved complete response, 36% had partial response and 9% had progressive disease.More number of patients achieved complete response in three weekly cisplatin arm than weekly cisplatin arm but the difference was statistically non- significant (p = 0.756) [5].

In three weekly cisplatin arm 15 patients had stage III disease, out of them 87% patients achieved complete response and 13% achieve partial response,26 patients had stage IV disease and out of them 46% patients achieved complete response,42% achieved partial response and 12% had progressive disease.In comparison, in weekly cisplatin arm(arm 2) 20 patients had stage III disease out of them 79% achieved complete response, 16% achieved partial response and 5% had progressive disease, 24 patients had stage IV disease out of them 36% patients achieved complete response, 52% achieved partial response and 12% had progressive disease.

In our study, more patients with oropharyngeal carcinoma achieved complete response than the other site—90.9% in 3 weekly cisplatin arm and 80% in weekly cisplatin arm [6] while patients with oral cavity had poor outcome in both the arm as complete response was achieved by only 50% patients in arm 1 and 33% in arm 2.

At 6th month follow-up, 21 patients (51%) in three weekly arm achieved complete response and 4 patients (10%) pateints had locoregional relapse whereas in weekly cisplatin arm 19 patients (42.2%) patients achieved complete response and 5 patients (11%) had locoregional relapse. Out of 25 patients of three weekly cisplatin arm,16 patients had either stable or progressive disease as compared to 20 patients out of 24 in weekly cisplatin arm.

Those patients with stable or progressive disease were managed with either adjuvant chemotherapy or surgery.

At 12th month follow-up, 20 patients (49%) had complete response and 5 patients (12%) relapsed whereas in weekly cisplatin arm,17 patients (38%) had complete response and 7 patients (15.5%) had locoregional relapse.

Toxicity

The main treatment toxicities are summarized in Table no. 2. Acute toxicities were observed more in three weekly cisplatin arm although mild to moderate nausea and vomiting occurred in almost all patients despite anti-emetic prophylaxis. The difference between the two arms in terms of grade 3 or 4 severe mucositis, grade 2 or moderate nausea, vomiting, grade 3 or severe dysphagia, acute skin reaction and ototoxicity was not statistically significant (p value > 0.05). However, there was statistically significant difference between the two arms in terms of haematological toxicity. Leukopenia (p value = 0.003) and thrombocytopenia (p value = 0.04) was significantly more frequent in the 3-weekly arm, whereas the difference for anaemia was insignificant.

Frequency in difference of acute renal failure in the form of deranged serum creatinine was also statistically significant (p value = 0.004) for both the arms as it was seen more in arm 2 and was of mild grade [7].

Statistical analysis was conducted using SPSS version 20.0. The qualitative data was compared by applying chi-square test or Fisher’s exact test, as appropriate. A p-value less than 0.05 was considered significant.

Discussion

Locally advanced Head and neck cancer accounts for 50–60% of all head and neck cancers, particularly in developing countries like India. Chemoradiotherapy has been demonstrated to be the standard of care in the non-surgical management of these patients. Benefits of using combined modality therapy for the treatment of locally advanced HNC comes at the cost of markedly increased acute toxicity. Therefore, using various schedules of concurrent cisplatin with EBRT has evolved as an area of interest to overcome the problem of increased acute toxicity.

Our study was aimed to compare concurrent 40 mg/m2 cisplatin weekly against concurrent 100 mg/m2 cisplatin three weekly with EBRT in definitive setting for locally advanced HNC at our institute.

The most common toxicity we observed in our patients was mucositis and was also the most common cause of interruption of the treatment, all the patients suffered mucositis during the course of the treatment.In three weekly cisplatin arm, 63% of the patients had grade 3 or severe mucositis while 52% of the patients had grade 3 mucositis in weekly cisplatin arm. Mucositis was observed to be slightly higher in three weekly arm but it was not statistically significant (p value = 0.714) [5, 8].

Haematological toxicity was another known adverse effect commonly encountered during concurrent chemordiotherapy which we managed with blood transfusion, nutrition support and supportive medication like colony stimulating factor. More haematological toxicity were observed in three weekly cisplatin arm patients. Anaemia was observed to be in 73% patients of three weekly arm and in 68% patients of weekly cisplatin arm 68%. Leukopenia was significantly higher in three weekly cisplatin arm patients (p value < 0.05), 93% of three weekly cisplatin arm patients developed leukopenia during the course of treatment while 64% patients in weekly cisplatin arm [8, 9]. Thrombocytopenia was also observed to be higher in three weekly cisplatin arm,41% patients developed thrombocytopenia in three weekly cisplatin arm and 23% in weekly cisplatin arm.

Acute renal toxicity is known side effect of cisplatin and it is dose dependent. In our study renal toxicity was significantly higher in three weekly cisplatin arm patients (p value < 0.05), 83% patients developed acute renal toxicity in three weekly arm and only 36% in weekly cisplatin arm [10, 11].

There is no statistically significant difference in response (complete as well as partial) between the two arms. Our study showed that weekly cisplatin arm experienced almost the same response as the three weekly cisplatin arm but with less toxicity [5, 12, 13].

The results of our study are comparable with the results of a meta-analysis of Weekly Versus Three-Weekly Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head and Neck Cancer conducted by PETR SZTURZ et al. [8].

Similar study was carried out in our institute using cetuximab with radiation in unresectable locally advanced head and neck cancer and results were comparable [14].

In our centre another similar study was performed in cervical cancer using taxane and cisplatin chemotherapy combination [15].

Our prospective randomised study on non-operative management of locally advanced HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with definite chemoradiotherapy with concurrent weekly 40 mg/m² versus three weekly 100 mg/m² cisplatin concludes that the complete response achieved was comparable in both the arms as the difference in clinical or radiological response was not statistically significant [5]. The acute toxicities were found to be more in three weekly arm especially haematological and acute renal toxicities and were statistically significant [7, 16, 17]. Other toxicities like mucositis, acute skin reaction, gastrointestinal toxicities were also found to be more with three weekly cisplatin arm but were not statistically significant [18, 19].

In our study the patients were equally distributed and prospectively randomised in both the arms in terms of age, gender, ECOG performance status, stage and site of primary lesion. As such in the study the treatment compliance and tolerance was better with weekly cisplatin but the treatment related complications were more with three weekly cisplatin, hence concurrent weekly cisplatin with definitive radiotherapy is an acceptable alternative standard of care to three weekly cisplatin in a limited resource setting where a large number of patients are treated on outpatient basis.

As our study is not powered enough to comment on overall survival and disease free survival, further randomised study is needed with large number of patients.

Abbreviations

EBRT

External Beam Radiotherapy

HNSCC

Head and neck squamous cell carcinoma

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.