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ORIGINAL ARTICLE
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An observational comparative study of weekly and 3 weekly concurrent cisplatin-based chemoradiotherapy in locally advanced head-and-neck cancer in a peripheral medical college


1 Department of Radiation Oncology, Burdwan Medical College, Purba Bardhaman, West Bengal, India
2 Department of Pathology, Diamond Harbour Government Medical College, Diamond Harbour, West Bengal, India

Date of Submission21-Jul-2022
Date of Decision28-Jul-2022
Date of Acceptance14-Aug-2022
Date of Web Publication22-Oct-2022

Correspondence Address:
Rajat Bandyopadhyay,
D 308, Shreshta Garden, Kalipark, Rajarhat Road, Kolkata - 700 136, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_119_22

  Abstract 


Introduction: Concurrent chemo-radiation with 100m/m2 three weekly cisplatin is the standard of care in inoperable locally advanced head and neck cancer (LAHNC) but is associated with significant toxicities. The objective of the study was to assess the tumour response and toxicities in the three weekly and lower dose weekly cisplatin based chemo radiation regimens. Methodology: The prospective study was conducted in a peripheral medical college from May 2020 to July 2021. One hundred and twelve patients were recruited, 56 in each arm. The three weekly arms received 100mg/m2 cisplatin whereas the weekly arm received weekly 40mg/m2 cisplatin both concurrently with radiation dose of 70 Gray in 35 fractions over seven weeks. One-way analysis of variance was used to compare means of three or more samples for numerical data. Unpaired proportions were compared by Chi-square test or Fischer's exact test. Results: One hundred patients completed the study and were evaluable, 42 in the three weekly arm and 48 in the weekly arm. Disease response at 12 months in the two arms was not statistically significant. The toxicities were lower in weekly arm as compared to three weekly arms but were not statistically significant. Conclusion: The study confirms that weekly concurrent cisplatin is an acceptable alternative treatment to three weekly regimens in inoperable LAHNC. The lower dose weekly concurrent cisplatin regime is better tolerated in our patients with increased treatment compliance.

Keywords: Cisplatin, concurrent chemo radiotherapy, locally advanced head and neck cancer



How to cite this URL:
Biswas R, Bandyopadhyay R, Saren S, Banerjee S. An observational comparative study of weekly and 3 weekly concurrent cisplatin-based chemoradiotherapy in locally advanced head-and-neck cancer in a peripheral medical college. J Mar Med Soc [Epub ahead of print] [cited 2022 Dec 7]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=359371




  Introduction Top


Head-and-neck cancers are the sixth most common cancers[1] and have strong association with smoking and drinking.[2] The incidence of human papilloma virus-related oropharyngeal cancer is increasing,[3] which responds better to radiation therapy and chemotherapy.[4] Head-and-neck cancer constitutes around 30% of cancer in India.[5] Most patients are male with inoperable locoregionally advanced disease.[6] The treatment of inoperable locoregionally advanced disease with radiation alone causes poor results. Concurrent chemoradiation with cisplatin is associated with significant overall and disease-free survival and is now the standard of care[7] in such cases. The standard regime of 100mg/m2 3 weekly cisplatin along with 70 Gray 35 fractions take external beam radiotherapy (EBRT)[8] has improved survival and disease control but is associated with increased toxicities, compliance issues, and treatment breaks.[9],[10],[11] Weekly lower dose cisplatin has been studied in other centers of the world and has comparable outcomes but lower toxicity. Our population of locally advanced head-and-neck cancer (LAHNC) patients often has poor nutritional status and has pronounced toxicity with high-dose concurrent chemoradiation impacting compliance and treatment outcome. Against this background, the present study was undertaken to assess the tumor response and toxicities in the lower dose weekly concurrent cisplatin-based chemoradiation in comparison to the standard 3 weekly higher dose cisplatin-based concurrent chemoradiation regimes in our population. The study was designed as a comparative observational study. The primary objective of the study was to assess the tumor response in the two arms. The secondary objective was to assess acute and late toxicities among the two arms.


  Methodology Top


The study was conducted in the Department Radiation Oncology from May 2020 to July 2021 with a median follow-up period for 1 year. The study was started after clearance from the Institutional Ethics Committee and written informed consent of the participant. Total sample size was 112 with 56 patients in each arm. All histologically proven cases of locally advanced squamous cell head-and-neck carcinoma patients aged between 18 and 70 years with ECOG 0-2 and creatinine clearance ≥50 ml/min attending the oncology outpatient department were included in the study. Patients with deranged blood counts, liver and renal dysfunction, prior history of radiotherapy or chemotherapy, pregnancy and cancers of skin, orbit, salivary glands, paranasal sinuses, nasopharynx and oral cavity, and those who received induction chemotherapy were excluded from the study. The radiation was planned to be delivered by Theratron 780 C with Cobalt 60 source with two-dimensional (2D) technique 5 days a week for 7 weeks to a total dose of 70 Gray in 35 fractions. The patients were immobilized using personalized thermoplastic devices. The chemotherapeutic agent used was cisplatin which was administered with adequate hydration and proper pre- and post-medication. The 3 weekly arms received 100 mg/m2 cisplatin with 70Gray in 35 fractions external-beam radiotherapy (EBRT), whereas the weekly arm received weekly 40 mg/m2 cisplatin with 70 Gray in 35 fractions EBRT. Data were collected as pre-designed pro forma and analyzed using appropriate statistical methods. RECIST criteria were used to assess tumor response. CTCAE (v 5) criteria were used to assess acute and late toxicities. Weekly assessments of the patients were done clinically and also by biochemical and hematological parameters.

For statistical analysis, the data have been summarized as mean and standard deviation for the numerical variables and count and percentages for the categorical variables. One-way analysis of variance was a technique used to compare the means of three or more samples for the numerical data (using the F distribution). A Chi-squared test was any statistical hypothesis test, wherein the sampling distribution of the test statistic is a Chi-square distribution when the null hypothesis is true. Unpaired proportions were compared by the Chi-square test or Fischer's exact test, as appropriate. If the calculated P value was below the threshold chosen for statistical significance, and then, the null hypothesis was rejected in favor of the alternative hypothesis. P ≤ 0.05 was considered statistically significant.


  Results Top


The total sample size was 112 with 56 patients in each arm. Four patients in the weekly arm and eight patients in the 3 weekly arms did not complete treatment as planned either due to toxicity or abandoned treatment midway. Out of 112 patients initially recruited, 100 patients completed the study and were evaluable, 52 patients in the weekly arm and 48 patients in the 3 weekly arms. The two arms were comparable in terms of age distribution, sex distribution, performance status, stage, primary site, histological grade, body surface area, and baseline creatinine clearance level [Table 1]. Both the groups received 70 Gray in 35 fractions EBRT. The follow-up was done for 1 year after the completion of treatment.
Table 1: Baseline characteristics

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In the 3 weekly arms, 1 (2.1%) patient had treatment interruption at the 4th week, 4 (8.5%) patients had treatment interruption at the 6th week, and 8 (17.0%) patients had treatment interruption at the 6th and 7th weeks. In the weekly arm, 1 (2.0%) patient had treatment interruption at the 4th week, 1 (2.0%) patient had treatment interruption at the 6th week, and 2 (3.9%) patients had treatment interruption at the 6th and 7th weeks. The association of treatment interruption with the two arms was not statistically significant (P = 0.0619).

Thirteen (27.7%) patients had complete response (CR) at the end of the treatment at the 6th week, 13 (27.5%) patients had CR at 3 months, 15(31.25%) patients had CR at 6 months and 15(31.25%) had CR at 1 year in the 3 weekly arms. 13(25.0%) patients had CR at 6 weeks, 12 patients had CR at 3 months, 13 patients(25.0%) had CR at 6 months, and 11(21.5%) patients had CR at 1 year. Association of CR in the arms was not statistically significant (P = 0.9203). In the 3 weekly arms, 13 (27.7%) patients had CR, 5 (10.6%) patients had progressive disease (PD), 16 (34.0%) patients had partial response (PR), and 13 (27.7%) patients had stable disease (SD) at the end of the treatment at 6 weeks. In the weekly arms, 13 (25.5%) patients had CR, 6 (11.8%) patients had PD, 18 (35.3%) patients had PR, and 14 (27.5%) patients had SD at the end of the treatment at 6 weeks. Association of response at the end of the treatment at 6 weeks with arms was not statistically significant (P = 0.9939).

In the 3 weekly arms, 13 (27.7%) patients had CR at 3 months, 6 (12.8%) patients had PD at 3 months, 16 (34.0%) patients had PR at 3 months, and 12 (25.5%) patients had SD at 3 months. In the weekly arm, 12 (23.5%) patients had CR at 3 months, seven (13.7%) patients had PD at 3 months, 18 (35.3%) patients had PR at 3 months, and 14 (27.5%) patients had SD at 3 months. Association of response at 3 months with the arms was not statistically significant (P = 0.9734). In the 3 weekly arms, 15 (31.25%) had CR at 6 months , six (12.5%) had PD at 6 months,17 (35.41%) patients had PR at 6 months and 10 (20.83%) patients had stable disease at 6 months. In the weekly arm,13 (25.0%) patients had CR at 6 months, 10(19.26%) patients had SD at 6 months, 16(30.76%) had PR at 6 months and 13 (25.0%) patients had SD at 6 months [Table 2]. Association of response at 6 months with arms was not statistically significant (P = 0.7866). Association of response at the end of the treatment versus subsets was not statistically significant (P = 0.0945).
Table 2: Response assessment

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The difference in the incidence of Grade 1 and Grade 2 skin toxicity in 3 weekly and weekly arms was not statistically significant (P = 0.2955) and (P = 0.2451), respectively [Table 3]. One (2.1%) patient had Grade 3 skin toxicity at the 5th week in the 3 weekly arms. Grade 3 toxicity first appeared in weekly arm at the 6th week. One (2.1%) patient had Grade 4 toxicity at the 6th week in 3 weekly arms. Grade 4 skin toxicity first appeared in the weekly group at the 7th week. One (1.9%) patient had Grade 4 skin toxicity at the 7th week in the weekly group, whereas 3 (6.4%) patients had Grade 4 skin toxicity at the 7th week in 3 weekly groups. At the 7th week, 6 (12.8%) patients had Grade 3 skin toxicity in 3 weekly group and 6 (11.5%) patients had Grade 3 skin toxicity in the weekly arm. The incidences of Grade 1 and Grade 2 mucositis in 3 weekly and weekly arms were similar and not statistically significant [Table 4]. Grade 3 mucositis first appeared in both the arms at the 6th week. Eight (17.0%) patients were found to have Grade 3 mucositis at the 6th week in 3 weekly arm and 9 (17.3%) patients had Grade 3 mucositis at the 6th week. Association of mucositis at the 6th week with arms was not statistically significant (P = 0.0530). In 3 weekly arms, 16 (34.0%) patients had Grade 3 mucositis and 6 (12.8%) patients had Grade 4 mucositis at the 7th week. In the weekly arm, 7 (13.5%) patients had Grade 3 mucositis and 3 (5.8%) patients had Grade 4 mucositis at the 7th week. Association of mucositis at the 7th week with the two arms was statistically significant (P = 0.0373).
Table 3: Skin toxicity

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Table 4: Mucositis

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Differences in xerostomia & Dysphagia in the 3 weekly and weekly arms were not statistically significant [Table 5] and [Table 6]. In the 3 weekly arms, the mean creatinine clearance at baseline (mean ± s. d.) was 68.9787 ± 5.2606. In the weekly group, the mean creatinine clearance at the 1st wk (mean ± s. d.) was 67.3137 ± 4.3474. The distribution of mean creatinine clearance at baseline with the arms was not statistically significant (P = 0.0899).
Table 5: Xerostomia

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Table 6: Dysphagia

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  Discussion Top


The analysis of our results shows that was no significant difference in response at 1 year among the two arms (p-value 0.56). The incidence of mucositis was lower in the weekly arm as compared to 3 weekly arms. The incidence of skin toxicity, anemia, and leukopenia was similar in the two groups. These results from our study are in agreement with other studies done elsewhere.

Mackiewicz et al.[12] studied acute toxicities in 104 patients with Arm A receiving 3 weekly 100 mg/m2 cisplatin plus concurrent radiotherapy (50 patients) and Arm B receiving weekly 40 mg/m2 cisplatin with radiotherapy (54 patients) and found a higher incidence of acute severe mucositis along with renal toxicity, neutropenia, and leukopenia in 3 weekly regimes than weekly cisplatin treatment administered with radiotherapy.

Sahoo et al.[13] made a comparative study of 30 patients about weekly versus 3 weekly cisplatin-based chemoradiation in LAHNCs with Arm A consisting of 15 patients, receiving injection cisplatin 30 mg/m2 weekly along with radiation and Arm B consisting of 15 patients, receiving injection cisplatin 100mg/m2 on a 3 weekly basis along with radiation. They found that the CR rate was slightly better in 3 weekly cisplatin arms compared to weekly cisplatin arm but there is a trend toward increase in Grades 3 and 4 mucositis along with Grade 3 vomiting in 3 weekly cisplatin arms.

Szturz et al.[14] did a systematic review and meta-analysis of aggregate data of 52 patients with standard three-weekly high-dose cisplatin (100 mg/m2, 3 doses) in Arm A and weekly low-dose protocol (50 mg/m2, 6 doses) in Arm B. Radiation doses were usually 60–66 Gray (Gy) in the postoperative setting and 66–70 Gray in the definitive setting. The study concluded that there was no difference in treatment efficacy as measured by the overall survival or response rate between the chemoradiation settings with low-dose weekly and high-dose 3 weekly cisplatin regimens. In the definitive treatment setting, the weekly regimen was more compliant and significantly less toxic with respect to severe (Grade 3–4) myelosuppression (leukopenia and neutropenia), severe nausea and/or vomiting, and severe nephrotoxicity.

Helfenstein et al.[15] conducted a study on 3 weekly or weekly cisplatin concurrently with radiotherapy for patients with squamous cell carcinoma of the head and neck. The multicenter, retrospective analysis, included 314 patients, with Arm A receiving 3 weekly cisplatin 100 mg/m2 plus concurrent radiotherapy on 127 patients and Arm B receiving weekly cisplatin 40 mg/m2plus concurrent radiotherapy on 187 patients and found no difference in survival between the two regimes, but weekly cisplatin may be accepted as alternative treatment considering the toxicity profile. Reaching a cumulative dose of ≥200mg/m2, cisplatin was shown to be associated with improved outcome.

Nanda et al.[16] carried out a prospective randomized study comparing concurrent chemo radiation with weekly cisplatin and 3 weekly cisplatin in locally advanced oropharyngeal carcinoma, on 60 patients, Arm A consisting of 29 patients, with cisplatin 40mg/m2 and concurrent chemoradiation and Arm B consisting of 31 patients, with cisplatin 100mg/m2 plus concurrent radiation of 70 Gray in 35 fractions in both the arms. The authors concluded that there was no statistical difference in overall response, acute radiation, and hematological toxicities between the two study groups.

Our study reaffirms that there is no statistically significant difference between weekly concurrent cisplatin-based chemoradiotherapy and 3 weekly cisplatin arms in terms of response and major toxicities in inoperable LAHNC. The present study is an observational study in a single tertiary care center with a small sample size which is its limitation.


  Summary and Conclusions Top


In the present study, no statistically significant outcome and toxicity are seen among the two compared groups, apart from a lesser incidence of mucositis in the weekly arm. Compliance being an issue, lesser toxicities may result in better compliance, treatment completion, and outcome. The present hospital-based study in a peripheral medical college confirms that weekly concurrent cisplatin regimen may be accepted as alternative treatment to the standard 3 weekly concurrent cisplatin regimens in view of less toxicities, similar response, and better tolerance.

Acknowledgment

We gratefully acknowledge the contribution of the patients and all staff of the Department of Radiation Oncology for their co-operation in the study. We are also indebted to Dr. Arunima Chaudhuri, Associate Professor, Department of Physiology, Dr. Abhishek Basu, Assistant Professor, and Dr. Pratibha Kole, Junior Resident, Department of Radiation Oncology for their help.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Mackiewicz J, Rybarczyk-Kasiuchnicz A, Łasińska I, Mazur-Roszak M, Świniuch D, Michalak M, et al. The comparison of acute toxicity in 2 treatment courses: Three-weekly and weekly cisplatin treatment administered with radiotherapy in patients with head and neck squamous cell carcinoma. Medicine (Baltimore) 2017;96:e9151.  Back to cited text no. 12
    
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Helfenstein S, Riesterer O, Meier UR, Papachristofilou A, Kasenda B, Pless M, et al. 3-weekly or weekly cisplatin concurrently with radiotherapy for patients with squamous cell carcinoma of the head and neck-A multicentre, retrospective analysis. Radiat Oncol 2019;14:32.  Back to cited text no. 15
    
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Nanda R, Katke A, Suneetha N, Thejaswini B, Pasha T, Jagannath KP, et al. A prospective randomized study comparing concurrent chemoradiation with weekly and 3 weekly cisplatin in locally advanced oropharyngeal carcinoma. South Asian J Cancer 2019;8:178-82.  Back to cited text no. 16
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