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Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Original article / research
Year : 2024 | Month : June | Volume : 18 | Issue : 6 | Page : XC01 - XC05 Full Version

Synergistic Potential of Methotrexate and Gefitinib: A Promising Palliative Approach for Advanced and Recurrent Head and Neck Cancers

Published: June 1, 2024 | DOI: https://doi.org/10.7860/JCDR/2024/71298.19550

Tabassum Samani, Arun Kumar Yadav, Deepanshi Jain, Utkarsha Singh, Roopali

1. Associate Professor, Department of Radiation Oncology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India. 2. Assistant Professor, Department of Radiation Oncology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India. 3. Junior Resident, Department of Radiation Oncology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India. 4. Junior Resident, Department of Radiation Oncology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India. 5. Assistant Professor, Department of Radiation Oncology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India.

Correspondence Address :
Dr. Tabassum Samani,
Associate Professor, Department of Radiation Oncology, Sarojini Naidu Medical College, Agra-226002, Uttar Pradesh, India.
E-mail: tabassumsamani@yahoo.co.in

Abstract

Introduction: Head and Neck Cancers (HNCs) in India account for 30% of all cancers, out of which 60-80% of patients present with advanced disease, leaving the patients with limited survival and poor Quality of Life (QoL). Poor nutritional conditions, advanced disease presentation, limited tolerance, and socio-economic constraints necessitate the development of appropriate and effective palliative treatment options that are also easily available. One such palliative approach has been explored, and its relevance and applicability are discussed here.

Aim: To study the role of weekly intramuscular injection Methotrexate (MTX) along with oral Tablet Gefitinib in advanced unresectable, recurrent, or residual HNCs.

Materials and Methods: A retrospective analysis of 50 patients was carried out in the Department of Radiation Oncology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India. All patients included had advanced HNC and were ineligible for curative treatment. All received weekly intramuscular injection MTX 40 mg/m2 and Tablet Gefitinib administered orally in a dose of 250 mg once daily. These patients were assessed for tumour response, acute toxicities, symptomatic relief, and median survival. All the data were recorded in Microsoft Excel and analysed using Statistical Package for Social Sciences (SPSS) software version 28.0.

Results: This study included 50 patients (45 males, 5 females) with a mean±SD age of 49±8.8 years, all diagnosed with histologically confirmed squamous cell carcinoma, predominantly at stage 3 (six patients) and stage 4 (44 patients). Median survival was 5.9 months. According to RECIST (Response Evaluation Criteria in Solid Tumours) criteria, no complete responses were observed; 18 (36%) had a partial response, 21 (42%) had stable disease, and 11 (22%) had progressive disease. The treatment was well-tolerated, providing notable relief in pain and dysphagia symptoms. In terms of toxicity, grade-3 mucositis was observed in 10 patients, and none had grade-4. Grade-3-4 neutropenia and anaemia were seen in six and eight patients, respectively.

Conclusion: The use of MTX and gefitinib combination in advanced HNCs has the potential to substantially alleviate pain, provide symptomatic relief concerning dysphagia and speech, and hence improve the overall QoL.

Keywords

Chemotherapy, Metronomic, Neoplasms, Squamous cell carcinoma, Upper aerodigestive tract neoplasms

Introduction
Globally, 57.5% of HNCs occur in Asia, particularly in India, where they account for approximately 30% of all cancers (1). According to GLOBOCAN 2020 data, cancer of the lip and oral cavity is the most common cancer in males in India, while in females, it ranks as the fourth most common (2). The majority of HNCs present in locally advanced stages (stages III and IV). Lack of knowledge among the population, socio-economic restraints, and limited availability of medical care to the susceptible population contribute to the higher incidence of locally advanced HNCs (3). This trend is also attributed to widespread habits such as tobacco consumption, alcoholism, and prevalent bidi and cigarette smoking across all segments of society in India. Squamous cell carcinomas constitute approximately 95% of these HNCs (4).

Advanced HNC patients quite often experience residual disease, recurrence, or metastasis, compromising survival and QoL. Extensive prior treatments reduce tolerance to standard chemotherapy. Around 60-80% of HNC patients present in an advanced stage (5), and this problem is further complicated by the non availability of tertiary cancer centres in every region of India and financial burdens, which increase the time between the diagnosis and definitive treatment (6). Effective, affordable, and well-tolerated palliative treatments are essential to improve overall survival and QoL. There are no evidence-based guidelines for the standard practice of palliative care in advanced HNCs. Surgery is typically not an option for patients with advanced lesions and poor performance status because a sizeable amount of disease would still be present (3). Chemotherapy aims to relieve symptoms, prevent complications, and improve overall and progression-free survival, as well as QoL. The chosen treatment regimen should prioritise being well-tolerated, cost-effective, and associated with minimal toxicity to ensure optimal patient outcomes.

Numerous phase II-III studies (7),(8),(9) comparing combination chemotherapy to single-agent therapy have consistently shown a statistically significant improvement in tumour response with the former but at the expense of increased rates of toxicity. In cases where prior combination chemotherapy has been ineffective and concerns about toxicity arise, single-agent chemotherapy is currently recommended (10). Notably, earlier studies have indicated that MTX along with tablet Gefitinib for recurrent HNCs can offer a good QoL on an outpatient basis (9),(11).

MTX has diverse applications in treating cancers like breast cancer, HNCs, osteogenic sarcoma, and more. While it demonstrates widespread distribution and favourable response rates, it has potential toxicities. Myelosuppression is the dose-limiting toxicity. Mucositis, often emerging 3-7 days post-MTX therapy, can also be dose-limiting. Nausea, vomiting, and dermatological manifestations may occur (4).

Approximately 80-90% of Head and Neck Squamous Cell Carcinomas (HNSCCs) exhibit increased expression or contain genetic variations in Epidermal Growth Factor Receptor (EGFR), and these changes directly influence overall survival and progression-free survival (12),(13),(14). Hence, gefitinib, an EGFR tyrosine kinase inhibitor, plays a significant role as targeted therapy in HNCs. In previous studies (9),(15), the combination of MTX with Gefitinib, an EGFR targeting agent, has shown notable positive effects and response rates in advanced HNCs. Gefitinib toxicity may manifest in the form of elevation in blood pressure, pruritus, dry skin with mainly a pustular, acneiform skin rash, mild nausea, vomiting, and mucositis (11),(16).

In lower-middle-income countries like India, especially in rural, illiterate, and below poverty-line populations, the accessibility and affordability of MTX and gefitinib chemotherapy make it a viable option. Recognising its notable positive effects, authors undertook a retrospective analysis within the department at Sarojini Naidu Medical College, Agra, Uttar Pradesh, India where most patients belong to the lower socio-economic strata. This analysis focused on patients with advanced recurrent or metastatic HNCs who underwent intramuscular administration of MTX weekly along with tablet Gefitinib orally once daily. The evaluation encompassed an assessment of subjective and objective responses and the toxicity profile associated with this treatment approach. Hence, the aim of the study was to carry out a retrospective analysis and study the role of weekly intramuscular injection MTX at a dose of 40 mg/m2 along with Tablet Gefitinib administered orally in a dose of 250 mg once daily in advanced unresectable, residual, recurrent HNCs.
Material and Methods
This cross-sectional study was conducted in the Department of Radiation Oncology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India. All procedures performed were by the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study included patients diagnosed with advanced (stage 3-4), residual, or recurrent HNCs between the years 2018 and 2021, and the data were analysed retrospectively from their case records in 2023. These patients were either deemed ineligible for curative treatment or had previously undergone curative treatment (in the form of surgery, chemotherapy, or radiotherapy) but experienced recurrence or residual disease, necessitating palliative care. The chosen palliative treatment for these patients involved the administration of intramuscular MTX (inj.MTX) at a weekly dosage of 40 mg/m2 (17),(18) with tablet Gefitinib administered orally in a dose of 250 mg once daily (16).

Inclusion criteria:

• Histologically proven Squamous Cell Carcinoma (SCC) of the head and neck
• Stage 3-4 disease/residual disease/recurrent disease
• Absence of contraindications for the prescribed therapy
• Availability of all clinical, pathological details, and supporting evidence.

Exclusion criteria:

• Patients eligible for curative treatment.
• Cancers of the nasopharynx, thyroid, and secondaries of the neck with unknown primary
• Pregnant or lactating females.

Study Procedure

A total of 50 patients met the criteria and were deemed suitable for inclusion in this study. The analysis was conducted retrospectively by examining the case records of these patients to assess the outcomes and implications of the palliative treatment.

Analysis: Baseline characteristics of the patients were systematically documented from their clinical case records. The American Joint Committee on Cancer (AJCC 8th edition)-TNM system (19) was employed for staging the disease. Weekly assessments were conducted to evaluate tolerance, treatment response, and treatment-related toxicity. Subjective response, specifically concerning pain, was gauged using the Mankoski Pain Scale (20) as follows:

0- Pain-free
1- Very minor annoyance - occasional minor twinges. No medication needed.
2- Minor annoyance - occasional strong twinges. No medication needed.
3- Annoying enough to be distracting. Mild painkillers are effective (aspirin, ibuprofen).
4- Can be ignored if you are really involved in your work, but still distracting. Mild painkillers relieve pain for 3-4 hours.
5- Can’t be ignored for more than 30 minutes. Mild painkillers reduce pain for 3-4 hours.
6- Can’t be ignored for any length of time, but you can still go to work and participate in social activities. Stronger painkillers (codeine, acetaminophen-hydrocodone) reduce pain for 3-4 hours.
7- Makes it difficult to concentrate and interferes with sleep. You can still function with effort. Stronger painkillers are only partially effective. Strongest painkillers relieve pain (extended-release form of oxycodone, morphine).
8- Physical activity severely limited. You can read and converse with effort. Nausea and dizziness set in as factors of pain. Strongest painkillers reduce pain for 3-4 hours.
9- Unable to speak. Crying out or moaning uncontrollably- near delirium. Strongest painkillers are only partially effective.
10- Unconscious. Pain makes you pass out. The strongest painkillers are only partially effective.

The score was further categorised as mild, moderate, and severe according to the Mankoski scale (20):

• Mild pain is defined as a score of 0-3
• Moderate pain is defined as a score of 4-6
• Severe pain is defined as a score of 7-10

Dysphagia was graded according to modified Takitas Grading (21) from 1-6 as mentioned below:

• Grade-1- able to swallow solids normally;
• Grade-2- mild difficulty in swallowing solids, needs water to swallow;
• Grade-3- not able to swallow solids, only swallows semisolids;
• Grade-4- not able to swallow solids and semisolids, only swallowing liquids;
• Grade-5- not able to swallow liquids but able to swallow saliva;
• Grade-6- not able to swallow saliva also, complete dysphagia.

Objective tumour response was analysed in alignment with RECIST Criteria 1.1 (22). The evaluation of chemotherapy-related toxicity focused on parameters such as neutropenia and anaemia, adhering to the Common Terminology Criteria for Adverse Events (CTCAE) classification (23). Regular monitoring and documentation of these criteria allowed for a comprehensive analysis of the treatment outcomes and associated effects in the studied patient cohort.

Statistical Analysis

All the data were recorded in Microsoft Excel and analysed using SPSS software version 28.0.
Results
In this study, a total of 50 patients met the inclusion criteria, and their demographic details are summarised in (Table/Fig 1). Among the participants, 45 were males and five were females, with a mean±SD age of 49±8.8 years. The distribution of primary tumour sites included the oral cavity in 35 (70%) patients, oropharynx in 8 (16%). Among the previously treated patients (42 in total), seven received radiotherapy only, nine received chemotherapy only, and 26 underwent concurrent chemoradiation. Additionally, eight patients were selected for upfront MTX therapy (Table/Fig 2).

Treatment time varied from a minimum of five weeks to a maximum of 35 weeks. Since the majority received injections on an outpatient weekly basis, the hospital stay ranged from 0 to 3 days. The average cost per cycle per patient was calculated to be INR 50/- as most of the time, the above-mentioned drugs were available through government supply. The median survival duration was determined to be 5.9 months (Table/Fig 3). In terms of treatment-related toxicity, 6 (12%) out of 50 patients developed grade-3 or 4 neutropenia, 8 (16%) patients experienced anaemia, and 10 (20%) patients complained of MTX-induced oral mucositis; however, all were well-managed conservatively. One (2%) patient developed a local injection site abscess. Gefitinib-induced acneiform rash and pruritus were witnessed in 1 (2%) patient, which was well managed by antihistaminic medications and topical moisturisers. Overall, the treatment was well-tolerated by most patients, with significant symptomatic relief observed in terms of pain and dysphagia as well as speech.

As per the RECIST 1.1, none of the patients exhibited a complete response, other criteria is shown in (Table/Fig 4).

Subjective symptomatic response, measured in terms of pain and dysphagia, was also evaluated, and pain was measured using the Mankoski Pain Scale (Table/Fig 5). Before treatment, all 50 patients were assessed: none had mild pain. After five weeks of treatment, 5 (10%) patients experienced mild pain, 35 (70%) had moderate pain, and 10 (20%) had severe pain. The distribution shifted from predominantly severe pain before treatment to mostly moderate pain after, with some patients reporting being pain-free. This indicates an overall improvement in symptomatic pain.

Out of the 50 patients, 28 (56%) had dysphagia. Before treatment, out of the 28, none had grade-1 dysphagia. After five weeks of treatment, 2 (4%) patients had grade-1 dysphagia (Table/Fig 6). Before treatment, most patients were in the grade-3-5 category, but after treatment, most were in the grade-2-4 category, indicating subjective improvement in dysphagia for all patients (Table/Fig 7).

Gross reduction in lesion size was also seen with lesions almost disappearing in some patients (Table/Fig 8)a, resolution in orocutaneous fistulas in some (Table/Fig 8)b, and reduction of ulcerated and excoriated lesions in some patients (Table/Fig 8)c.
Discussion
The present study’s analysis demonstrated that patients with advanced HNCs undergoing weekly MTX and gefitinib chemotherapy exhibited positive responses and good tolerance to the treatment. The adverse effect profile was acceptable and manageable. The ease of administration is also linked with good adherence to the treatment, along with disciplined follow-up. Nominal side-effects were observed, which were well-managed, and there was significant symptomatic improvement. The primary objective of this study was to alleviate distressing symptoms such as pain and difficulty in swallowing. Additionally, treatment-related toxicities and the QoL were evaluated. Given the lower socio-economic status of the patients, who sought assistance beyond the incurable stage, improving QoL and addressing cost concerns were crucial. Aggressive multimodality approaches were often unsuccessful due to poor performance status and unresectability in these advanced cases. Palliative treatment and/or best supportive care were deemed necessary.

In the period between 2000-2020, many studies (4),(24),(25),(26) were conducted investigating the role of MTX as a palliative treatment option in advanced HNCs. One such study was conducted by Banipal RPS and Mahajan MK which revealed that 38.8% of patients exhibited a favourable response, characterised by a reduction in tumour size by over 50%, while 39% of patients maintained stable disease with injection MTX (4). A 22.2% portion of patients experienced disease progression with single-agent chemotherapy. Following six weekly treatments with the injection of MTX, 63% of patients reported being free of pain, and 16% noted a reduction in pain. The median survival, coupled with good QoL, was determined to be 5.4 months. The present study’s findings aligned with these results, showing a median survival of 5.9 months.

A more recent study by Guigay J et al., compared two different agents for palliative treatment of advanced HNCs in the elderly. One arm received 2-weekly intravenous cetuximab, and the other arm received weekly intravenous MTX. The primary objective was not reached as no benefit of cetuximab compared with MTX was observed in terms of failure-free survival in this frail older population. However, the study confirmed that both cetuximab and MTX are viable options for recurrent and metastatic HNC patients, especially in the frail and old population (10).

While the present study explored the efficacy of the combination of MTX and gefitinib, Irshad R et al., compared the two treatment options in a randomised prospective comparative study. They observed that gefitinib has marginally better results than MTX in recurrent HNCs, with gefitinib having a slight advantage of being taken orally rather than intravenously, so there is no need for hospitalisation or i.v. cannulation. But on the whole, both MTX and gefitinib turn out to be good options in a resource-poor setting with acceptable toxicity and great efficacy profiles (15). Tang X et al., in their meta-analysis of seven randomised control trials on the efficacy and safety of gefitinib in advanced HNSCCs concluded that for recurrent patients, gefitinib is a promising agent, which is equivalent to MTX and MTX + fluorouracil, and tends to improve QoL (11).

The synergistic potential of MTX and gefitinib has been demonstrated previously (9),(26). In a retrospective analysis conducted by Anuradha V et al., from 2007 to 2008, patients were administered gefitinib (250 mg/day), MTX at 50 mg intramuscularly weekly, or a combination of both (9). Another regimen included 5-FU at 750 mg/m2/day for four days along with cisplatin at 75 mg/m2/day on day 1 in a 21-day cycle. MTX combined with gefitinib showed the highest median survival and superior overall QoL when compared to other treatment regimens. Weekly MTX demonstrated relative cost-effectiveness, followed by the combination of MTX with gefitinib. The combination of 5-FU with cisplatin appeared less favourable due to elevated complication rates and prolonged hospital stays. The present study revealed comparable findings, indicating cost-effectiveness, favourable tolerance, good patient adherence to the therapy, and an improvement in the QoL.

The trend is now shifting towards a more easy-to-administer palliative therapy with the advent of oral metronomic chemotherapy. An increasing number of studies have been conducted in recent years [26-28] to investigate the efficacy of MTX in oral formulation along with gefitinib and celecoxib. As demonstrated by Dusi VS et al., the gefitinib and MTX combination was well tolerated by patients with advanced HNCs with poor performance status (26). The majority of the patients who were otherwise not eligible beyond palliative care now had better QoL and longer Progression Free Survival (PFS). In their research, Naidu PD et al., found that oral metronomic chemotherapy results in patients achieving prolonged survival (27). Patil V et al., in their trial comparing MTX and celecoxib-based metronomic chemotherapy with intravenous cisplatin also concluded that oral metronomic chemotherapy is non inferior to intravenous cisplatin concerning overall survival in HNCs in the palliative setting and is associated with fewer adverse events (28).

Though combination chemotherapy utilising drugs such as Cisplatinum, 5-fluorouracil, or taxanes yields higher response rates and potentially improved progression-free survival in comparison to single-agent MTX (9),(28), there is no indication of an overall survival advantage. In this context, weekly MTX and daily gefitinib stand out as a practical and accepted treatment choice. Hence, MTX with gefitinib combination therapy could be a promising approach for patients with advanced HNCs, especially in lower-middle-income countries like India, providing positive outcomes while being manageable and cost-effective.

Limitation(s)

A single institute, smaller sample size, and retrospective study are the prominent limitations of this study.
Conclusion
MTX and gefitinib, when used in advanced HNC cases, act synergistically and contribute to substantial pain reduction and an overall improved QoL, hence proving to be a promising palliative approach. Locoregional disease control and improved socioeconomic compliance can be accomplished, and this approach is deemed advantageous due to its lower toxicity, cost-effectiveness, and convenient administration leading to better treatment adherence and better response rates.
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DOI and Others
DOI: 10.7860/JCDR/2024/71298.19550

Date of Submission: Apr 15, 2024
Date of Peer Review: May 04, 2024
Date of Acceptance: May 28, 2024
Date of Publishing: Jun 01, 2024

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? No
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Apr 15, 2024
• Manual Googling: May 07, 2024
• iThenticate Software: May 27, 2024 (15%)

ETYMOLOGY: Author Origin

EMENDATIONS: 7
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