INTRODUCTION:

Nasopharyngeal carcinoma (NPC) is the most frequent malignancy originating from nasopharyngeal epithelium¹. It is highly prevalent in Southeast Asia, being 20 to 30 incidence per 100,000 people². In 2012, Indonesia ranked among the top five countries with the highest NPC cases globally, accounting for 13,084 cases³. Recent data from 2020 reaffirmed NPC’s status as the fifth most prevalent cancer, contributing to 5% of all newly diagnosed cancer cases and 5.7% of cancer-related mortality⁴. Over 50% of NPC patients present with locally advanced disease (LA-NPC), with a 5-year survival rate of only 50-70%, while the rest experience distant metastasis and locoregional relapse⁵.

Although radiotherapy remains as the primary treatment for LA-NPC, the concealed anatomical location of nasopharynx poses. Currently, concurrent chemoradiotherapy (CCRT) is the established therapy due its ability to enhance radiotherapy sensitivity and reduce distant metastasis^6–9. However, thesevere toxicity associated with the treatment neccessitates the exploration of more effective agent to improve survival outcomes. Consequently, newer treatment targets, especially in the use of molecular targeted agents concurrently with radiotherapy, is being explored. Suggested from the National Comprehensive Cancer Network (NCCN), treatment for phase II-IV NPC patients is adding adjuvant simultaneous with chemoradiotherapy and chemoradiotherapy alone, following multiple prospective random studies^10-13.

Epidermal growth factor receptor (EGFR) is significantly expressed in highly human epithelial carcinomas and more than 80% of LA-NPC patients, with itsoverexpression has been correlated with the poor clinical prognosis^1,14. Previous study reported the effective outcome following the use of nimotuzumab, a humanized IgG1 monoclonal antibody that aim to the extracellular zone of EGFR⁵. Nimotuzinabplays a role as a biologic target therapy. Unlike another recognized anti-EGFR antibodies, Nimotuzumab's internal traits lead to high receptor absorption and low normal tissue absorption in tumors, which lead to the peak clinical advantage and the lack of serious dermatological toxicity⁶.

However, the potential of combining nimotuzunabwith radiotherapy requires further definition as this treatment modality has been rarely explored in Indonesia. Therefore, this study aims to evaluate the safety and efficacy of this treatment modality, particularlywithin Indonesian population. It is hypothesized that this modality will improve treatment outcomes, given its previously evidenced mechanism of action.

TREATMENT PROTOCOL:

Nimotuzumab at a dose of 200 mg was dissolved within 250 ml NaCl and titrated then administered once a week for five consecutive weeks. A combination of thirty five times of radiotherapy, each with a dose of 60-70 Gy (grey) was performed one hour after the administration of nimotuzumab to patient’s in head and neck (nasopharynx) region. Radiotherapy and Nimotuzumab were given concurrently.

Patient’s information was recorded through physical examination, laboratory tests, and computed tomography (CT) scans. Thephysical examinations included vital sign assessments, Karnofsky scores, and lymph node examinations. Any adverse effects were documented from patient’s initial visit and subsequent follow-up visits.

To assess treatment efficacy, this study measured the gross tumor volume (GTV) reduction of the primary tumor and the affected lymph nodes, as defined by International Commission on Radiation Units and Measurement Reports 50 and 62. The calculations of gross tumor volume were based on the contouring visible diseased areain cross-sectional CT scans, bothpre- and post-treatmentto evaluate primary tumor volume reduction (% vol_red∼100×1−vol_post/vol_pre)^15,16.

PATIENT AND OBSERVATION:

Patient Information and Clinical Findings:

A 52-year-old woman presented with a medical history of persistent left-sided nasal stuffiness, rhinorrhea, recurrent epistaxis, and hearing loss for 1.5 years before her hospital admission in October 2019. The patient presented with intracranial symptoms such as headaches, tingling sensation, diplopia, and left facial strabismusfora year before admission.

Timeline of Current Episode:

In April 2018, the patient reported a loss of hearing.In July 2018, she went to the hospital and had biopsy, CT scan, and MRI without initial treatment. Over a year after, in October 2019,the patient underwent apre-therapeutic assessments including CT scan and MRI. Radiotherapy was initiated with addition of Nimotuzumab. By February 2020, a post-therapeutic CT scan demonstrated animprovement in the patient’s condition.

Diagnostic assessment:

First biopsy of the nasal cavity showed undifferentiated non-keratinizing carcinoma. First CT scan and MRI showed a malignant mass in the right sinonasal with the dimension of 46.9 x 35.9 x35.1 (APxRLxCC) mm with infiltration to surrounding structures but with no intracranial and lymph node involvement (shown in Figure 1).

A pre-therapeutic CT scan and MRI at the time of admission in October 2019 showed a solid mass in the left and right nasopharynx with the dimension of 49.9 x 56.9 x 48.9 mm. In addition, a massive intracranial mass extension was found on the left temporoparietal lobe, along with massive perifocal edema (shown in Figure 2). This mass insists the right lateral ventricle was causing a shift in midline structure by 12.2 mm and non-communicating hydrocephalus. There was also multiple lymph nodes enlargement. Right neck node in the amount of 5.1 mm, left neck 5.4 mm, and supraclavicular 5.1 mm.

Figure 1. A first head MRI of the patient in July 2018.

Figure 2. Pre-therapeutic Head MRI and neck CT-scan in October 2019.

Diagnosis:

The patient was diagnosed with stage 4a nasopharyngeal carcinoma.

Follow-Up and Outcome of Interventions:

Post-therapeutic CT scan on February 2020 showed loss of nasopharyngeal mass, leaving no mass on the right nasopharynx and little mass remain on the left nasopharynx (+/- 2x2cm) (shown in Figure 3). The lymph node was no longer enlarge. Head CT scan showed good density with no mass and no shift in midline structures. While under treatment, the patient experienced mild side effects such as oral mucositis and leucopenia. The patient received leucogen to treat leucopenia. Overall, the treatment has improved all symptoms with negligible side effects, with post-therapeutic Karnofsky's score as high as 90.

Figure 3. Post-therapeutic Head MRI and CT scan on February 2020.

Patient Perspective:

The patient was initially afraid and worried about receiving medical care. However, her worsening condition led her to seek medical care once again. After receiving treatment, the patient felt a significantly improved condition. Notably, patient’s hearing, which had previously impaired, resulted in improved auditory quality.

Informed Consent:

The case was approved by the clinical ethics committee of the Surabaya Mitra Keluarga General Hospital. The patient and her family provided written informed consent for the publication of her data and any related images.

DISCUSSION:

NPC cases are usually at the advanced stage of the disease. The patients' prognosis is therefore inadequate. The main reasons for this late presentation are delayed medical treatment and the unusual and confusing nature of the symptoms presenting the clinician in inaccuracy. With the effective identification of early lesions, the clinician requires a high level of concern and enhanced patient recognition. This can be done by educating our society about the can clinical view of NPC^17–20.

Until now, the standard treatment of NPC is platinum-based radiotherapy and chemotherapy. Platinum acts as a sensitizer or some call it radiation modifiers, which are elements that can increase the selective killing of tumor cells from radiation. The most commonly used radiation sensitizers are cisplatin and 5-fluorouracil ^21–25. Even major improvements have been made in radiotherapy and chemotherapy modalities, approximately 20-50% of patients still progress to therapy fiasco, including relapse and metastasis, especially for NPC patients on advanced-stage ^26–28. Research by Widodo A., et al. (2020) showed that the addition of the adjuvant cisplatin can induce more statistically significant acute toxicity. ²⁹.

Recently, a new treatment method for NPC has been developed with fewer side effects compared to some previous treatments. There is Nimotuzumab combined with concurrent chemoradiotherapy ³⁰. The way it works is to inhibit protein kinase activity and bind it with optimal affinity also high specificity to the extracellular region of EGFR on the surface of cancer cells. In this way, Nimotuzumab can prevent cancer cells from receiving the messages that cells need to grow, develop, and spread ^32,32. in most studies, nimotuzumab has greater affinity than the endogenic ligand itself. it also has a lower effect on the incidence of erythropenia and neutropenia ³³.

In addition to nasopharyngeal carcinoma advanced-stage treatment lead by the Chinese Academy of Medical Sciences, a multicenter, randomized phase II clinical trial was conducted to track the safety of and prejudical effects of Nimotuzumab. These study concluded that patient given Nimotuzumab simultaneous with chemotherapy has 84.29% of 3-year surviving rate and greather than treating with radiotherapy-only (77.61%). It indicated that the nimotuzumab-radiotherapy should be synergistically affected. It had minor side effects and did not impair the normal output of radiotherapy^6,10,34,35.

Chemoradiotherapy associated with or without adjuvant chemotherapy has been approved for stages II-IV NPC patients by the National Comprehensive Cancer Network (NCCN) based on several prospective randomized trials^10,36. The meta-analysis showed no significant differences in hematological, gastrointestinal, and skin toxicities between the Concurrent chemoradiotherapy with Nimotuzumab and Concurrent chemoradiotherapy -only^11,13,37,38. Nimotuzumab was not unusual to have any clear toxicity though nausea and vomiting were normal in cisplatin-receiving patients. Moreover, patient-related oral mucositis was one of the highly general toxicities rather than Nimotuzumab¹⁰.

CONCLUSION:

The most commonly identified malignancy of the nasopharynx is nasopharyngeal carcinoma (NPC). One of the complications is intracranial symptoms. Nimotuzumab, humanized monoclonal antibody (mAb), showed to give negligible toxicity and is well-tolerated among LANPC patients. The appropriation of Nimotuzumab in locally advanced NPC with intracranial infiltration was tolerable and showed convincing clinical results. However, further randomized and multicenter trials are required to validate and enhance the therapeuticoutcomes of this intervention.

CONFLICT OF INTEREST:

The authors declare no competing interest.

ACKNOWLEDGEMENTS:

The authors thanks to the Research and Innovation Institute, Universitas Airlangga, for helping the proofreading and grammatical checked.

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Received on 06.06.2023 Modified on 17.02.2024

Research J. Pharm. and Tech 2024; 17(8):3582-3586.

DOI: 10.52711/0974-360X.2024.00559