Abstract
Background/Aim: Treatment options for squamous-cell carcinoma of the head and neck (HNSCC) include chemotherapy, surgery, radiation, and their combinations. However, these treatments have a risk of severe side-effects, including disfigurement and functional impairment. Therefore, treatment of locally-advanced or metastatic HNSCC is often challenging, and prognosis remains poor. The present case report describes the rapid eradication of a large neck HNSCC treated with first-line combination chemotherapy, a low-methionine diet, and oral recombinant methioninase (o-rMETase).
Case Report: A 58-year-old male patient was diagnosed with squamous-cell carcinoma originating at the base of the tongue, with a tumor tissue-modified viral human papillomavirus (HPV) DNA score of 24,988 in October 2024. The tumor was accompanied by nearby lymph-node swelling. The tumor became a very large mass in a few months and was classified as locally-advanced HNSCC with no distant metastasis (cT1N3M0). The patient received a 3-week cycle of combination chemotherapy as first-line treatment with docetaxel (137 mg), cisplatinum (137 mg) and 5-fluorouracil (6,865 mg) administered intravenously starting April 28th, 2025, combined with a low-methionine diet and o-rMETase (250 units twice daily). After the combination treatment was initiated, the tumor shrank rapidly, within the first few weeks, and was unnoticeable after 3 cycles of chemotherapy. Computed tomography after cessation of chemotherapy showed complete resolution of the neck mass and significant shrinkage of a lymph-node mass. The patient continues on a low-methionine diet and o-rMETase and has a normal appearance with no functional impairment. The HPV DNA score became negative after one cycle of chemotherapy.
Conclusion: The combination of first-line chemotherapy, a low-methionine diet, and o-rMETase rapidly eradicated a very large HNSCC. The present results suggest this combination should be further tested, including clinical trials, as the regimen is highly effective in the present case and can possibly avoid disfiguring surgery and harmful radiation.
- Head and neck cancer
- squamous cell
- chemotherapy
- docetaxel
- cisplatinum
- 5-fluorouracil
- methionine addiction
- Hoffman effect
- oral recombinant methioninase
- low-methionine diet
- combination therapy
- rapid response
Introduction
Head and neck squamous cell carcinoma (HNSCC) is the seventh-most common cancer in the world, with a high mortality rate and an estimated 450,000 deaths annually (1, 2). Approximately 30-40% of patients with HNSCC are diagnosed at an early disease stage and have a favorable prognosis (3, 4). However, more than 60% are diagnosed with locally-advanced disease at the time of initial presentation (5, 6). Locally-advanced HNSCC carries a high risk of local and distant recurrence, and a poor prognosis. Therefore, it is typically treated with a multidisciplinary approach including surgery, radiation therapy, and chemotherapy (7, 8). However, despite advances in these therapeutic techniques, severe side-effects, such as deterioration of the oral cavity by radiation therapy and disfiguring surgery, remain a problem. Outcomes for patients with advanced HNSCC remain suboptimal, highlighting the need for improved and more personalized treatment strategies (9-11).
Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect (12-27). Methionine addiction is targeted pre-clinically and clinically by a low-methionine diet and recombinant methioninase (rMETase) (28-33). The methioninase gene, from the soil bacterium Pseudomonas putida, was cloned into Escherichia coli to ferment and produce rMETase (34, 35). rMETase has shown pre-clinical efficacy in all major types of cancer [reviewed in (28)] and is showing promise clinically as a dietary supplement, usually in combination with a low-methionine diet and first-line chemotherapy (29-33). A breakthrough occurred in 2017 when it was shown that rMETase is highly effective when administered orally (o-rMETase) (36, 37).
The present report is on a male patient with a very large HNSCC treated with first-line chemotherapy, a low-methionine diet, and o-rMETase.
Case Report
The patient, a 58-year-old male, noticed a swelling of his left neck. He was diagnosed with SCC (cT1N3M0) by radiological and pathological examinations on October 1st, 2024, at the University of California Irvine Medical Center. The tumor originated at the base of the tongue and was accompanied by swelling of nearby lymph nodes. A blood test was performed on December 11th, 2024, for the tumor tissue-modified viral human papillomavirus (HPV) DNA score which was 24,988. The tumor had grown so large in a few months that it was classified as locally-advanced HNSCC, with no evidence of distant metastasis (Figure 1 and Figure 2). The initial treatment options were surgery, radiation therapy, and chemotherapy in that order, but the patient chose chemotherapy to avoid functional impairment and disfigurement that can result from surgery or radiation therapy. On April 28th, 2025, at the University of California Irvine Medical Center, the patient started 3-week cycles of combination chemotherapy as first-line treatment, consisting of docetaxel (137 mg diluted in 500 ml saline), cisplatinum (137 mg diluted in 500 ml saline), and 5-fluorouracil (6,865 mg diluted in 500 ml saline), administered intravenously through an implanted port. Institutional Review Board approval was not necessary since the patient received standard first-line chemotherapy. The chemotherapy was in combination with a low-methionine diet and o-rMETase (250 units at 30 min after the two major meals of the day), as a dietary supplement, for which the patient gave informed consent.
A 58-year-old male patient was diagnosed in December 2024 with locally-advanced squamous cell carcinoma originating at the left side of the base of the tongue. In 2025, he received a 3-week cycle of combination chemotherapy (chemo) as first-line treatment, consisting of docetaxel, cisplatinum, and 5-fluorouracil, combined with methionine restriction. The large tumor rapidly shrank after the first chemotherapy cycle. After two cycles, the tumor had shrunk further; and after 3 cycles, it had disappeared, leaving no functional impairment.
Computed tomography images of the neck area before (A) and after (B) three cycles of first-line chemotherapy in combination with oral recombinant methioninase and a low-methionine diet. The large mass in the left neck (white arrows) and the swelling of nearby lymph nodes (black arrow) observed before treatment had resolution and a significant reduction, respectively, after the completion of chemotherapy.
After the combination therapy was initiated, the very large tumor shrank rapidly within the first few weeks (Figure 1). The patient received two additional cycles of chemotherapy in May and June, and the tumor became unnoticeable (Figure 1). Furthermore, a blood test performed on May 19th, 2025, showed that the tumor tissue-modified viral HPV DNA score had become negative. Computed tomography at the end of chemotherapy showed complete resolution of the neck mass and a significant reduction of the lymph-node mass (Figure 2). This combination of chemotherapy and methionine restriction resulted in complete disappearance of the tumor without any side-effects, including lack of functional impairment.
Discussion
To our knowledge, the present study is the first case report in which a locally-advanced, large HNSCC mass rapidly shrank between the first and second cycles of first-line chemotherapy combined with methionine restriction and was completely eradicated after the third cycle of chemotherapy.
Locally-advanced or metastatic HNSCC is usually treated by a multidisciplinary approach combining surgery, radiation therapy, and chemotherapy (7, 8). Despite advances in these treatment techniques, side-effects such as disfigurement and functional impairment in surgery, severe damage to the oral cavity and teeth in radiotherapy, and treatment resistance in chemotherapy, remain unresolved problems (9-11). As a result, the treatment of advanced-stage HNSCC is often challenging, and achieving a favorable outcome is often not possible. Therefore, effective treatment strategies that can improve outcomes of these patients are needed.
Methionine-restriction therapy targets methionine addiction, which is a fundamental and general hallmark of cancer termed the Hoffman effect (12-28). We have developed o-rMETase for patients with cancer as a dietary supplement (29-37). In vitro and in vivo studies have shown the efficacy of methionine restriction for all major cancer types. Furthermore, methionine-restriction has been shown to be more effective when combined with chemotherapy for various cancer types [reviewed in (28)]. However, the efficacy of methionine restriction for HNSCC has not been studied, and the present study is the first case to suggest its clinical efficacy.
The present case shows the potential effectiveness of combining chemotherapy with methionine restriction for locally-advanced HNSCC. This suggests the possibility of a novel treatment strategy that is able to induce remission while avoiding the severe side-effects that remain a problem with conventional treatments. The present report is a case study, which is a limitation. Further case studies and clinical trials are needed to determine the safety and efficacy of the present combination therapy, as well as its long-term effects. Additionally, the possible efficacy of methionine restriction in combination with immunotherapy should be studied, as treatment guidelines for immunotherapy have already been established for HNSCC (38).
Methionine restriction is effective because it targets a fundamental hallmark of cancer (12-28, 39-47).
Acknowledgements
This article is dedicated to the memory of A.R. Moossa, MD; Sun Lee, MD; Professor Philip Miles; Richard W. Erbe, MD; Professor Milton Plesur; Professor Gordon H. Sato; John W. Littlefield, MD; Professor Li Jiaxi; Masaki Kitajima, MD; Joseph R. Bertino, MD; Shigeo Yagi, PhD; J.A.R. Mead, PhD; Eugene P. Frenkel, MD; John Medelsohn, MD; Professor Lev Bergelson; Professor Sheldon Penman; Professor John R. Raper; and Joseph Leighton, MD.
Footnotes
Authors’ Contributions
YA was the major contributor to writing the manuscript and RMH revised the article. QH and SL produced rMETase. KM, BMK, JSK, YM, NY, KH, ShM, KI, TH, SeM, HT and SD critically read and approved the final article.
Conflicts of Interest
The Authors declare no competing interests regarding this work.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received July 16, 2025.
- Revision received August 3, 2025.
- Accepted August 6, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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