Abstract
Background/Aim: Positron emission tomography (PET) is an important imaging modality, especially in oncology. [18F]fluorodeoxyglucose PET (FDG-PET) is the most used cancer PET imaging. However, since the elevated glucose use by cancers, termed the Warburg effect, is usually only moderate, FDG often does not provide a strong or well-delineated signal. Malignancies have a stronger addiction to methionine, known as the Hoffman effect, and thus [11C]methionine PET (MET-PET) has demonstrated superiority over FDG-PET in gliomas and other brain tumors. Our team is pioneering the use of MET-PET for tumors of the trunk for both better detection of cancer and to determine candidates for methionine-restriction therapy. The present study provides examples of cancers of organs in the trunk in which MET-PET outperforms FDG-PET in detecting and delineating primary and metastatic cancer. Patients and Methods: In all cases, MET-PET and FDG-PET were performed simultaneously. An evaluation of the images was conducted by a nuclear medicine physician. Results: Four cases, including prostate, bladder, esophageal, and breast cancer demonstrated the superiority of MET-PET compared to FDG-PET. Conclusion: MET-PET can out-perform FDG PET for accurate detection of primary and metastatic cancer in the trunk and can determine the extent of methionine addiction of cancer, thereby indicating whether cancer patients can benefit from methionine-restriction therapy.
- Methionine
- deoxyglucose
- PET
- comparison
- methionine addiction
- Hoffman effect
- breast cancer
- prostate cancer
- bladder cancer
- esophageal cancer
[18F]fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used in oncology (1). FDG-PET combined with computed tomography (CT) is frequently used to detect and stage cancer (2-4). FDG-PET is based on the addiction of cancer to glucose discovered by Otto Warburg (5), and called the Warburg effect. However, normal tissues such as the brain have a high glycolytic metabolism, which presents difficulties for FDG-PET in detecting cancers growing in the brain and cancer in other organs with similar glucose use as the host organ (6, 7). Regarding anatomy, the detection of tumors in proximity to the urinary tract such as the bladder poses a challenge for FDG-PET since FDG is excreted through the urinary tract (8). Furthermore, inflammatory cells that are high in glucose metabolism (9), sometimes show false positives in FDG-PET (10).
[11C]methionine PET (MET-PET) is based on the methionine addiction of cancer (11, 12), termed the Hoffman effect (13), which is at least in part due to overuse of methionine for elevated transmethylation reactions that appear to be universal in cancer (14, 15). [11C]MET is the most frequently-used tracer in PET imaging of brain tumors (16). MET-PET provides a high detection rate of brain tumors and good lesion delineation, which is superior to FDG-PET (17), making it prevalent. MET-PET is effective for diagnosis (18, 19), treatment (20, 21) and to estimate prognosis (22, 23) in gliomas.
We hypothesized that MET-PET would be useful in the diagnosis of cancers in the trunk, since all cancers are methionine addicted (11, 12) and MET-PET may have higher sensitivity than FDG-PET (24).
Patients and Methods
Prior to FDG-PET or MET-PET imaging, the cancer patients followed a minimum fasting time of 6 hours. The patients were administered [11C]MET intravenously at a dose of 370 MBq per kilogram of body weight, along with hydration with a 0.9% sodium chloride solution. The level of physical activity was reduced, and a 10-minute rest interval was taken following the injection. The MET-PET scan was performed using a Vereos Digital PET/CT instrument (Philips, Amsterdam, the Netherlands). A total of 23,040 lutetium-yttrium oxyorthosilicate (LYSO) crystals were employed in a 64-ring arrangement for the PET scanner. The patient was administered FDG intravenously at a dose of 4.4 MBq/kg body weight for FDG-PET within one month after MET-PET imaging. The FDG-PET used the same methodology as described above. A low-amperage CT scan was acquired to apply attenuation correction to the PET images. The scan was conducted with the following parameters: a current of 213 mA, a voltage of 120 kV, and a CT slice thickness of 5 mm. The recorded value for the CT dose index was 10.7 milligrays (mGy). After performing a non-enhanced CT scan, a PET examination was performed on the entire body in the caudocranial direction, covering the region from the upper thighs to the vertex. Every position of the bed was captured for a period of 2 minutes. The 3D reconstruction technique employed in this study was ordered subset expectation maximization. This approach entailed the utilization of 30 subgroups and the execution of two iterations. An evaluation of the images was conducted by a nuclear medicine physician. Informed consent was obtained from all subjects involved in this study.
Results
Case reports. Case 1. A 58-year-old male was diagnosed with prostate cancer with distant metastasis in 2017. He underwent hormone therapy, radiotherapy, and chemotherapy. The patient’s PSA level decreased, and his disease was stable until 2021. However, the patient’s PSA increased from 2022, and a CT scan showed suspected bone metastasis. FDG-PET and MET-PET were performed to re-evaluate staging. While FDG-PET did not show mediastinal lymph-node metastasis, MET-PET was able to (Figure 1), which led to the next treatment of chemotherapy.
Multiple mediastinal lymph-node nodules of metastatic prostate cancer. (A) [11C]methionine positron emission tomography (MET-PET) imaging. (B) [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. White arrows indicate mediastinal lymph nodes with metastatic cancer.
Case 2. A 69-year-old male was diagnosed with bladder cancer. Chemotherapy and radiotherapy were administered after trans-urethral removal of the bladder tumor in 2018. Chemotherapy and radiotherapy were administered for a left-lung metastasis in 2019. FDG-PET and MET-PET were conducted to re-evaluate the stage of the disease after cystoscopy confirmed recurrence in the left uretheral orifice. MET-PET was able to detect recurrence at the same site, which FDG-PET could not detect it (Figure 2). MET-PET was useful in this case because the urinary tract system is difficult to evaluate with FDG-PET.
Local recurrence of bladder cancer. (A) [11C]methionine positron emission tomography imaging (MET-PET). (B) [18F]fluorodeoxyglucose positron emission tomography imaging (FDG-PET). Arrows indicate local recurrence of bladder cancer.
Case 3. An 83-year-old female with scleroderma and pulmonary hypertension was diagnosed with esophageal cancer using CT. FDG-PET showed the surrounding tissue had increased uptake of FDG, obscuring the esophageal tumor. However, the tumor was visible with MET-PET (Figure 3). There was background inflammatory disease, which obscured the cancer evaluation on FDG-PET, but not MET-PET.
Massive esophageal-cancer tumor. (A) [11C]methionine positron emission tomography (MET-PET) imaging. (B) [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. White arrows indicate esophageal cancer.
Case 4. A 59-year-old woman was diagnosed with left-breast cancer in 2018. After total resection of the left breast, hormone therapy was introduced since the sentinel lymph node was negative at the time of surgery. The patient’s left-axillary lymph nodes subsequently became enlarged three years post-mastectomy and biopsy showed malignancy. FDG-PET and MET-PET were performed to diagnose metastatic recurrence. The left axillary lymph nodes were well defined with better uptake of [11C]MET than [18F]FDG (Figure 4). In this case, complete response was subsequently achieved by a combination of methionine restriction effected by a low-methionine diet and oral recombinant methioninase (o-rMETase) combined with chemotherapy (24). Thus, MET-PET is a potential biomarker to determine which cases respond well to methionine restriction.
Left axillary lymph-node metastasis of breast cancer. (A) [11C]methionine positron emission tomography (MET-PET) imaging. (B) [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. Red arrows indicate left axillary lymph-node metastasis of breast cancer.
Discussion
In the present study, we showed the superiority of MET-PET compared to FDG-PET in a series of cancers in organs of the trunk. MET-PET has been previously shown to be superior to FDG-PET in the brain, and plays an important role for diagnosis, treatment and follow-up (18-23, 25-35). All cancer types are addicted to methionine (11, 12). Methionine addiction, termed the Hoffman effect (11-15, 36), is much stronger than the Warburg effect of glucose addiction (24). Methionine restriction is an emerging treatment option in the oncology field and has shown efficacy in all cancer types in mouse models, especially in combination with chemotherapy on high-stage cancer 37-48.
We have previously shown a complete response case of stage IV breast cancer by combining methionine restriction with o-rMETase and chemotherapy as described in Case 4 (49). MET-PET is also expected to serve as a biomarker to predict the effect of methionine restriction treatment (50).
FDG-PET is a clinically very-important tool, but physiology and anatomy make it difficult to use in some cases. It is often difficult to distinguish benign inflammation from malignant tissue, and in patients with diabetes, the accuracy of its assessment can be problematic because of the high circulating glucose levels. Hyperglycemia affects FDG-PET (51) and increases FDG uptake in skeletal muscle by up-regulating GLUT-4 (52). This leads to an increase in false negatives in diabetes with uncontrolled blood glucose (53). The results of FDG-PET should be evaluated with caution in these cases.
MET-PET does not have the limits of FDG-PET and should be more widely used in the future to detect primary tumors and metastasis of the trunk. MET-PET can determine the extent of a cancer’s addiction to methionine, which is a candidate biomarker for response to methionine-restriction-based chemotherapy.
The present study demonstrated stronger methionine addiction than glucose addiction in a series of cancers of the trunk. Future studies should greatly expand MET-PET imaging of cancer of the trunk.
o-rMETase is showing promise in the clinic in multiple case studies of advanced cancer (49, 54-64). Methionine addiction is a promising target for cancer since it is tightly linked to malignancy (65-71) and is a universal hallmark of cancer (72-74).
Acknowledgements
This paper is dedicated to the memory of A. R. Moossa, MD, Sun Lee, MD, Professor Gordon H. Sato, Professor Li Jiaxi, Masaki Kitajima, MD, Shigeo Yagi, PhD, Jack Geller, MD, Joseph R Bertino, MD, J.A.R. Mead, PhD., Eugene P. Frenkel, MD, Professor Sheldon Penman, Professor Lev Bergelson, Professor John R. Raper, and Joseph Leighton, MD.
Footnotes
Authors’ Contributions
MS, TS, and RMH wrote the article. TS provided the case reports of PET. MS, TS, CH, QH, RM, KM, SM, BMK, NK, YI, AN, and RMH critically reviewed the article.
Conflicts of Interest
The Authors declare no competing interests regarding this work.
Funding
The Robert M. Hoffman Foundation for Cancer Research provided funds for this study.
- Received April 26, 2024.
- Revision received May 28, 2024.
- Accepted June 24, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).