Dynamic changes in ¹⁸F-borono-L-phenylalanine uptake in unresectable, advanced, or recurrent squamous cell carcinoma of the head and neck and malignant melanoma during boron neutron capture therapy patient selection

Abstract

Background

We evaluated dynamic changes in ¹⁸F–borono-L-phenylalanine (¹⁸F–BPA) uptake in unresectable, advanced, or recurrent squamous cell carcinoma of the head and neck (SCC) and malignant melanoma (MM) during boron neutron capture therapy (BNCT) patient selection.

Methods

Dynamic changes in the maximum standardized uptake value (SUVmax), tumor-to-normal tissue ratio (TNR), and tumor-to-blood pool ratio (TBR) for ¹⁸F–BPA were evaluated in 20 patients with SCC and 8 patients with MM.

Results

SUVmax in SCC tumors decreased significantly from 30 to 120 min. There was a non-statistically significant decrease in SUVmax for SCC tumors from 30 to 60 min and from 60 to 120 min. Patients with MM had nonsignificant SUVmax changes in ¹⁸F–BPA uptake on delayed imaging. Nonsignificant ¹⁸F–BPA TNR and TBR changes were seen in patients with SCC and MM.

Conclusions

Dynamic changes in SUVmax for ¹⁸F–BPA uptake had a washout pattern in SCC and a persistent pattern in MM. Dynamic ¹⁸F–BPA -PET studies should be performed to investigate the pharmacokinetics of ¹⁸F–BPA in humans and select appropriate candidates who may benefit from BNCT.

Background

Boron neutron capture therapy (BNCT) has been used for various types of intractable cancers, including glioblastoma, head and neck tumors, and melanoma [1–6]. This type of radiation therapy is based on nuclear reactions between neutrons and boron-10 (¹⁰B). After a targeted tumor contains a considerable concentration of ¹⁰B, the region to be treated is exposed to thermal neutrons. The nuclear reactions between these neutrons and ¹⁰B produce alpha particles and ⁷Li in a very short range (<10 μm) that should kill the cell. The success of BNCT depends on sufficient accumulation of ¹⁰B in tumor cells relative to adjacent tissues [5, 6]. Therefore, it is necessary to assess ¹⁰B concentration in tumor tissue before BNCT is performed [7].

Positron emission tomography (PET) using ¹⁸F–borono-L-phenylalanine (¹⁸F–BPA) has been used to screen for appropriate candidates who can benefit from BNCT [2, 3, 8–11]. Before BNCT, the ¹⁰B concentration in tumor tissue is estimated by measuring the tumor-to-normal tissue ratio (TNR) and the tumor-to-blood pool ratio (TBR) with ¹⁸F–BPA PET imaging [2, 3, 12, 13]. Hanaoka et al. demonstrated a significant positive correlation between levels of BPA and ¹⁸F–BPA accumulation in an animal model [14]. ¹⁰B accumulation is not consistent across patients; it is reported to also depend on tumor type [15, 16]. Thus, knowledge of the dynamic changes in ¹⁰B accumulation by tumor type is critical for performing BNCT. However, there is still limited information in the literature regarding dynamic changes in ¹⁸F–BPA uptake in various tumor types in humans. The purpose of this study was to examine the dynamic changes in the maximum standardized uptake value (SUVmax) of ¹⁸F–BPA in squamous cell carcinoma of the head and neck (SCC) and malignant melanoma (MM). TNR and TBR of ¹⁸F–BPA in SCC and MM were also evaluated.

Methods

General

The study protocol was approved by the institutional review board and independent ethics committee of our hospital. All patients provided written informed consent before inclusion in the trial.

Radiosynthesis of ¹⁸F–BPA

¹⁸F–BPA was synthesized with direct electrophilic radiofluorination of BPA (Sigma-Aldrich, St. Louis, MO, USA) using ¹⁸F–acetyl hypofluorite as described previously [7, 17]. Purification of ¹⁸F–BPA was performed by high performance liquid chromatography (HPLC) using a YMC-Pack ODS-A column (20 × 150 mm; YMC, Kyoto, Japan) eluted with 0.1% acetic acid at a flow rate of 10 mL/min. The radiochemical purity of ¹⁸F–BPA as determined by HPLC was >99.5%. Its specific activity was 25 MBq/μmol.

Patients and PET/CT protocol

This study included 20 patients with SCC and 8 patients with MM who underwent ¹⁸F–BPA PET/CT from March 2012 to August 2016. Patients had histologically confirmed malignant tumors and an Eastern Cooperative Oncology Group performance status of 0–1. We defined adequate organ function for patients with unresectable cancer on the basis of the normal range observed by our hospital laboratory. Adequate organ function was determined by neutrophil count ≥1500 /μL, platelet count ≥75,000 /μL, hemoglobin ≥9.0 g/dL, serum bilirubin ≤1.5 mg/dL, aspartate transaminase (AST) ≤ 100 IU/L, alanine aminotransferase (ALT) ≤ 100 IU/L, serum creatinine ≤1.5 mg/dL, and baseline left ventricular ejection fraction >60%. The main exclusion criteria were congestive heart failure, uncontrolled angina pectoris, arrhythmia, symptomatic infectious disease, severe bleeding, pulmonary fibrosis, obstructive bowel disease or severe diarrhea, and symptomatic pleural or pericardial effusion. This study was approved by the ethics committees of our institution.

Dynamic changes in ¹⁸F–BPA uptake were evaluated in 20 patients with SCC and 8 patients with MM. PET images were acquired using a Discovery 600 scanner (GE Healthcare, Milwaukee, WI, USA). PET images were reconstructed as using a 3D ordered-subset expectation maximization algorithm. PET image evaluation and quantification of SUV were performed using AW Volume Share 4.5 software. SUV was defined as regional radioactivity divided by injected radioactivity normalized to body weight. PET/CT images were taken 30, 60, and 120 min after ¹⁸F–BPA injection (4.0 MBq/kg of body weight). Regions of interest (ROIs) were drawn on the reconstructed PET images. Tumor SUVmax in ROIs was defined as the area of highest activity. ROIs were also drawn around normal tissue surrounding the tumor to calculate the TNR for ¹⁸F–BPA and the blood pool in order to calculate the TBR for ¹⁸F–BPA. The retention index (RI) was defined as the difference in SUVmax between early and delayed ¹⁸F–BPA PET imaging, expressed as a percentage of the initial uptake (RI = (SUVdelayed − SUVearly)/SUVearly × 100%). The difference in SUVmax and RI were calculated to evaluate the change in tracer levels in malignant lesions at 30, 60 and 120 min after ¹⁸F–BPA injection. Quantitative values above zero were defined as increased SUVmax and values below zero were defined as decreased SUVmax.

Statistical analysis

SUVmax, TNR, and TBR were analyzed using paired one-way ANOVA. The paired t-test was used to determine the significance of differences in dynamic SUVmax values, TNR, and TBR. P < 0.05 was considered to indicate a statistically significant difference. For statistical analysis, JMP software (version 11.0, SAS Institute, Inc., Cary, NC, USA) was used.

Results

Patient characteristics are summarized in Table 1. SUVmax, TNR, and TBR for ¹⁸F–BPA in SCC and MM are summarized in Table 2. Only SUVmax showed significant differences between 30 and 120 min in patients with SCC.

Table 1.

Patient characteristics

Histology of the primary tumor	Number	Gender	Age, years
		Male/Female	Mean ± SD (range)
Squamous cell carcinoma	20	3/17	57.6 ± 16.1 (16–81)
Malignant melanoma	8	2/6	59.1 ± 13.7 (37–76)

Abbreviation: SD Standard deviation

Table 2.

PET values for squamous cell carcinoma and malignant melanoma

PET value	Histology	18F–BPA at 30 min	18F–BPA at 60 min	18F–BPA at 120 min
		Mean ± SD	Mean ± SD	Mean ± SD
SUVmax	Squamous cell carcinoma	5.58 ± 2.29	4.79 ± 1.95	3.83 ± 1.56
	Malignant melanoma	9.41 ± 5.44	8.30 ± 4.61	7.39 ± 4.40
TNR	Squamous cell carcinoma	3.21 ± 1.66	3.28 ± 1.63	2.79 ± 1.52
	Malignant melanoma	7.89 ± 6.50	7.69 ± 4.91	6.68 ± 4.24
TBR	Squamous cell carcinoma	3.97 ± 1.76	3.84 ± 1.67	3.37 ± 1.52
	Malignant melanoma	9.82 ± 7.65	8.43 ± 4.33	8.33 ± 4.13

Abbreviations: ¹⁸F–BPA ¹⁸F–borono-L-phenylalanine, PET Positron emission tomography, SD Standard deviation, SUVmax Maximum standardized uptake value, TNR Tumor-to–normal tissue accumulation ratio, TBR Tumor-to-blood pool ratio

Figure 1 is a box plot of SUVmax for tumors at 30, 60, and 120 min after injection. SUVmax in SCC tumors decreased significantly from 30 to 120 min, but the decrease was not statistically significant from 30 to 60 min and from 60 to 120 min. All 20 patients with SCC had gradual decreases in SUVmax from 30 to 120 min (Table 2). On the other hand. Nonsignificant ¹⁸F–BPA differences on delayed imaging were seen in patients with MM (Fig. 1, Tables 2 and 3). In contrast to patients with SCC, not all patients with MM had decreases in SUVmax from 30 to 60 min, 60 to 120 min, and 30 to 120 min.

Fig. 1.

Box plot of SUVmax for tumors at 30, 60, and 120 min after ¹⁸F–BPA injection

Table 3.

Statistically significant differences in dynamic SUVmax changes in squamous cell carcinoma and malignant melanoma

		Squamous cell carcinoma	Malignant melanoma
From 30 min to 60 min
P value		0.1064	0.6504
Difference in SUVmaxa	Mean ± SD (Range)	1.02 ± 0.61 (0.2–2.7)	1.1 ± 1.7 (−1.4–2)
RI	Mean ± SD (Range)	17.6 ± 7.3 (4.7–28.0)	12.0 ± 15.5 (−17.1–29.9)
	Number of patients with increase	0	3
	Number of patients with decrease	20	5
From 60 min to 120 min
P value		0.1263	0.7098
Difference in SUVmax	Mean ± SD (Range)	0.96 ± 0.56 (0.3–2.6)	0.91 ± 0.74 (−0.2–2.3)
RI	Mean ± SD (Range)	20 ± 6.6 (5.2–29.2)	13.6 ± 10.9 (−0.02–32.4)
	Number of patients with increase	0	1
	Number of patients with decrease	20	7
From 30 min to 120 min
P value		0.0023	0.412
Difference in SUVmax	Mean ± SD (Range)	1.98 ± 1.02 (0.6–4.7)	2.03 ± 2.38 (−1.1–7)
RI	Mean ± SD (Range)	34.0 ± 8.7 (8.7–46.7)	22.4 ± 22.3 (−13.4–52.1)
	Number of patients with increase	0	2
	Number of patients with decrease	20	6

^aDifference in SUVmax difference was calculated as delayed SUVmax minus earlier SUVmax

Abbreviations: RI Retention index, SD Standard deviation, SUVmax Maximum standardized uptake value

Nonsignificant TNR and TBR for ¹⁸F–BPA were seen on delayed imaging in both patient groups (Table 2). Representative ¹⁸F–BPA PET images are shown in Figs. 2 and 3.

Fig. 2.

Representative ¹⁸F–BPA PET images in a 50-year-old man with squamous cell carcinoma of the external auditory canal. ¹⁸F–BPA PET images at (a) 30 min (SUVmax = 11.0, TNR = 5.0, TBR = 8.5), (b) 60 min (SUVmax = 8.9, TNR = 5.2, TBR = 6.9), and (c) 120 min (SUVmax = 6.3, TNR = 4.5, TBR = 5.3) after injection

Fig. 3.

Representative ¹⁸F–BPA PET images of malignant melanoma in a 39-year-old woman with sphenoid sinus melanoma. ¹⁸F–BPA PET images at (a) 30 min (SUVmax = 8.2, TNR = 7.5, TBR = 5.9), (b) 60 min (SUVmax = 9.6, TNR = 9.6, TBR = 6.9), and (c) 120 min (SUVmax = 9.3, TNR = 9.3, TBR = 7.2) after injection

Discussion

The aim of this study was to examine dynamic ¹⁸F–BPA changes in SUVmax in SCC and MM as part of the patient selection process for BNCT. In SCC, dynamic changes in SUVmax for ¹⁸F–BPA uptake had a washout pattern, compared with a persistent pattern of ¹⁸F–BPA uptake in MM.

¹⁸F–BPA was developed to predict ¹⁰B accumulation in tumors and normal tissues with PET [18]. Studies have shown that there are a variety of amino acid transporters, such as Systems L, A, ASC, and B [19, 20]. System L is the primary contributor to ¹⁸F–BPA uptake, which is correlated with total L-amino acid transporter (LAT) expression, more specifically LAT1 and LAT4. Many tumors overexpress LAT1 or LAT4 [21–23]. Previous studies have shown that the expression of amino acid transporters in tumors varies widely, and it sometimes reflects proliferation speed and malignancy [24]. However, reasons for differences in dynamic changes in ¹⁸F–BPA uptake between SCC and MM remain uncertain. It is unclear whether ¹⁸F–BPA undergoes metabolic transformation, although metabolic transformation of L-phenylalanine has been reported [25]. LAT and the metabolic transformation of ¹⁸F–BPA may contribute to dynamic changes in ¹⁸F–BPA accumulation in tumors. Further studies with more participants and evaluation of processes involved in ¹⁸F–BPA metabolic transformation are needed to resolve this question.

In clinical BNCT, ¹⁸F–BPA accumulation was measured about 1 h after ¹⁸F–BPA administration [26–29]. However, the number of dynamic studies of ¹⁸F–BPA uptake in humans is limited. Therefore, we focused on dynamic ¹⁸F–BPA uptake in humans. Our study showed that SUVmax for ¹⁸F–BPA uptake in SCC has a washout pattern. It is very important to realize that some tumor histological types may have a washout pattern. ¹⁸F–BPA uptake in different tumor types may be vary with extended distribution time in ¹⁸F–BPA PET imaging. Further dynamic ¹⁸F–BPA -PET studies should be performed to determine who are appropriate candidates that can benefit from BNCT.

In this study, we did not evaluate the pharmacokinetics of BPA or the BPA-fructose complex because we focused on dynamic accumulation of ¹⁸F–BPA in human tumors. Hanaoka et al. showed a positive association between the levels of BPA and ¹⁸F–BPA accumulation in a rat model [14]. However, the biodistribution of ¹⁸F–BPA in animals and humans is different [30]. In addition, metabolic transformation of ¹⁸F–BPA and BPA in vivo may also differ. Direct pharmacokinetic comparisons between ¹⁸F–BPA and BPA levels in tumors are required during and at the end of BNCT in humans to define early and delayed ¹⁸F–BPA imaging times.

The present study had some limitations. Two different tumor types were examined in our study. Our ¹⁸F–BPA findings for SCC were consistent with previous studies [28, 31]. However, the characteristics of dynamic ¹⁸F–BPA accumulation in radioresistant head and neck carcinomas, such as mucoepidermoid carcinomas and adenoid cystic carcinomas, is unknown [3]. Various intractable cancers that can be treated with BNCT represent a wide spectrum of histopathological backgrounds. Further studies involving more patients, each representing a specific pathological entity, are therefore needed.

Conclusions

Dynamic changes in SUVmax for ¹⁸F–BPA uptake in SCC has a washout pattern, while ¹⁸F–BPA uptake in MM has a persistent pattern. Dynamic ¹⁸F–BPA -PET studies should be performed as part of a human pharmacokinetic study of ¹⁸F–BPA and to select appropriate candidates who may benefit from BNCT.

Abbreviations

¹⁸F–BPA

¹⁸F–borono-L-phenylalanine;

ALT

Alanine aminotransferase

AST

Aspartate transaminase

BNCT

Boron neutron capture therapy

HPLC

High-performance liquid chromatography

LAT

System L amino acid transporter

MM

Malignant melanoma

PET

Positron emission tomography

RI

Retention index

ROIs

Regions of interest

SCC

Squamous cell carcinoma of the head and neck

SUVmax

Maximum standardized uptake value

TBR

Tumor-to-blood pool ratio

TNR

Tumor-to–normal tissue accumulation ratio

Authors’ contributions

Author contributions were as follows. Conception and design: HK. Analysis and interpretation of data: TM, HK. Drafting of the manuscript or revising it critically for important intellectual content: all authors. Final approval of the submitted manuscript: all authors.

Ethics approval and consent to participate

This study was reviewed and approved by the National Cancer Center Hospital Research Ethics Review Committee. The committee’s reference number is 2011–165.

Consent for publication

Written informed consent was obtained from all patients for publication of this study. A copy of the written consent forms is available from the Editor-in-Chief of this journal for review.

Competing interests

The authors declare that they have no competing interests.

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