The Role of BPA-PET in Prediction of H&N Cancer Treatment failure after BNCT Yu-Ming Liu, Yi-Wei Chen, Pin-Lun Li, Ko-Han Lin, Yu-Wen Hu, Ling-Wei Wang Div. of Radiation Oncology, Dept.of Oncology Taipei Veterans General Hospital Taiwan

Cancer of the Lip and Oral Cavity (C00-C08), World Age-Standardised Incidence Rates, World Regions, 2008 Estimates, Cancer Research UK

Mortality of Cancer in Taiwan (2010) Liver Lung Colorectal Oral, pharynx Esophagus Stomach Prostate Pancreas non hodgkin lymphoma Leukemia Total

Treatment of head & neck cancer Surgery and radiation therapy with or without chemotherapy, but despite therapy, many cancers recur. Further treatment for recurrent H & N cancer after multi-disciplined treatment is not uncommon Photon beams re-irradiation is not recommended because of high complication and low successful rate.

115 previously irradiated patients without overt metastases LONG-TERM OUTCOME OF CONCURRENT CHEMOTHERAPY AND REIRRADIATION FOR RECURRENT AND SECOND PRIMARY HEAD-AND-NECK SQUAMOUS CELL CARCINOMA 115 previously irradiated patients without overt metastases Surgical resection, concurrent chemotherapy and re-irradiation The median lifetime radiation dose was 131 Gy. The median F/U for survival patients was 67.4 months (18.5–158.7). The median OS and PFS was 11 and 7 months (range, 0.2–158.7) The 3-year OS = 22 % PFS = 33 % Locoregional control = 51 % Freedom from distant metastasis = 61 % For recurrent and second primary head-and-neck cancer, trimodality therapy with OP, C/T and re-RT for a full second dose offers potential for long-term survival. Owing to the substantial toxicity and lack of an optimal regimen, re-irradiation of recurrent head-and-neck cancer should be limited to clinical trials. Salama et al., Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 2, pp. 382–391, 2006

In theory, BNCT provides a means to selectively eradicate malignant cells and spare normal cells. To ensure success, a sufficient amount of 10B should be selectively delivered to the tumor and an adequate number of thermal neutrons should be absorbed in order to sustain a lethal 10B(n,α) 7Li capture reaction [Ono et al., IJROBP 34: 1081-1086, 1996]. For BPA-based BNCT, it is necessary to analyze the actual distribution of BPA in vivo before determining factors for its indication, as well as before planning treatment and predicting outcome. For these purposes, numerous authors have used 18F-BPA-PET prior to employing BPA-based BNCT.

Trial in Taiwan A phase I/II trial of boron neutron capture therapy (BNCT) for recurrent head and neck cancer at Tsing Hua Open-Pool Reactor (THOR) ” was drafted at Taipei Veterans General Hospital (TVGH) in 2008 and was approved by Institution Review Board of TVGH and our Department of Health in 2009. The primary end points: treatment toxicities and tumor response rate. The secondary end points: time to tumor progression, progression-free survival, overall survival, and change of quality of life. Web site: www. clinicaltr ials .gov; ID: N CT01173172. August 2010 – Jan. 2014

Schema Pt (D-14±3) (D-7) 1st BNCT (D-1) 2nd (D22±3) 2nd BNCT (D29±3) registration (D-14±3) 1st CT Sim (D-7) 1st BNCT (D-1) 2nd CT Sim (D22±3) 2nd BNCT (D29±3) FDG-PET/CT or MRI Evaluation (D84±3) 1st 18F-BPA PET T/N (D-12) 1st THOR (D-3) 2nd 18F-BPA PET T/N (D21) 2nd THOR (D26±3) The BPA-uptake in ‘ ‘normal’’ tissue was measured in the subcutaneous connective tissue several cm away from the tumors. 20– 25 Gy(Eq) to 80% of GTV/Fx for 2 Fx at interval of 30 days. BPA injection - 1 st phase: 180 mg/kg/h for 2 h before neutron irradiation - 2nd phase: 1.5 mg/kg/min concurrent with irradiation and stopped when beam was off. Response Evaluation Criteria in Solid Tumors (version 1.1). MRIs before and after BNCT were performed for tumor size evaluation

High response rate with acceptable toxicity was obtained for this clinical trial with BNCT at THOR. The decreased T/N ratios after first fraction of BNCT may indicate that the second fraction is less efficient than the previous one.

Hypothesis & Aim The success of BNCT ultimately depends upon the selective delivery of 10B-atoms to tumor cells. Boron concentrations in surrounding normal structures as well as in the tumor itself, for which 18F-BPA PET was utilized. To the best of our knowledge, treatment failure of local recurrence and features of 10B uptake in tumors according to 18F-BPA-PET images have yet to be adequately assessed. The present study therefore aimed to qualitatively and quantitatively elucidate the features of 18F-BPA-PET imaging in the outcome of BNCT therapy of recurrent head and neck cancer patients.

T/N ratio by pre-treatment BPA-PET After IV. 60 min, Tumor mean value =7.0; Normal tissue mean value =1.6 T/N=4.37

Methods and Materials 12 advanced recurrent head & neck tumor patients who had received BNCT from 2010/8 to 2013/12 in Taiwan without distant failure In-field failure vs. complete response. The relationship between patient characters, disease status, pre-BNCT RT, 1st T/N ratio, treatment dosage, BPA-PET data, and clinical response were analyzed.

BPA-PET scan for 10B uptake

BNCT Treatment GTV according to pretreatment MR and 18F-PET/CT scan

Response Evaluation by 18F-PET/CT

Maxillary sinus carcinoma rT3, CR

Patient and tumor characters Pt No. Age/Sex Primary Site Pathology Prior OP Prior RT Dose (Gy/course) Recurrent Stage Tumor diameter (cm) 1 68/M Hypopharynx Squamous Y 134.6/2 T1N2a 4.00 2 71/M Gingiva 66 T4 7.50 3 49/F Nasal Cavity Sinonasal Ca 120/2 5.00 4 57/M Tongue 70 T3 4.50 5 52/M Tongue base T4a 5.30 6 46/M NPC Undiff Ca 136/2 3.90 7 54/M Maxillary sinus N 8.90 8 48/M Spindle cell sarcoma 107/2 T4b 6.00 9 58/F Non-keratinizing Ca 122/2 2.50 10 59/M T1 11 56/M Oral 129.5/2 0.88 12 62/M Buccal 128/2 6.60

Prescription Dose, T/N ratio, tumor response and survival status Pt No. Interval (month) 1st T/N 1st Fx D80 (Gy-eq) 2nd T/N 2nd Fx D80 (Gy-eq) Total Dose (Gy-eq) Tumor Response Survival Status Surv (months) 1 9.97 3.00 19.1 2.60 12.50 31.60 PD DOC 12.2 2 26.77 3.80 25.1 1.75 12.70 37.80 6.3 3 13.93 4.46 31.1 2.78 17.30 48.40 CR 32.5 4 6.37 3.73 19.6 2.00 13.50 33.10 Response 13.3 5 6.50 3.33 13.7 2.09 9.30 23.00 DOI 8.5 6 7.73 6.16 36.9 2.57 21.10 58.00 alive 38.6 7 17.07 5.69 35.0 2.50 18.10 53.10 35.2 8 28.17 20.0 19.40 39.40 26.0 9 33.70 1.05 1.79 9.90 29.00 37.3 10 42.37 19.2 2.71 18.30 37.50 6.8 11 5.13 3.30 20.01 8.8 12 9.57 3.92 26.5 2.27 16.80 43.30 6.4 DOC: death of cancer; DOI: death of incurrent cause PD: progression disease; CR: complete response; Response: partial response & stable disease

Measurement of BPA-PET

Parameter definition Only 1st BPA-PET data were analysis BPA_max Only 1st BPA-PET data were analysis BPA-M: BPA uptake value inside GTV volume Min BPA_M: min BPA uptake value inside GTV Max BPA_M: max BPA uptake value inside GTV BPA_H: BPA uptake value ≧ 30% of BPA_M (min. BPA-M + 30% of max BPA-M) BPA_L: BPA uptake < 30% of BPA_M Vol_L/H (cm3): Volume ratio between BPA_L and BPA_H according to BPA-PET BPA_L/H: BPA uptake value ratio between BPA_L and BPA_H according to BPA-PET BPA_H BPA_L BPA_min

BPA_H BPA_L

Results CR(-) CR(+) p Age 61±7 52±5 0.093 M/F 5/1 Pathology SqCC 5/6 2/6 0.099 Pre RT Dose (Gy) 92.5±33 108.3±28 0.284 Interval s/p EBRT (months) 15.5±12 19.1±14 0.605 Recurrent T stage 0.639 T1 1 2 T3 T4 3 Tumor (cm) 5.1±1.8 4.8±2.7 0.801 1st T/N 3.1±1.1 4.2±1.5 0.211 Total Dose-eq (Gy) 33±7 42.7±13.6 0.16 Volume L/H 1.5±0.8 0.7±0.2 0.134 BPA L/H 0.6±0.1 0.396

Tumors were easily identified as high uptake areas in all cases Tumors were easily identified as high uptake areas in all cases. Areas of the dorsum tongue to middle pharynx were expressed as high uptake areas in all of the cases. 18F-BPA-PET is useful in demonstrating the presence of a tumor. Thus, it is crucial high uptake area corresponding to the dorsum area of the tongue when diagnosing a tumor using this technique.

18F-BPA-PET Right maxilla Mucoepidermoid carcinoma Brain parenchyma (a) Parotid gland (b). The high uptake area: - Tumor (arrows); - Dorsum surface of the tongue (arrowheads). Differentiation between the two structures was difficult on the 18F-BPA-PET

18F-BPA-PET Aanterior maxilla adenocarcinoma High uptake area: - Tumor (arrow). - Surface of the oral tongue and tongue base (arrowhead) Left maxilla squamous cell carcinoma High uptake area - Jaw bone (arrows). - Tumor (arrowheads).

Tumor to brain (T/B) ratio = radioactivity of tumor/brain. Normal tissue to brain (N/B) ratio = radioactivity of normal tissue/brain.

1st head and neck cancer patient treated with up-front BNCT and conventional radiotherapy. BNCT followed by chemoradiation as first-line therapy of a patient diagnosed with large, inoperable head and neck carcinoma

Case Report 53 y/o woman CC:: obstructed nose and headache. Dx: Intranasal poorly differentiated carcinoma, A 7.4 × 6 .7 × 4 .4 cm tumour causing exophthalmos and diplopia BNCT, 400 mg/kg of L- BPA -fructose ivf. GTV dose = 31 Gy (W), PTV dose = 28 Gy (W), Optic chiasm = 4 Gy (W ) IMRT was given 6 weeks later with 44 Gy/17 Fx, followed by SBRT booster dose of 6 Gy. Iv with cetuximab (250 mg/m 2) + cisplatin (40 mg/m 2), weekly during IMRT. A radiological complete response was achieved one month after RT.

Summary Histology of squamous cell carcnoma, Total Dose-eq (Gy), Volume BPA uptake heterogeneity data might be a prognostic factor for clinic response though no statistic significance. The volume BPA uptake heterogeneity data were 0.7±0.2 (0.44-1.0) in CR group and 1.5±0.8 (0.71-2.69) in non-CR group, respectively There is only 12 patients in this study. F/U of 20 months (6.4 – 38.6 months). The CR is depended on the FDG-PET 3 months after BNCT. However, its predictive and prognostic value remains to be clarified.

Conclusion BNCT is an effective treatment for advanced local recurrent head and neck tumor with high percentage image CR rate in 20 months follow-up (6.4 – 38.6 months). Though no statistic significance noted, volume of BPA uptake heterogeneity might be a prognostic factor for clinic response. The low BPA uptake volume might need further RT boost for local control.

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