Report of
FNCA FY2021 Online Workshop on Radiation Oncology

Outline of Workshop

The FNCA FY2021 Online Workshop on Radiation Oncology was held on November 26th, 2021. The meeting was organized by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) in cooperation with Nuclear Safety Research Association (NSRA). Representatives from 11 FNCA member countries, namely Bangladesh, China, Indonesia, Japan, Kazakhstan, Korea, Malaysia, Mongolia, The Philippines, Thailand and Vietnam participated in the workshop (WS).

This project carries out international joint clinical studies in order to establish treatment protocols for uterine cervix cancer, nasopharyngeal cancer and breast cancer, which affect large number of people in FNCA member countries, and finally to improve the technique of radiation oncology in the Asian region.

Opening Session
Prof. KATO Shingo, the Project Leader of Radiation Oncology Project opened the WS with his opening remarks.
Mr. FUNABIKI Takahisa, MEXT, Mr. WADA Tomoaki, FNCA Coordinator of Japan and Dr. TAMADA Masao, FNCA Advisor of Japan gave their remarks respectively.

Mr. WADA introduced the project-related parts from "Conclusion and Recommendation" summarized in the 21_st FNCA Coordinators Meeting.

WS participants had a silent prayer for Dr CHO Chul Koo who was a former project leader of Korean and passed away in August 2021.

Prospective Observational Study of 3D-Image guided brachy therapy for Locally Advanced Cervical Cancer (CERVIX-V)
This is a new protocol for cervical cancers following Cervix-IV. The patient enrollment started in 2018.
76 patients were enrolled into Cervix-V in total. The number of patients by county is
Bangladesh (1), China (10), Indonesia (9), Japan (7), Kazakhstan (6), Korea (0), Malaysia (11), Mongolia (3), Philippines (8) Thailand (21) and Vietnam (0).

Japan presented the summary of analyzed clinical data of Cervix-V.

Out of 76 patients, 68 patients were eligible.
As preliminary analysis of Cervix-V, 60 patients whose follow-up periods exceeded 6 months were analyzed.
All patients were treated with 3D-IGBT and 21 patients were treated with the hybrid (the combination of interstitial and intracavitary brachytherapy) technique.

Compared to the reference doses, 95% of cases satisfied those doses.
- Grade 3 acute hematological toxicity was observed in 13 (22%) patients. These toxicities were manageable.
- Grade 3 or worse acute non-hematological toxicity was observed in 2 (3%) patients so far.
- Grade 3 or worse late toxicity has not been observed so far.
- The 2-year overall survival (OS), local control (LC), and disease-free survival (DFS) were 91%, 91%, and 76%, respectively.

The target number of patients for this study is 100, and the original enrollment deadline is May 2022. This protocol was drafted in 2017, but the clinical trial began in 2018. In addition, due to the impact of Covid-19, it is difficult to predict future enrollment. Extension of the registration period was proposed and agreed upon. The patients' enrollment will be continued until November 2023.

Phase II Study of Neoadjuvant Chemotherapy with Concurrent Chemoradiotherapy (CCRT) for Nasopharyngeal Carcinoma (NPC-III)
120 patients have been registered in this protocol.
The number of patients by county is Bangladesh (1), China (9), Indonesia (12), Japan (0), Kazakhstan (0), Korea (0), Malaysia (31), Mongolia (0), Philippines (7) Thailand (0) and Vietnam (60).

Japan presented the summary of analyzed clinical data of NPC-III. The Summary are as follows.
- Patients enrollment was completed in 2019.
- Current Total number of patients enrolled in NPC-III is 120.
- Median follow up period is 41 months.
- Registrations for NPC-III complete with some data missing.
- T and N stage matched and unmatched comparison with NPC-I (CCRT and adjuvant chemotherapy) showed worse local control but comparable OS.

The percent of distant metastasis (bone metastasis) is relatively high while NPC-III patients' stages are mostly 3 or 4 and only 62% patients received bone scintigraphy in pretreatment. It was recommended to perform a subset analysis to evaluate this point.

The primary endpoint of this clinical trial is 3-year PFS. The patients need to be followed up for 1 more year. With successful submission of all follow-up data, a final report will be issued.

Phase II Study of Hypofractionated Radiotherapy for Breast Cancer (Postmastectomy Radiation Therapy (PMRT)/BREAST-I)
The total number of registered PMRT patients was 222 (Bangladesh (84), China (13), Indonesia (0), Japan (15), Kazakhstan (20), Korea (0), Malaysia (0), Mongolia (26), Philippines (18), Thailand (0) and Vietnam (46)).

Japan presented the summary of analyzed clinical data of PMRT/BREAST-I. The Summary is as below.
- 222 cases have been enrolled and analyzed while the target accrual number is 200.
- 15% of grade 2 and over acute dermatitis and 1% of grade 2 subcutaneous acute toxicity have been observed.
- No grade 3 or over late toxicity has been observed.
- The 5 year locoregional control, progression free survival and overall survival rates are 96.3%, 81.0% and 90.9% respectively.

The enrollment of patients into this protocol was completed in 2019 and the primary endpoint of the protocol is 5-year local recurrence free survival. Participants were requested to follow up the patients for 3 more years. Also, total follow up period is 10 years. Co-researchers are requested to continue to check late adverse events during the period.

Phase II Study of Hypofractionated Radiotherapy for Breast Cancer (Whole Breast Irradiation / BREAST-I)
The total number of registered WBI patients was 227 (228 breast lesions). The number by country is Bangladesh (31), China (6), Indonesia (16), Japan (134), Kazakhstan (14), Korea (9), Malaysia (0), Mongolia (3), Philippines (0), Thailand (14) and Vietnam (0). Total number of WBI patients was 229. (229 patients / 230 breast lesions).
The summary of the clinical data is as follows.

Japan presented the summary of analyzed clinical data of WBI/BREAST-I. The Summary is as below.

- 227 cases were enrolled in HF-WBI protocol from February 2013 until October 2018.
- 227 patients with 228 tumors who completed the treatment were analyzed.
- 13% of grade 2-3 acute dermatitis had been observed.
- 1 locoregional recurrence, 4 distant metastases and 3 breast cancer death have been observed.
- No grade 3 or over late toxicity has been observed.
- The 5 year locoregional control rate, progression free survival rate and overall survival rate are 98.9%, 95.5% and 95.9% respectively.

The enrollment of patients into this protocol was completed in 2018. Total follow up period is 10 years. Co-researchers are requested to continue to check late adverse events during the period.

New Clinical Trials
In 2019's WS, palliative radiotherapies for bone metastasis and brain metastasis were proposed and discussed as new clinical trials. In 2020, surveys were conducted among the project members in order to draft protocols and the results of the surveys were introduced in the 2020's WS.

1) Palliative Radiotherapy for Bone Metastasis
A new protocol (draft) on prospective observational study of single fraction radiotherapy for painful bone metastasis (Bone-1) was proposed by Japan.
The protocol was generally adopted by the FNCA members with a few points to be finalized.

- Whether or not to include moderate pain patients with NRS 5-7.
- Lesion counts and total irradiation field size.
- Whether or not to include lesions other than the spine

These points will be discussed further on and aim to finalize and initiate administrative procedures to start the study by next workshop in 2022.

2) Palliative Radiotherapy for Bone Metastasis
Another new protocol (draft) titled "Survival benefits of palliative WBRT in NSCLC with brain metastases unsuitable for surgery of SRS: An external validation of prognostic models" was presented by Thailand.
They proposed a prognostic model as an external validation study with head to head comparison of many models, including the model from his hospital in Thailand. The objective is to predict the added benefit of whole brain RT for individual patients. The benefits of this study are as follows.

Firstly, it could be fast study with enough sample size (retrospective study with allowing for reasonable missing data).
Secondly, we can use a web-based model to calculate the added benefit of whole brain RT. Also, we can generate the specific model for each country if sample size is enough for that country.

The first action to do a survey based on a check list ( to survey 5 patients in each country to see feasibility of predictors) was proposed. A full proposal and record form will be followed.
Following questions were raised from WS participants.

- Is it possible to include all brain met with any primary cancer?
- Could we use ECOG performance status rather than KPS?
- Could all participants from FNCA countries access the data without whole brain RT?
These issues will be addressed in finalized checklist for survey later.

3) New RCA Project
A new IAEA/RCA project "Standardizing Radiotherapy in Palliative Care" was introduced by Dr WAKATSUKI Masaru (Japan), project leading country coordinator.
This project will start from 2022. The overall objective is to improve the QoL for cancer patients in the RCA region by improving the clinical management of palliative radiotherapy in the RCA government parties.
It is expected that this project will be closely linked to this FNCA Radiation Oncology Project. FNCA members are encouraged to participate in the RCA project as well.

FNCA Breakthrough Prize
Dr. MIZUNO Hideyuki, QST(Japan) was awarded Excellent Researcher Prize under FNCA Breakthrough Prize conducted by the Cabinet Office of Japan (CAO). His longtime QA/QC activities of dose audits for radiation therapies were highly evaluated.

Future Plans
1) 2022's Workshop
2022's workshop will be held in Mongolia if the spread of Covid-19 pandemic has settled down.

2) Future Clinical Trial
Prof. KATO reminded the WS members that the 21st FNCA Coordinators Meeting suggested that a radiation therapy for prostate cancers could be considered as a new clinical trial. Along with this proposal, the project members are encouraged to send their opinions on new clinical trials.

Minutes of
FNCA FY2021 Workshop on Radiation Oncology Project

(1) The FNCA FY2021 Online Workshop on Radiation Oncology was held on November 26th, 2021. The meeting was organized by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) in cooperation with Nuclear Safety Research Association (NSRA). Representatives from 11 FNCA member countries, namely Bangladesh, China, Indonesia, Japan, Kazakhstan, Korea, Malaysia, Mongolia, The Philippines, Thailand and Vietnam participated in the workshop.

Opening Session
(2) Prof. KATO Shingo, the Project Leader of Radiation Oncology Project opened the workshop with his opening remarks.

(3) Mr. FUNABIKI Takahisa, MEXT, Mr. WADA Tomoaki, FNCA Coordinator of Japan and Dr. TAMADA Masao, FNCA Advisor of Japan gave their remarks respectively.

(4) Mr. WADA introduced this project-related parts from "Conclusion and Recommendation" summarized in the 21st FNCA Coordinators Meeting held on 30th June 2021.

(5) Newly joined members were introduced.

(6) The workshop agenda was confirmed.

(7) Prof. KATO dedicated a memorial message to Dr. CHO Chul Koo who was a former project leader of Korea and passed away in August 2021.The workshop participants had a silent prayer time for Dr CHO.

Session 1: Prospective Observational Study of 3D-Image Guided Brachytherapy for Locally Advanced Cervical Cancer (CERVIX-V)

(8) Dr. OKONOGI Noriyuki, Chief Physician, Clinical Research Group of Pelvic Tumor, Department of Charged Particle Therapy Research, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology (QST), presented the summary of analyzed clinical data of Cervix-V.

(9)76 patients were enrolled into Cervix-V in total, and 68 patients were eligible. As a preliminary analysis of Cervix-V, 60 patients whose follow-up periods exceeded 6 months were analyzed.

(10) All patients were treated with 3D-IGBT. 21 patients were treated with the hybrid (the combination of interstitial and intracavitary brachytherapy) technique.

(11) Compared to the reference doses, 95% of cases satisfied those doses.
- Grade 3 acute hematological toxicity was observed in 13 (22%) patients. These toxicities were manageable.
- Grade 3 or worse acute non-hematological toxicity was observed in 2 (3%) patients so far.
- Grade 3 or worse late toxicity has not been observed so far.
- The 2-year overall survival (OS), local control (LC), and disease-free survival (DFS) were 91%, 91%, and 76%, respectively.

(12) The target number of patients for this study is 100, and the original enrollment deadline is May 2022. This protocol was drafted in 2017, but the clinical trial began in 2018. In addition, due to the impact of Covid-19, it is difficult to predict future enrollment. Extension of the registration period was proposed and agreed upon. The patients' enrollment will be continued until November 2023.

Session 2: Phase II Study of Neoadjuvant Chemotherapy with Concurrent Chemoradiotherapy (CCRT) for Nasopharyngeal Carcinoma (NPC-III)
(13) Dr. MAKISHIMA Hirokazu, Assistant Processor, Department of Radiation Oncology, Faculty of Medicine, University of Tsukuba presented the summary of analyzed clinical data of NPC-III. The Summary are as follows.

- Patients enrollment was completed in 2019.
- Current Total number of patients enrolled in NPC-III is 120.
- Median follow up period is 41 months.
- Registrations for NPC-III complete with some data missing.
- T and N stage matched and unmatched comparison with NPC-I (CCRT and adjuvant chemotherapy) showed worse local control but comparable OS.

(14) The percent of distant metastasis (bone metastasis) is relatively high while NPC-III patients' stages are mostly 3 or 4 and only 62% patients received bone scintigraphy in pretreatment. It was recommended to perform a subset analysis to evaluate this point.

(15) The primary endpoint of this clinical trial is 3-year PFS. The patients need to be followed up for 1 more year. With successful submission of all follow-up data, a final report will be issued.

Session 3: Phase II Study of Hypofractionated Radiotherapy for Breast Cancer (Postmastectomy Radiation Therapy (PMRT)/BREAST-I)
(16) Prof. KARASAWA Kumiko, Professor and Head Division, Department of Radiation Oncology, Tokyo Women's Medical University presented the summary of analyzed clinical data of PMRT/BREAST-I. The Summary are as follows.

- 222 cases have been enrolled and analyzed while the target accrual number is 200.
- 15% of grade 2 and over acute dermatitis and 1% of grade 2 subcutaneous acute toxicity have been observed.
- No grade 3 or over late toxicity has been observed.
- The 5 year locoregional control, progression free survival and overall survival rates are 96.3%, 81.0% and 90.9% respectively.

(17) The enrollment of patients into this protocol was completed in 2019 and the primary endpoint of the protocol is 5-year local recurrence free survival. Participants were requested to follow up the patients for 3 more years. Also, total follow up period is 10 years. Co-researchers are requested to continue to check late adverse events during the period.

Session 4: Phase II Study of Hypofractionated Radiotherapy for Breast Cancer (Whole Breast Irradiation (WBI)/ BREAST-I)
(18) Prof. KARASAWA presented the summary of analyzed clinical data of WBI / BREAST-I. The Summary are as follows.

- 227 cases were enrolled in HF-WBI protocol from February 2013 until October 2018.
- 227 patients with 228 tumors who completed the treatment were analyzed.
- 13% of grade 2-3 acute dermatitis had been observed.
- 1 locoregional recurrence, 4 distant metastases and 3 breast cancer death have been observed.
- No grade 3 or over late toxicity has been observed.
- The 5 year locoregional control rate, progression free survival rate and overall survival rate are 98.9%, 95.5% and 95.9% respectively.

(19) The enrollment of patients into this protocol was completed in 2018. Total follow up period is 10 years. Co-researchers are requested to continue to check late adverse events during the period.

Session 5: New Clinical Trials
1) Palliative Radiotherapy for Bone Metastasis
(20) Dr. MAKISHIMA, proposed the concept and protocol of the new prospective observational study of single fraction radiotherapy for painful bone metastasis (Bone-1). The protocol was generally adopted by the FNCA members with a few points to be finalized.

- Whether or not to include moderate pain patients with NRS 5-7.
- Lesion counts and total irradiation field size.
- Whether or not to include lesions other than the spine

These points will be discussed further on and aim to finalize and initiate administrative procedures to start the study by next workshop in 2022.

2) Palliative Radiotherapy for Brain Metastasis
(21)Dr. Kullathorn Thephamongkhol, Lecturer, Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Siriraj Hospital, Mahidol University introduced a protocol draft on palliative radiotherapy for brain metastasis, titled " Survival benefits of palliative WBRT in NSCLC with brain metastases unsuitable for surgery of SRS: An external validation of prognostic models".

(22)Dr. Thephamongkhol proposed a prognostic model as an external validation study with head-to-head comparison of many models, including the model from our hospital in Thailand. The objective is to predict the added benefit of whole brain RT for individual patients. The benefits of this study are as follows.

Firstly, it could be fast study with enough sample size (retrospective study with allowing for reasonable missing data).
Secondly, we can use a web-based model to calculate the added benefit of whole brain RT. Also, we can generate the specific model for each country if sample size is enough for that country.

(23)Dr. Thephamongkhol proposed the first action as check list survey as 5 patients in each country to see feasibility of predictors. Full proposal and record form will be followed.

(24) Following questions were raised from workshop participants.

- Is it possible to include all brain met with any primary cancer?
- Could we use ECOG performance status rather than KPS?
- Could all participants from FNCA countries access the data without whole brain RT?

These issues will be addressed in finalized checklist for survey later.

3) New RCA Project
(25) Dr. WAKATSUKI Masaru, Director of Department of Radiation Medicine, QST Hospital, Quantum Life and Medical Science Directorate, National, QST gave a presentation on a new IAEA/RCA project "Standardizing Radiotherapy in Palliative Care".

(26) This project will start from 2022. The overall objective is to improve the QoL for cancer patients in the RCA region by improving the clinical management of palliative radiotherapy in the RCA government parties.
It is expected that this project will be closely linked to this FNCA Radiation Oncology Project. FNCA members are encouraged to participate in the RCA project as well.

FNCA Breakthrough Prize
(27) Dr. MIZUNO Hideyuki, Principal Researcher, Quality Control Section, QST Hospital, Quantum Life and Medical Science Directorate, QST was awarded Excellent Researcher Prize under FNCA Breakthrough Prize conducted by the Cabinet Office of Japan (CAO). His longtime QA/QC activities of dose audits for radiation therapies were highly evaluated.

Session 6: Future Plans-
1) 2022's Workshop
(28) 2022's workshop will be held in Mongolia if the spread of Covid-19 pandemic has settled down.

2) Future Clinical Trial
(29) Prof. KATO reminded the project members that the 21st FNCA Coordinators Meeting suggested that a radiation therapy for prostate cancers could be considered as a new clinical trial. Along with this proposal, the project members are encouraged to send their opinions on new clinical trials.

Program of
FNCA 2021 Online Workshop on Radiation Oncology Project

Date & Time: 15:00-17:00, 26^th November (Fri) ,2021
Place: Web-Meeting (via ZOOM )
Organized by: Nuclear Safety Research Association (NSRA)
Chair(Facilitator): Prof. KATO Shingo, Japan
Language: English

(Japan Time)