Linkou-Proton and Radiation Therapy Center

The characteristic of Proton Therapy

Proton therapy is currently the most expensive and advanced medical facility in the world. There are 36 proton centers and more than 90,000 cases in the world till late 2012, and the facility and patient number are still booming. Comparing to the X-ray, the proton passes through tissues with lower entrance dose, but releases large amounts of energy when it reaches the desired depth of treatment (the Bragg peak), and deposits no dose to the normal tissues behind tumor. Therefore, proton therapy not only attacks tumor precisely but lowers the dose of normal tissue and rate of complication. The proton therapy is shown a better choice in some specific type of tumor. With proton therapy, for example, the cure rate of skull base tumor, liver cancer, and early lung cancer are higher and the complication rate of pediatric tumor and head and neck cancer are lower.

 

The potential benefits of proton therapy

• Lower radiation dose of normal tissue
• Fewer treatment-related complication and improving the life quality
• Lower risk of subsequent tumor caused by the radiation
• Higher cure rate by increasing the dose to tumor

Varian TrueBEAM Radiotherapy Linear Accelerator

The Varian TrueBEAM Radiotherapy Linear Accelerator provides not only 6MV and 10MV high-energy photon beams at a traditional dose rate (600 MU/min), but also special high intensity modes in 6MV and 10 MV-FFF (Flattening Filter Free). The maximum output dose can reach 2400 MU per minute, which is four times the normal mode of 600 MU per minute, thus dramatically decreasing treatment time for patients. Furthermore, the accuracy in mechanical movements and beam control of TrueBEAM is also the most advanced among all accelerator equipment. This device uses an all- digital method to combine radiotherapy and image-guided positioning to provide the best quality of radiotherapy to patients with the simplest operations. Due to the high dose rate, the radiation shielding plan has to be carefully re-evaluated for the operation venue in order to ensure protection from radiation for both staff and patients. At the same time, the high- precision mechanical apparatus and high-accuracy digital control system require a more comprehensive verification procedure to ensure the high quality of the equipment.

For quality verification, according to the standard operating procedure for testing received by medical physicists, the verification includes the complete testing of the following: mechanical movement accuracy of each component, energy of the output beam, validity of dose distribution, and effectiveness of each operative function. Overall, the mechanical movement accuracy of TrueBEAM is < 1 mm and the beam energy accuracy is < 0.5%. The level of accuracy is sufficient for executing stereotactic radiotherapy, stereotactic radiosurgery (SRT/SRS) or even stereotactic body radiotherapy (SBRT), which requires the highest accuracy.

Image Guided Radiation Therapy (IGRT)

Traditionally, physicians need to increase the safety margin around the tumor for conventional radiation therapy to ensure that the radiation remains within the tumor area; thus, we cannot effectively spare normal tissue organ. These limitations were mainly due to patient setup uncertainties and internal organ motion. Image-guided radiation therapy (IGRT) provides high-resolution, two-dimensional imaging and three- dimensional volumetric images prior to treatment to pinpoint bony landmarks or internal markers to ensure treatment accuracy and that the same position is targeted in every treatment session. Furthermore, it minimizes the deviation of internal organ motion or patient setup uncertainties, as well as decreases the irradiation to normal organs.

Through more precise targeting of the beam to tumors, doses to the tumors can be increased and the non-target volumes can be reduced. Higher radiation doses in tumors have been shown to enhance tumor control and better spare non-target regions, reducing the possibility of side effects after radiotherapy.

The On-Board Imager® kV imaging system with cone-beam CT and imaging fusion technique provides more precise localization information and better treatment quality and accuracy. Due to the need of x-ray imaging and patient positioning correction before each treatment for image guided radiotherapy, it takes about four to five minutes more than the conventional radiation therapy treatment time.

Respiratory Gating Radiotherapy

The respiratory gating radiotherapy technique is especially useful for tumors that move, such as those in lung and liver cancer. CGMH introduces the Real-time Position Management TM (RPM) respiratory gating system, which gates the beam delivery during treatment to account for organ motion. Information about tumor movement can be realized by using an infrared camera to detect the patient breathing in and out during treatment; then the respiratory gating signal can trigger the LINAC accelerator x-ray beam to treat the tumor within the gated phase to assure the accuracy of treatment position. A non-invasive marker box is placed on the patient’s body and the infrared system tracks the chest wall’s movement during the CT imaging. The big bore CT simulator with four-dimensional CT capability provides the correlation of respiratory phase and tumor location with a dynamic time frame. During the treatment, the radiation beam is gated to when the target falls within the treatment field while avoiding critical organs. In this case, we can treat patients with high accuracy while minimizing treatment errors, and the patient can breathe normally and remain comfortable and with high compliance during the treatment. This technique takes about five to ten minutes more than regular treatment time.

Deep inspiration breath hold radiotherapy (DIBH)

The deep inspiration breath-hold technique (DIBH) can be applied to patients with breast or lung cancer as one of the respiratory gating techniques. The main purposes are expanding the lung volume and increasing the distance of the heart to the treatment region, as well as to minimize overall organ motion. The patient needs to be able to control himself or herself during the deep inspiration breath-hold, based on the visualization goggle display.

Edge

Edge is the state-of-art linear accelerator presented by Varian. The high precision and integrated machine intelligence are the main features of Edge. With its advanced technology, Edge is capable of generating a highly conformal dose distribution. The movement of six degrees of freedom and breathing monitoring empowers us to track the tumor precisely in real-time. Besides its revolutionary improvement in traditional radiotherapy, the machine is built as a weapon for radiosurgery.

Vision RT

Vision RT is one of the most rapidly growing technology that detects the body surface of the patient in 3D to ascertain the setup and patient movement certainty. Through real-time tracking of the body surface, Vision RT can greatly enhance the speed and the correctness during set up for the patient. Additionally, it can also reduce the burden of immobilization but ensure the patient in an accurate position simultaneously. Recently, it has been applied in a wide variety of cancer radiotherapy treatments, including breast cancer, brain tumor, and head and neck cancers.

Dr. Ji-Hong HONG Specialty: Gynecologic tumors, Prostate cancer, Genitourinary tumors, Gastrointestinal tumors	Dr. Joseph Tung-Chieh CHANG Specialty: Proton Therapy. Head and Neck Cancer. Nasopharyngeal cancer Radiotherapy, Breast cancer, Hepatoma, GI cancer, Health related Quality of life research, Patient Decision Making Sharing and Coaching
Dr. Ngan-Ming TSANG Specialty: Head and neck cancer, Nasopharyngeal carcinoma, Thyroid cancer, Digestive system cancer, Liver cancer, Colorectal cancer	Dr. Chen-Kan TSENG Specialty: Radiotherapy for adult CNS tumor, esophageal cancer, sarcoma, and the pediatric cancers, radiosurgery
Dr. Chun-Chieh WANG Specialty: Proton and Photon radiotherapy for brain, lung and Gyn cancers. Combining RT with immunotherapy.	Dr. Ping-Ching PAI Specialty: Breast cancer, esophageal cancer, brain tumor, chest tumor
Dr. Chien-Yu LIN Specialty: Radiotherapy for Head and Neck Cancer, Nasopharyngeal Cancer	Dr. Kang-Hsing FAN Specialty: Proton therapy, radiotherapy for prostate cancer and genitourinary tract cancer, radiotherapy for head and neck cancer
Dr. Bing-Shen HUANG Specialty: Liver and upper GI cancers, Nasopharyneal cancer and head and neck cancers	Dr. Tsung-Min HUNG Specialty: Esophageal cancer, Nasopharyneal carcinoma, Head and neck cancers

 

Beam Delivery System

The proton therapy machine has two different treatment techniques to meet the individual needs of tumor treatment, Pencil Beam Scanning and Wobbling. The principle of Wobbling involves sending a narrow proton beam through a magnetic field of the X- and Y-axes and deflectors while it expands with a rotation of a specific radius into a broader beam with a wider range. When it passes through the ridge filter, the vertical axis expands into SOBP, passes through the compensator and collimator, and then conforms before reaching the body. Another method that can reduce unnecessary normal tissue dose involves using layer stacking and a multileaf collimator (MLC) that can adjust the field size. This way, the dose distribution can be done as shown in the figure below. The figure clearly shows that the orange block, which represents normal tissue, receives a much smaller dose. This advanced technology is being used by our Proton Therapy Center. Since the energy output of the cyclotron is fixed (230MeV), by using the energy selection system (ESS), the energy level that reaches the treatment site can be adjusted. Different energy levels can penetrate different depths. Therefore, by using adjustment mechanisms, the tumor is divided into different layers of the same width. Treatment starts from the deepest layer and gradually moves upwards, while the use of the multileaf collimator follows the 3D shape of the tumor.

 

The principle of Pencil Beam Scanning involves sending a narrow proton beam through a magnetic field of the X- and Y-axes and distributing it directly in the field by scanning. This technique controls the weighted dose of each point in the field to achieve "Intensity Modulated Proton Therapy (IMPT)". This advanced technology is currently in the Proton Therapy Optimization Plan and is essentially the direction of the future of proton therapy.

Patient Position System 

Digital Imaging Positioning System: To ensure the positional accuracy of proton therapy, every treatment room is equipped with a digital imaging guiding system, which acquires images through three different methods: digital radiography, fluoroscopy and computed tomography.

A. Digital radiography can acquire two orthogonal two-dimensional images to match the treatment site. 

B. Fluoroscopy can view lesion displacement caused by a variety of reasons, such as breathing, and adjust treatment to such breathing with the aid of proton therapy equipment.

C. Computed tomography is used to compare its image with the simulated image from the computer treatment plan system to ensure the accuracy of the treatment site.

X-ray Imaging Positioning System

Digital Radiography

Robotic Couch

After the Digital Imaging Positioning System determines the correct patient position on the couch, this information is immediately sent to the robotic couch for a 6-dimensional shift. The robotic couch is a specialized couch developed by combining an industrial computer-controlled robotic arm and a radiotherapy couch. The robotic couch has a total of six drive motors, which enable it to move along six axes and rotate with an accuracy of 0.01 mm. Not only can it measure the weight of a patient (maximum user weight 200 kg), but it can also compensate for inclinations due to weight. It is the most advanced and accurate couch among radiotherapy equipment today.

Comparison between proton therapy and other radiotherapies

	Proton therapy	RapidArc	Cyberknife	Tomotherapy	Gamma Knife
Treatment sites	Whole Body	Whole Body	Whole Body	Whole Body	Head only (<3cm)
Beam	Proton Beam	X-Ray	X-Ray	X-Ray	Gamma-Ray
Low dose bath area	Limited	Moderate	Moderate	Moderate	Moderate
Radiation dose to nearby normal tissue	Limited	Fair	Fair	Fair	Fair
Image-Guided Radiation Therapy	Yes	Yes	Yes	Yes	No
Fractionation	Yes	Yes	Yes	Yes	No
Treatment time for each fraction	20~60 mins	<5 mins	20 mins-2 hours	<30 minutes	20 ~60 mins
Pros	Reduce radiation dose exposure to normal tissue in order to reduce  treatment-related toxicities	Rapidly deliver 360 degree volumetric Modulated Arc Therapy (VMAT) and reduce the discomfort of long treatment time.	Use x-ray images to correct setup or positioning errors during the treatment	Use tomography (CT) for setup localization before treatment	High fixation and treatment accuracy
Cons	Expensive	Due to the complexity of the plan, it takes more time for treatment planning.	Repeated x-ray imaging further increases the treatment time and radiation dose	Not able to instantly correct the treatment error caused by displacement of localization	Only can treat small head lesions. Treatment time will be increased as radioactive sources decay.

 

A lot of curable cancer could achieve high curative and low complication rate when using proton beam therapy combining with surgical treatment or chemotherapy. As shown in the figure, the radiation dose was represented by different colors. Areas covered by blue color are low dose area, and areas covered by red color representing the high ones. In addition to irradiating cancer cells, proton beam therapy could avoid scattered radiation dose affecting the surrounding normal tissues. Therefore, the figure of proton beam therapy clearly shows the surrounding normal tissues receive scanty or no radiation dose. Aside from improving life quality during and after radiotherapy, using the proton beam therapy could also lower the risk of secondary cancer occurring in the previously normal tissues caused by radiotherapy.

Brain tumor

Lowering the radiation dose to normal brain tissues could further minimize the damage to brain tissue. This would reduce the impact on memory and endocrine function. Thereby, the quality of life is less affected after treatment.

• Indication: (1) Resected tumor with positive margin    (2) Inoperable tumor with indication of radiosurgery, such as larger arteriovenous malformation, acoustic neuroma, pituitary adenoma and etc…

Head and neck cancer

When the proton beam therapy is utilized in treating the cancer in nasopharynx or oral cavity, radiation dose in oral cavity, hypopharynx and esophagus could be lowered or reduced to no dose. In this way, damage to the oral mucosa and throat was cut down, which could reduce the complication of pain, dry mouth, taste change and lowering the need of nasogastric tube insertion. For other head and neck cancer, the possibilities of dry mouth, mucositis, sore throat, hearing impairment, trismus, neck fibrosis and swallowing difficulties are lower in patient using proton beam therapy than ones using photon therapy, and therefore improving patients’ quality of life.

Esophageal cancer

Reducing the irradiation dose to the heart and lung could minimize the impact on cardiopulmonary function. It would therefore lower the complication rate of surgical treatment after concurrent chemotherapy and radiotherapy.

Lung cancer

Reducing the irradiation dose to the heart, normal lung and esophagus could minimize the impact on cardiopulmonary function and lung fibrosis. It also reduced the pain while swallowing. By using proton beam therapy, complications caused by conventional concurrent chemotherapy and radiotherapy, such as esophagitis, heart burning sensation, pneumonia, and shortness of breath are lowered.

Indication: Stage I to III

Contraindication: infiltrative tumor, multiple distant metastases (more than 3 sites)

Breast cancer

Common complications such as mild skin redness, swelling and eruption still occur in patients receiving proton beam therapy. The benefit of using proton beam therapy lies in reducing the radiation dose of heart, lung and contralateral breast. Using proton beam thereby reduce the risk of myocardial infarction, pulmonary function decline and secondary cancer in contralateral breast. Recent researches have shown that left breast cancer patients treated by conventional radiotherapy have higher risk of myocardial infarction as long-term complication. Therefore, the proton therapy could reduce the risk of myocardial infarction significantly.

• Indication: (1) Internal or lower chest wall tumor    (2) Higher radiation dose of heart in conventional radiotherapy    (3) Bilateral reconstructed breast with permanent implantation    (4) Internal mammary lymph node metastasis    (5) Poor cardiopulmonary function    (6) Young age patient with intention to reduce lung and contralateral breast radiation dose

• Contraindication: distant metastasis

Liver tumor

Proton beam therapy could achieve high radiation dose in liver tumor, and therefore reach a good local control. It also minimizes the influence of liver function and lower side effect in gastro-intestinal tract, such as nausea and vomiting. Patients who receive proton beam therapy would have lower rate of liver dysfunction, ascites and death.

• Indication: (1) Patient that is inoperable or unwilling to receive surgical resection    (2) Tumor less than 5 cm: Tumor control rate is around 90~95%    (3) Tumor  from 5~10cm: Tumor control rate is around 85%    (4) Tumor larger than 10 cm: Tumor control rate is around 45%    (5) Tumor recurrence after previous surgical resection or failed to treat the tumor with radiofrequency ablation and trans-arterial chemo-embolization (6) Unable to control the lesion with surgical or other intervention    (7) Residual solitary tumor after small other small lesion being controlled.

• Contraindication: (1) Infiltrative tumor    (2) Multiple large tumor    (3) Distant metastasis    (4) For tumor that is close to gastro-intestinal tract, further evaluation is needed

Pancreatic cancer

By using proton beam therapy, radiation dose to liver, kidney and gastro-intestinal tract could be lowered, and therefore the influences on organ function are reduced. The benefits of using proton beam therapy in pancreatic cancer result in the reduction of complication such as nausea, vomiting, poor appetite or body weight loss. The better quality of life helps those patients more tolerable to the concurrent chemotherapy, which is almost the standard treatment in most patients. The higher completion rate of the chemotherapy results in elevation in overall survival. This is especially important in cancers with very poor prognosis such as pancreatic cancer.

• Indication: (1) Inoperable tumor without distant metastasis    (2)  High risk of recurrence after surgical treatment    (3) Concurrent chemo-radiotherapy to increase the possibility of complete resection before surgical treatment

• Contraindication: (1) Extensive lymph node metastasis    (2) Distant metastasis

Gynecology tumor

Proton beam therapy would result in lower scattering radiation dose to small intestine, colon and ovary, which lower the complication of diarrhea. Endocrine function decline would also be less affected.

Pediatric tumor

Children are more sensitive to the effects of radiation because they are still in the process of body growing and development. Proton beam therapy could significantly reduce the moderate and low scattering dose, and therefore reduce the influence on children growth and development. Furthermore, it also reduces the risk of secondary tumor. Take pediatric brain tumor for example, the benefit of proton beam therapy is that normal tissues behind the tumor have no radiation dose at all. In this circumstances, risks of secondary tumor and mental and development disorder are lowered.

The necessary evil when killing tumor

High-energy X ray produced by linear accelerator could be said as the standard modality of radiotherapy. The high penetrating ability of high-energy X-ray would even penetrate through the human body. Therefore, normal tissues in front of the tumor would receive higher radiation dose, and the tissue behind still receive residual dose. Take a 3-cm tumor for example, the X-ray would release its energy in its way through the tumor, but the damaged area would exceed 3 cm. Therefore, normal tissues are affected.

During the war between radiation and tumor cell, some of the cancer cells are perished, but some are merely injured. However, those injured cells could be repaired and grow again under sufficient time, energy and nutrient. To totally eradicate cancer cells, adequate radiation dose is needed. However, when we try to concentrate the radiation dose to the tumor, the price is that normal tissue prior to the tumor cell would receive radiation dose higher than tumor cell itself. Meanwhile, the X-ray keep on going after passing through the tumor area, and therefore causing dose accumulation in normal tissue behind the tumor. The resulting damage may cause secondary cancer or other disorder day after day.

The radiation dose to normal tissues is the necessary evil of conventional radiotherapy. To avoid complication from scattering radiation, conventional radiotherapy utilizes the photon beam from different angle, intending to even the dose that scattered to surrounding normal tissues.

Complications of conventional radiotherapy (Photon beam therapy)

(1) Acute complication: Usually occur during radiotherapy. Complications mostly occur as acute inflammation and mucosa damage. They would occur within weeks and resolve few weeks after completing radiotherapy.

(2) Chronic / late complication: Usually occur months or years after radiotherapy. Most late complications occur as chronic inflammation, fibrosis and vascular disorder, and mostly they would not resolve.

The quality and quantity of complication vary according to the radiation dose, body part and personal body nature. Some have no complication and some have severe complication. There is no universal condition of complication severity. Moreover, complication does not correlate to the cure rate. A fully cured patient may have severe complication or have little complication.

What are the common complications?

Due to the tumor destruction and inflammatory reaction, patients would have general reactions as mild local swelling, malaise and poor appetite in initial days of radiotherapy. The resting specific complication varies according to the tumor location, including nausea, vomiting, oral pain, taste change, dysphagia, voice change, body weight loss, diarrhea, hair loss, skin scaling… etc. Especially in head and neck, abdominal and large area irradiation, more severe reaction may occur. Long term complication may occur as dry mouth, trismus and swelling difficulties in head and neck cancer; lung fibrosis and difficulties in breathing in lung; liver function decline and gastro-intestinal ulcer…etc in abdominal and pelvic irradiation.

Since the start of the proton center on 2015/11/04, a total of 3,768 patients have completed proton therapy. Patients with liver tumors accounted for nearly one-fourth of the total number of patients (Figure 1). Other major categories include head and neck cancers, brain cancers, breast cancers, and lung cancers.

Between 2015 and 20212 a total of 200 patients with liver cancer have received and completed proton therapy. In the prospective observation of the treatment outcome, the one-year and two-year local control rate is 94.3% and 90.4%, respectively. There was no local tumor recurrence after a two-year observation. The one-year overall survival rate is 76.2%. Proton therapy provides treatment with extremely high precision (Figure 2) and offers excellent local tumor control. However, liver cancer is notorious for its nature of multi-focal recurrence. Even though the proton therapy provided a high local control rate, there are still around 60% of the treated patients suffered from tumor recurrence in unirradiated areas. Proton therapy is not the only treatment for liver cancer, and we also provide multi-modality treatment in cooperation with other specialists to offer the optimal treatment outcome.

The picture on the left side shows the treatment plan of proton therapy. The right one shows the MRI image that was taken four months after the end of treatment. By comparing the two pictures, the accuracy of proton therapy is evident.

As of January 2019, there were 94 patients who received a complete course of proton therapy. The local control rate was 95.4% but 2 patients developed distant metastases after the treatment. According to a retrospective analysis from our institute, even comparing to the advanced X-ray radiotherapy technique, proton therapy still significantly reduced the radiotherapy-related side effects, e.g., oral mucositis, nasogastric tube placement, and body weight loss. The incidences of chemotherapy-related side effects, like leukopenia and neutropenia, were also significantly lower, possibly because of better nutritional status. The higher chemotherapy and radiotherapy completion rate may also have the potential to be translated into long-term survival benefits.

Chang-Gung Memorial Hospital provides Faster and Finer Pencil-beam Scanning Treatment than MD Anderson Cancer Center

Papers from recent 3 years

1. Kao, W. H., J. H. Hong, L. C. See, H. P. Yu, J. T. Hsu, I. J. Chou, W. C. Chou, M. J. Chiou, C. C. Wang and C. F. Kuo (2017). "Validity of cancer diagnosis in the National Health Insurance database compared with the linked National Cancer Registry in Taiwan." Pharmacoepidemiol Drug Saf.
2. Lei, K. F., C. H. Kao and N. M. Tsang (2017). "High throughput and automatic colony formation assay based on impedance measurement technique." Anal Bioanal Chem 409(12): 3271-3277.
3. Chou, Y. C., C. Y. Lin, P. C. Pai, C. K. Tseng, C. E. Hsieh, K. P. Chang, C. L. Hsu, C. T. Liao, C. C. Wang, S. C. Chin, T. C. Yen, T. Y. Ho, J. H. Hong, K. F. Lei, J. T. Chang and N. M. Tsang (2017). "Dose-escalated radiation therapy is associated with better overall survival in patients with bone metastases from solid tumors: a propensity score-matched study." Cancer Med 6(9): 2087-2097.
4. Fan, K. H., Y. C. Chen, C. Y. Lin, C. J. Kang, L. Y. Lee, S. F. Huang, C. T. Liao, S. H. Ng, H. M. Wang and J. T. Chang (2017). "Postoperative radiotherapy with or without concurrent chemotherapy for oral squamous cell carcinoma in patients with three or more minor risk factors: a propensity score matching analysis." Radiat Oncol 12(1): 184.
5. Hsieh, C. E., K. C. Ho, C. H. Hsieh, T. C. Yen, C. T. Liao, H. M. Wang and C. Y. Lin (2017). "Pretreatment Primary Tumor SUVmax on 18F-FDG PET/CT Images Predicts Outcomes in Patients With Salivary Gland Carcinoma Treated With Definitive Intensity-Modulated Radiation Therapy." Clin Nucl Med 42(9): 655-662.
6. Hung, T. M., K. H. Fan, E. Y. Chen, C. Y. Lin, C. J. Kang, S. F. Huang, C. T. Liao, S. H. Ng, H. M. Wang and J. T. Chang (2017). "An elective radiation dose of 46 Gy is feasible in nasopharyngeal carcinoma treated by intensity-modulated radiotherapy: A long-term follow-up result." Medicine (Baltimore) 96(6): e6036.
7. Hung, T. M., C. R. Lin, Y. C. Chi, C. Y. Lin, E. Y. Chen, C. J. Kang, S. F. Huang, Y. Y. Juang, C. Y. Huang and J. T. Chang (2017). "Body image in head and neck cancer patients treated with radiotherapy: the impact of surgical procedures." Health Qual Life Outcomes 15(1): 165.
8. Li, Y. L., J. T. Chang, L. Y. Lee, K. H. Fan, Y. C. Lu, Y. C. Li, C. H. Chiang, G. R. You, H. Y. Chen and A. J. Cheng (2017). "GDF15 contributes to radioresistance and cancer stemness of head and neck cancer by regulating cellular reactive oxygen species via a SMAD-associated signaling pathway." Oncotarget 8(1): 1508-1528.
9. Lin, S. M., H. Y. Ku, T. C. Chang, T. W. Liu and J. H. Hong (2017). "The prognostic impact of overall treatment time on disease outcome in uterine cervical cancer patients treated primarily with concomitant chemoradiotherapy: a nationwide Taiwanese cohort study." Oncotarget 8(49): 85203-85213.
10. Lin, Y. C., G. Lin, J. H. Hong, Y. P. Lin, F. H. Chen, S. H. Ng and C. C. Wang (2017). "Diffusion radiomics analysis of intratumoral heterogeneity in a murine prostate cancer model following radiotherapy: Pixelwise correlation with histology." J Magn Reson Imaging 46(2): 483-489.
11. Lu, Y. C., A. J. Cheng, L. Y. Lee, G. R. You, Y. L. Li, H. Y. Chen and J. T. Chang (2017). "MiR-520b as a novel molecular target for suppressing stemness phenotype of head-neck cancer by inhibiting CD44." Sci Rep 7(1): 2042.
12. Yap, W. K., Y. C. Chang, C. K. Tseng, C. H. Hsieh, Y. K. Chao, P. J. Su, M. M. Hou, C. K. Yang, P. C. Pai, C. R. Lin, C. E. Hsieh, Y. Y. Wu and T. M. Hung (2017). "Predictive value of nodal maximum standardized uptake value of pretreatment [18F]fluorodeoxyglucose positron emission tomography imaging in patients with esophageal cancer." Dis Esophagus 30(8): 1-10.
13. Kao, W. H., Shen, Y. L., Hong, J. H. What are the Potential Benefits of Using Proton Therapy in Taiwanese Cancer Patients? Biomedical Journal 2015; (ahead of print)
14. Chi-Cheng Yang, Shinn-Yn Lin* &amp; Chen-Kan Tseng. Maintenance of multidomain neurocognitive functions in pediatric patients after proton beam therapy: A prospective case-series study, Applied Neuropsychology: Child. 2019; 8(4): 389-395.
15. Fan KH, Chao YK, Chang JT*, Tsang NM, Liao CT, Chang KP, Lin CY, Wang HM, Hsu CL, Huang SF. (2019, 08) A retrospective analysis of the treatment results for advanced synchronous head and neck and esophageal cancer. BJR|Open.
16. https://doi.org/10.1259/bjro.20190015. Published Online: August 06, 2019.
17. Li YC, Cheng AJ, Lee LY, Huang YC, Chang JT*. (2019, 07) Multifaceted Mechanisms of Areca Nuts in Oral Carcinogenesis: the Molecular Pathology from Precancerous Condition to Malignant Transformation. J Cancer. 10(17):4054-4062.
18. You GR, Cheng AJ, Lee LY, Huang YC, Liu H, Chen YJ, Chang JT*. (2019, 01) Prognostic signature associated with radioresistance in head and neck cancer via transcriptomic and bioinformatic analyses. BMC Cancer. 2019 Jan 14;19(1):64.
19. Huang PW, Lin CY, Hsieh CH, Hsu CL, Fan KH, Huang SF, Liao CT, Ng SK, Yen TC, Chang JT*, Wang HM*. (2018, 04) A phase II randomized trial comparing neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in advanced squamous cell carcinoma of the pharynx or larynx. Biomed J. 41(2):129-136. (共同通訊作者)
20. Lin CY, Fan KH, Lee LY, Hsueh C, Yang LY, Ng SH, Wang HM, Hsieh CH, Lin CH, Tsao CK, Kang CJ, Fang TJ, Lee LA, Huang SF, Chang KP, Yen TC, Tay ZY, Wen YW, Lee SR, Liao CT. (2020, 04) Precision Adjuvant Therapy Based on Detailed Pathological Risk Factors for Resected Oral Cavity Squamous Cell Carcinoma: Long Term Outcome Comparison of CGMH and NCCN Guidelines.  Int J Radiat Oncol Biol Phys. 106(5):916-925. doi:10.1016/j.ijrobp.2019.08.058. Epub 2019 Sep 6.
21. Cheng NM*, Hsieh CE, Liao CT, Ng SH, Wang HM, Fang YD, Chou WC, Lin CY*, Yen TC*. (2019, 05) Prognostic Value of Tumor Heterogeneity and SUVmax of Pretreatment 18F-FDG PET/CT for Salivary Gland Carcinoma With High-Risk Histology. Clin Nucl Med. 44(5):351-358. (共同責任作者)
22. Hsieh CE, Cheng NM, Chou WC, Venkatesulu BP, Chou YC, Liao CT, Yen TC, Lin CY*. (2018, 12) Pretreatment Primary Tumor and Nodal SUVmax Values on 18F-FDG PET/CT Images Predict Prognosis in Patients With Salivary Gland Carcinoma. Clin Nucl Med. Clin Nucl Med. 43(12):869-879.
23. Kao W-H, Hong J-H, See L-C, et al. Validity of cancer diagnosis in the National Health Insurance database compared with the linked National Cancer Registry in Taiwan. Pharmacoepidemiology and Drug Safety. 2018;27(10):1060-1066. doi:10.1002/pds.4267
24. Kao W-H, Kuo C-F, Chou I-J, et al. Prostate-selective alpha antagonists increase fracture risk in prostate cancer patients with and without a history of androgen deprivation therapy: a nationwide population-based study. Oncotarget. 2018;9(4):5263-5273. doi:10.18632/oncotarget.23828
25. Kao W-H, Kuo C-F, Chiou M-J, et al. Adverse birth outcomes in adolescent and young adult female cancer survivors: a nationwide population-based study. British Journal of Cancer. 2020;122(6):918-924. doi:10.1038/s41416-019-0712-2.
26. Ching-Hsin Lee , Sheng-Ping Hung, Ji-Hong Hong, Joseph Tung-Chieh Chang, Ngan-Ming Tsang, Kun-Ming Chan,  Jeng-Hwei Tseng, Shih-Chiang Huang, Shi-Ming Lin, Jau-Min Lien, Nai-Jen Liu, Chen-Chun Lin, Wei-Ting Chen, Wan-Yu Chen, Po-Jui Chen, Bing-Shen Huang. How Small is TOO Small New Liver Constraint Is Needed— Proton Therapy of Hepatocellular Carcinoma Patients with Small Normal Liver.  PloS one. 13: e0203854, 2018, 9
27. Hung SP, Huang BS, Hsieh CE, et al. Clinical Outcomes of Patients With Unresectable Cholangiocarcinoma Treated With Proton Beam Therapy. Am J Clin Oncol 2020;43:180-6.
28. Hsieh CE, Venkatesulu BP, Lee CH, et al. Predictors of Radiation-Induced Liver Disease in Eastern and Western Patients With Hepatocellular Carcinoma Undergoing Proton Beam Therapy
29. How small is TOO small? New liver constraint is needed- Proton therapy of hepatocellular carcinoma patients with small normal liver. Int J Radiat Oncol Biol Phys 2019;13:e0203854.
30. Hsieh CE, Lee LY, Chou YC, et al. Nodal failure patterns and utility of elective nodal irradiation in submandibular gland carcinoma treated with postoperative radiotherapy - a multicenter experience. Radiat Oncol 2018;13:184.
31. Yap WK, Chang YC, Hsieh CH, et al. Favorable versus unfavorable prognostic groups by post-chemoradiation FDG-PET imaging in node-positive esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. Eur J Nucl Med Mol Imaging 2018;45:689-98.
32. Lin, C.-H.; Hung, T.-M.; Chang, Y.-C.; Hsieh, C.-H.; Shih, M.-C.; Huang, S.-M.; Yang, C.-K.; Chang, C.-F.; Chan, S.-C.; Yap, W.-K. Prognostic Value of Lymph Node-To-Primary Tumor Standardized Uptake Value Ratio in Esophageal Squamous Cell Carcinoma Treated with Definitive Chemoradiotherapy. Cancers 2020, 12, 607.
33. Lin HC, Chan SC, Cheng NM, et al. Pretreatment (18)F-FDG PET/CT texture parameters provide complementary information to Epstein-Barr virus DNA titers in patients with metastatic nasopharyngeal carcinoma. Oral Oncol 2020;104:104628.
34. Chuang WC, Tsang NM, Chuang CC, Chang KP, Pai PC, Chen KH, et al. (2020) Association of subcutaneous and visceral adipose tissue with overall survival in Taiwanese patients with bone metastases – results from a retrospective analysis of consecutively collected data. PLoS ONE 15(1): e0228360. https://doi.org/10.1371/journal.pone.0228360
35. Ho, T., Chao, C., Chin, S. et al. Classifying Neck Lymph Nodes of Head and Neck Squamous Cell Carcinoma in MRI Images with Radiomic Features. J Digit Imaging (2020). https://doi.org/10.1007/s10278-019-00309-w
36. Lee, C., Chen, P., Lai, H. et al. A scoping review of medical education research for residents in radiation oncology. BMC Med Educ 20, 13 (2020). https://doi.org/10.1186/s12909-020-1927-x
37. Lin, Y., Lin, C., Lu, H. et al. Deep learning for fully automated tumor segmentation and extraction of magnetic resonance radiomics features in cervical cancer. Eur Radiol 30, 1297–1305 (2020). https://doi.org/10.1007/s00330-019-06467-3

Education Pamphlet on Proton Therapy

Q:  How the radiotherapy (including proton therapy) kill cancer?

It was well known by doctors that X-ray could penetrate our body since 1890s. Because of this property, X-ray is widely used to exam different part of human body like chest, teeth or bone. Besides, a high energy X-ray (thousand times to diagnostic X-ray) could treat cancer or benign tumor.

Radiotherapy kills cancer by using high energy X-ray or particles which has high penetrating power to give tumor irradiation. This kind of treatment could kill cancer or suppress benign tumor growing.

This high energy radiation is made from special machines, like X-ray from linear accelerator, proton beam from cyclotron/synchrotron or from radioactive isotopes which would release gamma ray.

The mechanism for radiotherapy to treat cancer is that tumor cell have worse ability to repair after radiation damage and normal tissue have better ability for recovering. This difference was used to by radiation oncologist to treat disease. To avoid severe acute toxicities and late complications, we use fractionated treatment clinically, which could achieve tumor control and make normal tissue damage as low as possible. According to cancer type, disease severity and different treatment modalities, radiotherapy take minutes to hour every day from Monday to Friday and would cost 1 week to 2 months long.

There are also risks to take radiotherapy. High energy radiation would kill cancer but also damage normal tissue near cancer cell and thus complications (ex. Swallowing difficulty after radiotherapy to oropharyngeal cancer) occur. So radiation oncologist need evaluate the patient comprehensively before radiotherapy.

Q:  What the timing for Proton Therapy?

Radiotherapy (including Proton Therapy) usually combine with operation to cure cancer. Before operation, radiotherapy could reduce the tumor size and make operation easier. On the other hand, it is used to treat residual cancer cells after operation in order to prevent disease recurrence. However, radiotherapy could also be used for primary treatment to avoid operation and preserve organ function. Photon radiotherapy is generally used for cancer treatment and proton therapy is a new treatment having ability to reduce side effects even increase probability of tumor control.

Q:  What the process of proton therapy?

In our Proton and Radiotherapy Center, there have 4 treatment room in operation. You can make an appointment by telephone or from our web site. Please prepare the complete medical records, which would help radiation oncologist to evaluate your disease correctly and design a proper treatment plan. The contents of medical record needed is listed in following question. After you decide to take proton therapy, there had two nurses responsible for questions about proton therapy during the treatment process. All your problem could be solved by our doctor or professional nurses.

All the patients would receive comprehensive evaluation of their disease. The radiation oncologist would make a treatment plan according to each patient’s disease condition and tumor shape. This plan need a customized cast and simulation with computer tomography(CT) and would be calculated by computer. The time need for a plan is about 2 to 3 weeks and patient would start treatment after the plan finished.

The customized cast is needed to make sure your position is just like the simulation day. Some patient would need magnetic resonance imaging(MRI) exam to clearly define tumor region. Radiation oncologist would define treatment field (including tumor location and organ having to be spare) according to different kinds of image and the medical physicists would make a treatment plan base these terms. The final would be confirmed by the doctors before treatment.

The treatment would take 1 to 8 weeks, five days a week from Monday to Friday based on disease complexity. You would spend 30-60 minutes a day. If children patient needing sedation, there have to cost more time to do the treatment. The proton therapy is painless and feeless, and would not cause radiation residue after treatment.

Q:  Is proton therapy suitable for my disease? What kinds of cancer could managed with proton therapy?

In order to build a reasonable understanding about proton therapy, we should know that there also have limitations of proton therapy. Proton therapy is not suitable for all patients. It is kind of radiotherapy, and is suitable for different kinds tumor from whole body. Disease which could be treated by current photon radiotherapy can also executed by proton therapy. However, it can’t replace the role of chemotherapy, target therapy or most operations. For patient who is with disseminated disease or have multiple metastasis, the effects on overall survival is little even proton therapy could reach good local disease control, and thus these kind of patients would not be suggested to receive proton therapy.

Q:  What is the indications of Proton Stereotactic Radiosurgery?

Proton stereotactic radiosurgery is suit for patients with following conditions:
1. Intracranial tumors or vascular lesion, which is from 3~10 centimeter and the number of tumor/lesion is less than three.
2. Residual tumor after operation or recurrent tumor after treatment
3. Patient who is inoperable.

Q:  What information should I prepare before the clinic for proton therapy consultation?

Patient came for proton therapy consultation should prepare following information including:
1. Pathology reports
2. Previous radiation therapy and medical treatment record
3. Medical records and images like sonography, X-rays, computer tomography(CT), Magnetic Resonance Imaging(MRI) and positron emission tomography (PET).

Q:  How could I contact Chang-Gung Hospital to take evaluation of proton therapy?

If you want to know whether proton therapy is suitable to treat your disease, you may contact us for a professional evaluation. The contact information is following:
International Medical Center: +886-3-3184301
Tel: +886-3-3281200 ext. 5477
Email: wecare@chang-gung.com, isc@cgmh.org.tw