Development of a digital star-shot analysis system for comparing radiation and imaging isocenters of proton treatment machine.

PURPOSE: To directly compare the radiation and imaging isocenters of a proton treatment machine, we developed and evaluated a real-time radiation isocenter verification system. METHODS: The system consists of a plastic scintillator (PI-200, Mitsubishi Chemical Corporation, Tokyo, Japan), an acrylic phantom, a steel ball on the detachable plate, Raspberry Pi 4 (Raspberry Pi Foundation, London, UK) with camera module, and analysis software implemented through a Python-based graphical user interface (GUI). After kV imaging alignment of the steel ball, the imaging isocenter defined as the position of the steel ball was extracted from the optical image. The proton star-shot was obtained by optical camera because the scintillator converted proton beam into visible light. Then the software computed both the minimum circle radius and the radiation isocenter position from the star-shot. And the deviation between the imaging isocenter and radiation isocenter was calculated. We compared our results with measurements obtained by Gafchromic EBT3 film (Ashland, NJ, USA). RESULTS: The minimum circle radii were averaged 0.29 and 0.41 mm while the position deviations from the radiation isocenter to the laser marker were averaged 0.99 and 1.07 mm, for our system and EBT3 film, respectively. Furthermore, the average position difference between the radiation isocenter and imaging isocenter was 0.27 mm for our system. Our system reduced analysis time by 10 min. CONCLUSIONS: Our system provided automated star-shot analysis with sufficient accuracy, and it is cost-effective alternative to conventional film-based method for radiation isocenter verification.

Monte Carlo simulation-based patient-specific QA using machine log files for line-scanning proton radiation therapy.

BACKGROUND: Quality assurance (QA) is a prerequisite for safe and accurate pencil-beam proton therapy. Conventional measurement-based patient-specific QA (pQA) can only verify limited aspects of patient treatment and is labor-intensive. Thus, a better method is needed to ensure the integrity of the treatment plan. PURPOSE: Line scanning, which involves continuous and rapid delivery of pencil beams, is a state-of-the-art proton therapy technique. Machine performance in delivering scanning protons is dependent on the complexity of the beam modulations. Moreover, it contributes to patient treatment accuracy. A Monte Carlo (MC) simulation-based QA method that reflects the uncertainty related to the machine during scanning beam delivery was developed and verified for clinical applications to pQA. METHODS: Herein, a tool for particle simulation (TOPAS) for nozzle modeling was used, and the code was commissioned against the measurements. To acquire the beam delivery uncertainty for each plan, patient plans were delivered. Furthermore, log files recorded every 60 µs by the monitors downstream of the nozzle were exported from the treatment control system. The spot positions and monitor unit (MU) counts in the log files were converted to dipole magnet strengths and number of particles, respectively, and entered into the TOPAS. For the 68 clinical cases, MC simulations were performed in a solid water phantom, and two-dimensional (2D) absolute dose distributions at 20-mm depth were measured using an ionization chamber array (Octavius 1500, PTW, Freiburg, Germany). Consequently, the MC-simulated 2D dose distributions were compared with the measured data, and the dose distributions in the pre-treatment QA plan created with RayStation (RaySearch Laboratories, Stockholm, Sweden). Absolute dose comparisons were made using gamma analysis with 3%/3 mm and 2%/2 mm criteria for 47 clinical cases without considering daily machine output variation in the MC simulation and 21 cases with daily output variation, respectively. All cases were analyzed with 90% or 95% of passing rate thresholds. RESULTS: For 47 clinical cases not considering daily output variations, the absolute gamma passing rates compared with the pre-treatment QA plan were 99.71% and 96.97%, and the standard deviations (SD) were 0.70% and 3.78% with the 3%/3 mm or 2%/2 mm criteria, respectively. Compared with the measurements, the passing rate of 2%/2 mm gamma criterion was 96.76% with 3.99% of SD. For the 21 clinical cases compared with pre-treatment QA plan data and measurements considering daily output variations, the 2%/2 mm absolute gamma analysis result was 98.52% with 1.43% of SD and 97.67% with 2.72% of SD, respectively. With a 95% passing rate threshold of 2%/2 mm criterion, the false-positive and false-negative were 21.8% and 8.3% for without and with considering output variation, respectively. With a 90% threshold, the false-positive and false-negative reduced to 11.4% and 0% for without and with considering output variation, respectively. CONCLUSIONS: A log-file-based MC simulation method for patient QA of line-scanning proton therapy was successfully developed. The proposed method exhibited clinically acceptable accuracy, thereby exhibiting a potential to replace the measurement-based dosimetry QA method with a 90% gamma passing rate threshold when applying the 2%/2 mm criterion.

Toxicity of Proton Therapy versus Photon Therapy on Salvage Re-Irradiation for Non-Small Cell Lung Cancer.

This study evaluated the toxicity associated with radiation techniques on curative re-irradiation (re-RT) in patients with thoracic recurrence of non-small cell lung cancer (NSCLC). From 2011 to 2019, we retrospectively reviewed the data of 63 patients with salvage re-RT for in-field or marginal recurrence of NSCLC at two independent institutions. Re-RT techniques using X-ray beams and proton beam therapy (PBT) were also included. Re-RT had a 2-year overall survival (OS) and local progression-free survival of 48.0% and 52.0%, respectively. Fifteen patients experienced grade 3 or higher toxicity after re-RT. The complication rates were 18.2% (4/22) and 26.8% (11/41) in PBT patients and X-ray patients, respectively. Airway or esophageal fistulas occurred in seven patients (11.1%). Fistulas or severe airway obstruction occurred in patients with tumors adjacent to the proximal bronchial tree and esophagus, who underwent hypofractionated radiotherapy (RT) or concurrent chemotherapy, and with a higher dose exposure to the esophagus. In conclusion, salvage re-RT was feasible even in patients with local recurrence within the previous RT field. PBT showed similar survival outcomes and toxicity to those of other techniques. However, thoracic re-RT should be performed carefully considering tumor location and RT regimens such as the fraction size and concurrent chemotherapy.

High-Throughput 3D Tumor Spheroid Array Platform for Evaluating Sensitivity of Proton-Drug Combinations.

Proton beam therapy (PBT) is a critical treatment modality for head and neck squamous cell carcinoma (HNSCC). However, not much is known about drug combinations that may improve the efficacy of PBT. This study aimed to test the feasibility of a three-dimensional (3D) tumor-spheroid-based high-throughput screening platform that could assess cellular sensitivity against PBT. Spheroids of two HNSCC cell lines-Fadu and Cal27-cultured with a mixture of Matrigel were arrayed on a 384-pillar/well plate, followed by exposure to graded doses of protons or targeted drugs including olaparib at various concentrations. Calcein staining of HNSCC spheroids revealed a dose-dependent decrease in cell viability for proton irradiation or multiple targeted drugs, and provided quantitative data that discriminated the sensitivity between the two HNSCC cell lines. The combined effect of protons and olaparib was assessed by calculating the combination index from the survival rates of 4 × 4 matrices, showing that Cal27 spheroids had greater synergy with olaparib than Fadu spheroids. In contrast, adavosertib did not synergize with protons in both spheroids. Taken together, we demonstrated that the 3D pillar/well array platform was a useful tool that provided rapid, quantitative data for evaluating sensitivity to PBT and drug combinations. Our results further supported that administration of the combination of PBT and olaparib may be an effective treatment strategy for HNSCC patients.

Monitor unit prediction model for wobbling proton therapy with ridge filters.

PURPOSE: We introduced an output factor (cGy/MU) prediction model for wobbling proton beams over the full range of proton energy, scatterer thickness, and the width of spread-out Bragg peak (SOBP). MATERIALS AND METHODS: From December 2015 to August 2020, 1990 wobbling proton fields were used to treat patients, where 1714 fields had a diameter smaller than 11 cm and 276 had a diameter between 11 and 16 cm, which were designated as small and middle wobbling radius cases, respectively. The output factor is defined as the ratio of proton absorbed dose at mid-depth of SOBP to monitor unit (MU). It depends dominantly on proton energy, scatterer thickness, and the width of SOBP. We established the prediction model using the polynomial fitting function and determined its coefficients for the small and middle wobbling radius cases. We evaluated the accuracy of our prediction model by calculating the difference between predicted and measured output factors. RESULTS: For the small wobbling radius cases, the mean value of the output factor difference was 0.22% with a standard deviation of 1.3%. For the middle wobbling radius cases, the mean value was 0.20% and with a standard deviation of 0.79%. The large deviation was especially observed for wobbling proton beams having small field size and small width of SOBP. CONCLUSIONS: We made a prediction model of output factor for wobbling proton beams, thereby determining MU of each beam. This included the dependency of the output factor on the proton energy between 70 and 230 MeV, scatterer thickness, and the width of SOBP. For 93.6% of the small and 95.5% of the middle wobbling radius cases, the deviation between predicted and measured output factor was below 3%. The cases with deviations of predicted and measured output factor above 3% had small field size and small width of SOBP. The accuracy of our prediction model would be improved by adopting the field size effect and measuring more cases of small field size and small SOBP width in the future.

Quality assurance of isocentres for passive proton beam nozzles using motion capture cameras.

PURPOSE: The objective of this work is to determine mechanical, radiation, and imaging isocentres in three-dimensional (3D) coordinates and verifying coincidence of isocentres of passively scattered proton beam using a visual tracking system (VTS) and an in-house developed phantom named the Eagle. METHODS: The Eagle phantom consists of two modules: The first, named Eagle-head, is used for determining 3D mechanical isocentre of gantry rotation. The second, named Eagle-body, is used for determining 3D radiation and imaging isocentres. The Eagle-body has four slots wherein radiochromic films were inserted for measuring the 3D radiation isocentre and a metal bead was embedded in the centre of one cube to determine the imaging isocentre; this was determined by analysing cone-beam computed tomography images of the cube. Infrared reflective markers that can be tracked by VTS were attached to the Eagle at predetermined locations. The tracked data were converted into 3D treatment room coordinates. The developed method was compared with other methods to assess accuracy. RESULTS: The isocentres were determined in mm with respect to the laser isocentre. The mechanical, radiation, and imaging isocentres were (-0.289, 0.189, 0.096), (-0.436, -0.217, 0.009), and (0.134, 0.142, 0.103), respectively. When compared with other methods, the difference in coordinates was (-0.033, -0.107, 0.014) and (0.003, 0.067, 0.039) for radiation and imaging isocentres, respectively. CONCLUSION: The developed system was found to be useful in providing fast and accurate measurements of the three isocentres in the 3D treatment room coordinate system.

Feasibility of two-dimensional dose distribution deconvolution using convolution neural networks.

PURPOSE: The purpose of this study was to investigate the feasibility of two-dimensional (2D) dose distribution deconvolution using convolutional neural networks (CNNs) instead of an analytical approach for an in-house scintillation detector that has a detector-interface artifact in the penumbra region. METHODS: Datasets of 2D dose distributions were acquired from a medical linear accelerator of Novalis Tx. The datasets comprise two different sizes of square radiation fields and 13 clinical intensity-modulated radiation treatment (IMRT) plans. These datasets were divided into two datasets (training and test) to train and validate the developed network, called PenumbraNet, which is a shallow linear CNN. The PenumbraNet was trained to transform the measured dose distribution [M(x, y)] to calculated distribution [D(x, y)] by the treatment planning system. After training of the PenumbraNet was completed, the performance was evaluated using test data, which were 10 × 10 cm2 open field and ten clinical IMRT cases. The corrected dose distribution [C(x, y)] was evaluated against D(x, y) with 2%/2 mm and 3%/3 mm criteria of the gamma index for each field. The M(x, y) and deconvolved dose distribution with the analytically obtained kernel using Wiener filtering [A(x, y)] were also evaluated for comparison. In addition, we compared the performance of the shallow depth of linear PenumbraNet with that of nonlinear PenumbraNet and a deep nonlinear PenumbraNet within the same training epoch. RESULTS: The mean gamma passing rates were 84.77% and 95.81% with 3%/3 mm gamma criteria for A(x, y) and C(x, y) of the PenumbraNet, respectively. The mean gamma pass rates of nonlinear PenumbraNet and the deep depth of nonlinear PenumbraNet were 96.62%, 93.42% with 3%/3 mm gamma criteria, respectively. CONCLUSIONS: We demonstrated the feasibility of the PenumbraNets for 2D dose distribution deconvolution. The nonlinear PenumbraNet which has the best performance improved the gamma passing rate by 11.85% from the M(x, y) at 3%/3 mm gamma criteria.

Early clinical outcomes of helical tomotherapy/intensity-modulated proton therapy combination in nasopharynx cancer.

This study aimed to evaluate the feasibility of combining helical tomotherapy (HT) and intensity-modulated proton therapy (IMPT) in treating patients with nasopharynx cancer (NPC). From January 2016 to March 2018, 98 patients received definitive radiation therapy (RT) with concurrent chemotherapy (CCRT). Using simultaneous integrated boost and adaptive re-plan, 3 different dose levels were prescribed: 68.4 Gy in 30 parts to gross tumor volume (GTV), 60 Gy in 30 parts to high-risk clinical target volume (CTV), and 36 Gy in 18 parts to low-risk CTV. In all patients, the initial 18 fractions were delivered by HT, and, after rival plan evaluation on the adaptive re-plan, the later 12 fractions were delivered either by HT in 63 patients (64.3%, HT only) or IMPT in 35 patients (35.7%, HT/IMPT combination), respectively. Propensity-score matching was conducted to control differences in patient characteristics. In all patients, grade ≥ 2 mucositis (69.8% vs 45.7%, P = .019) and grade ≥ 2 analgesic usage (54% vs 37.1%, P = .110) were found to be less frequent in HT/IMPT group. In matched patients, grade ≥ 2 mucositis were still less frequent numerically in HT/IMPT group (62.9% vs 45.7%, P = .150). In univariate analysis, stage IV disease and larger GTV volume were associated with increased grade ≥ 2 mucositis. There was no significant factor in multivariate analysis. With the median 14 month follow-up, locoregional and distant failures occurred in 9 (9.2%) and 12 (12.2%) patients without difference by RT modality. In conclusion, comparable early oncologic outcomes with more favorable acute toxicity profiles were achievable by HT/IMPT combination in treating NPC patients.

Investigations of line scanning proton therapy with dynamic multi-leaf collimator.

PURPOSE: Scanning proton therapy has dosimetric advantage over passive treatment, but has a large penumbra in low-energy region. This study investigates the penumbra reduction when multi-leaf collimators (MLCs) are used for line scanning proton beams and secondary neutron production from MLCs. METHODS: Scanning beam plans with and without MLC shaping were devised. Line scanning proton plan of 36 energy layers between 71.2 and 155.2 MeV was generated. The MLCs were shaped according to the cross-sectional target shape for each energy layer. The two-dimensional doses were measured through an ion-chamber array, depending on the presence of MLC field, and Monte Carlo (MC) simulations were performed. The plan, measurement, and MC data, with and without MLC, were compared at each depth. The secondary neutron dose was simulated with MC. Ambient neutron dose equivalents were computed for the line scanning with 10 × 10 × 5 cm3 volume and maximum proton energy of 150 MeV, with and without MLCs, at lateral distances of 25-200 cm from the isocenter. The neutron dose for a wobbling plan with 10 × 10 × 5 cm3 volume was also evaluated. RESULTS: The lateral penumbra width using MLC was reduced by 23.2% on average, up to a maximum of 32.2%, over the four depths evaluated. The ambient neutron dose equivalent was 18.52% of that of the wobbling beam but was 353.1% larger than the scanning open field. CONCLUSIONS: MLC field shaping with line scanning reduced the lateral penumbra and should be effective in sparing normal tissue. However, it is important to investigate the increase in neutron dose.

Two-dimensional in vivo rectal dosimetry during high-dose-rate brachytherapy for cervical cancer: a phantom study.

BACKGROUND: The aim of the present study was to verify the dosimetric accuracy of two-dimensional (2D) in vivo rectal dosimetry using an endorectal balloon (ERB) with unfoldable EBT3 films for high-dose-rate (HDR) brachytherapy for cervical cancer. The clinical applicability of the technique was discussed. MATERIAL AND METHODS: ERB inflation makes the EBT3 films unrolled, whereas its deflation makes them rolled. Patient-specific quality assurance (pQA) tests were performed in 20 patient plans using an Ir-192 remote afterloading system and a water-filled cervical phantom with the ERB. The dose distributions measured in ERBs were compared with those of the treatment plans. RESULTS: The absolute dose profiles measured by the ERBs were in good agreement with those of treatment plans. The global gamma passing rates were 96-100% and 91-100% over 20 pQAs under the criteria of 3%/3 mm and 3%/2 mm, respectively, with a 30% low-dose threshold. Dose-volume histograms of the rectal wall were obtained from the measured dose distributions and showed small volume differences less than 2% on average from the patients' plans over the entire dose interval. The positioning error of the applicator set was detectable with high sensitivity of 12% dose area variation per mm. Additionally, the clinical applicability of the ERB was evaluated in volunteers, and none of them felt any pain when the ERB was inserted or removed. CONCLUSIONS: The 2D in vivo rectal dosimetry using the ERB with EBT3 films was effective and might be clinically applicable for HDR brachytherapy for cervical and prostate cancers to monitor treatment accuracy and consistency as well as to predict rectal toxicity.

Proton range verification in inhomogeneous tissue: Treatment planning system vs. measurement vs. Monte Carlo simulation.

In particle radiotherapy, range uncertainty is an important issue that needs to be overcome. Because high-dose conformality can be achieved using a particle beam, a small uncertainty can affect tumor control or cause normal-tissue complications. From this perspective, the treatment planning system (TPS) must be accurate. However, there is a well-known inaccuracy regarding dose computation in heterogeneous media. This means that verifying the uncertainty level is one of the prerequisites for TPS commissioning. We evaluated the range accuracy of the dose computation algorithm implemented in a commercial TPS, and Monte Carlo (MC) simulation against measurement using a CT calibration phantom. A treatment plan was produced for eight different materials plugged into a phantom, and two-dimensional doses were measured using a chamber array. The measurement setup and beam delivery were simulated by MC code. For an infinite solid water phantom, the gamma passing rate between the measurement and TPS was 97.7%, and that between the measurement and MC was 96.5%. However, gamma passing rates between the measurement and TPS were 49.4% for the lung and 67.8% for bone, and between the measurement and MC were 85.6% for the lung and 100.0% for bone tissue. For adipose, breast, brain, liver, and bone mineral, the gamma passing rates computed by TPS were 91.7%, 90.6%, 81.7%, 85.6%, and 85.6%, respectively. The gamma passing rates for MC for adipose, breast, brain, liver, and bone mineral were 100.0%, 97.2%, 95.0%, 98.9%, and 97.8%, respectively. In conclusion, the described procedure successfully evaluated the allowable range uncertainty for TPS commissioning. The TPS dose calculation is inefficient in heterogeneous media with large differences in density, such as lung or bone tissue. Therefore, the limitations of TPS in heterogeneous media should be understood and applied in clinical practice.

Normal lung sparing Tomotherapy technique in stage III lung cancer.

PURPOSE: Radiation pneumonitis (RP) has been a challenging obstacle in treating stage III lung cancer patients. Beam angle optimization (BAO) technique for Tomotherapy was developed to reduce the normal lung dose for stage III non-small cell lung cancer (NSCLC). Comparative analyses on plan quality by 3 different Intensity-modulated radiation therapy (IMRT) methods with BAO were done. MATERIALS AND METHODS: Ten consecutive stage IIIB NSCLC patients receiving linac-based static IMRT (L-IMRT) with total 66 Gy in 33 fractions to the PTV were selected. Two additional Tomotherapy-based IMRT plans (helical beam (TH-IMRT) and static beam (TD-IMRT)) were generated on each patient. To reduce the normal lung dose, Beam angles were optimized by using complete and directional block functions in Tomotherapy based on knowledge based statistical analysis. Plan quality was compared with target coverage, normal organ sparing capability, and normal tissue complication probability (NTCP). Actual beam delivery times and risk of RP related with planning target volume (PTV) were also evaluated. RESULTS: The best PTV coverage measured by conformity index and homogeneity index was achievable by TH-IMRT (0.82 and 1.06), followed by TD-IMRT (0.81 and 1.07) and L-IMRT (0.75 and 1.08). Mean lung dose was the lowest in TH-IMRT plan followed by TD-IMRT and L-IMRT, all of which were ≤20 Gy. TH-IMRT plan could significantly lower the lung volumes receiving low to medium dose levels: V5~30 when compared to L-IMRT plan; and V5~20 when compared to TD-IMRT plan, respectively. TD-IMRT plan was significantly better than L-IMRT with respects to V20 and V30 and there was no significant difference with respect to V40 among three plans. The NTCP of the lung was the lowest in TH-IMRT plan, followed by TD-IMRT and L-IMRT (6.42% vs. 6.53% vs. 8.11%). Beam delivery time was the shortest in TD-IMRT plan followed by L-IMRT. As PTV length increased, NTCP and Mean lung dose proportionally increased significantly in all three plans. CONCLUSION: Advantageous profiles by TH-IMRT could be achieved by BAO by complete and directional block functions. Current observation could help radiation oncologists to make wise selection of IMRT method for stage IIIB NSCLC.

Monte Carlo simulation of secondary neutron dose for scanning proton therapy using FLUKA.

Proton therapy is a rapidly progressing field for cancer treatment. Globally, many proton therapy facilities are being commissioned or under construction. Secondary neutrons are an important issue during the commissioning process of a proton therapy facility. The purpose of this study is to model and validate scanning nozzles of proton therapy at Samsung Medical Center (SMC) by Monte Carlo simulation for beam commissioning. After the commissioning, a secondary neutron ambient dose from proton scanning nozzle (Gantry 1) was simulated and measured. This simulation was performed to evaluate beam properties such as percent depth dose curve, Bragg peak, and distal fall-off, so that they could be verified with measured data. Using the validated beam nozzle, the secondary neutron ambient dose was simulated and then compared with the measured ambient dose from Gantry 1. We calculated secondary neutron dose at several different points. We demonstrated the validity modeling a proton scanning nozzle system to evaluate various parameters using FLUKA. The measured secondary neutron ambient dose showed a similar tendency with the simulation result. This work will increase the knowledge necessary for the development of radiation safety technology in medical particle accelerators.

A new method and device of aligning patient setup lasers in radiation therapy.

The aim of this study is to develop a new method to align the patient setup lasers in a radiation therapy treatment room and examine its validity and efficiency. The new laser alignment method is realized by a device composed of both a metallic base plate and a few acrylic transparent plates. Except one, every plate has either a crosshair line (CHL) or a single vertical line that is used for alignment. Two holders for radiochromic film insertion are prepared in the device to find a radiation isocenter. The right laser positions can be found optically by matching the shadows of all the CHLs in the gantry head and the device. The reproducibility, accuracy, and efficiency of laser alignment and the dependency on the position error of the light source were evaluated by comparing the means and the standard deviations of the measured laser positions. After the optical alignment of the lasers, the radiation isocenter was found by the gantry and collimator star shots, and then the lasers were translated parallel to the isocenter. In the laser position reproducibility test, the mean and standard deviation on the wall of treatment room were 32.3 ± 0.93 mm for the new method whereas they were 33.4 ± 1.49 mm for the conventional method. The mean alignment accuracy was 1.4 mm for the new method, and 2.1 mm for the conventional method on the walls. In the test of the dependency on the light source position error, the mean laser position was shifted just by a similar amount of the shift of the light source in the new method, but it was greatly magnified in the conventional method. In this study, a new laser alignment method was devised and evaluated successfully. The new method provided more accurate, more reproducible, and faster alignment of the lasers than the conventional method.

The first private-hospital based proton therapy center in Korea; status of the Proton Therapy Center at Samsung Medical Center.

PURPOSE: The purpose of this report is to describe the proton therapy system at Samsung Medical Center (SMC-PTS) including the proton beam generator, irradiation system, patient positioning system, patient position verification system, respiratory gating system, and operating and safety control system, and review the current status of the SMC-PTS. MATERIALS AND METHODS: The SMC-PTS has a cyclotron (230 MeV) and two treatment rooms: one treatment room is equipped with a multi-purpose nozzle and the other treatment room is equipped with a dedicated pencil beam scanning nozzle. The proton beam generator including the cyclotron and the energy selection system can lower the energy of protons down to 70 MeV from the maximum 230 MeV. RESULTS: The multi-purpose nozzle can deliver both wobbling proton beam and active scanning proton beam, and a multi-leaf collimator has been installed in the downstream of the nozzle. The dedicated scanning nozzle can deliver active scanning proton beam with a helium gas filled pipe minimizing unnecessary interactions with the air in the beam path. The equipment was provided by Sumitomo Heavy Industries Ltd., RayStation from RaySearch Laboratories AB is the selected treatment planning system, and data management will be handled by the MOSAIQ system from Elekta AB. CONCLUSION: The SMC-PTS located in Seoul, Korea, is scheduled to begin treating cancer patients in 2015.