Clinical efficacy and safety of proton beam or photon radiation in combination with immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma.

e16113 Background: Management of advanced hepatocellular carcinoma (HCC) remains a challenge. IMbrave150, a pivotal trial reported impressive overall survival benefit using combination strategy of atezolizumab and bevacizumab compared to sorafenib. We wonder the efficacy and safety when combining radiotherapy with immune checkpoint inhibitors (ICIs), which radiation might provide better local treatment and possible trigger abscopal effect. The aim of this study is retrospectively reporting the real-world efficacy and tolerability of proton beam or photon radiation plus ICIs in patients with advance stage HCC. Methods: We retrospectively reviewed all BCLC stage C HCC patients who have received combination therapy with ICIs plus proton or photon therapy with well documented basic characteristics and prompt treatment efficacy evaluation between 1st of January 2016 to 31st of October 2019 at a single medical center in Taiwan. 20 patients had ICIs plus proton and 32 patients had ICIs plus photon were included for analysis. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier estimator. Results: Baseline characteristics were generally similar between ICIs plus proton or ICIs plus photon, while most patients in proton group did not receive prior systemic treatment and had less local therapies prior ICIs combine with radiotherapy. Median follow-up time was 10.7 months. The median Progression free survival (PFS) was not reached in ICIs plus proton group and 3.6 months (95% CI 2.7-4.6) in ICIs plus photon group (P = 0.007). The median OS was not reach in ICIs plus proton group and 12.1months (95% CI 6.4-17.7) in ICIs plus photon group (P = 0.007). Comparing ICIs plus proton group versus photon group, objective tumor response is 50% versus 9%, disease control rate is 80% versus 47% in each group. During follow-up, 7 patients (35%) in proton group achieved complete remission (CR). There was difference in radiation filed, 19 patients (95%) in proton group and 15 patients (47%) in photon group targeted on liver tumors, and more patient received > 50Gy treatment dose in proton group compared to photon group (90% versus 20%). Proton group has lower failure rate in both inner- or out-field compared to photon group. Grade 1 to grade 2 skin-dermatological and gastrointestinal toxicity remained the most frequent reported adverse events in both groups. There are only one therapy related grade 3 dermatitis in ICIs plus proton group and one grade 3 hepatitis, one grade 5 pneumonitis in ICIs plus photon group. Conclusions: This study reported real-world efficacy and safety of ICIs in combination with proton or photon therapy. Most adverse events were manageable. The combination of ICIs and proton therapy has impressive CR rate and OS benefit. Further prospective randomized trial is warranted for confirm our finding.

Proton versus photon radiotherapy for primary hepatocellular carcinoma: A propensity-matched analysis

Background Proton radiotherapy has a dosimetric advantage over photon radiotherapy. Many retrospective studies have shown promising results with proton radiotherapy in treating hepatocellular carcinoma (HCC). However, clinical evidence demonstrating the benefit of protons over photons is still limited. We therefore compared the clinical outcomes of the two modalities using medical research databases from our medical foundation.Methods We conducted a propensity score-matched cohort study based on our multi-institution medical organization research database. From January 2007 to January 2018, a total of 413 patients (photon: 349; proton: 64) who were diagnosed with HCC and primarily treated with radiotherapy with curative intent were enrolled. Overall survival (OS) and radiation-induced liver disease (RILD) were assessed. Stratified analysis was also performed to evaluate the heterogeneous effects of the two arms.Results A total of 110 patients (photon: 55; proton: 55) were analyzed in the propensity-matched series. The matched groups were balanced for baseline tumor risk factors. Cox regression analysis revealed a significant survival benefit in the proton group (p=0.032, HR 0.56, 95% CI 0.33-0.96). The median overall survival in the proton group was not reached and that in the photon group was 17.4 months. The biological equivalent dose of radiotherapy was significantly higher in the proton group than in the photon group (median, 96.56 Gray [relative biological effectiveness] vs. 62.5 Gray, p<0.001). The risk of RILD was significantly lower in the proton group (11.8% vs. 36%, p=0.004).Conclusions Proton radiotherapy could deliver a higher radiation dose than photon radiotherapy without increasing the risk of RILD and result in a better overall survival rate for those diagnosed with HCC and treated with radiotherapy with curative intent.

Proton versus photon radiotherapy for primary hepatocellular carcinoma: A propensity-matched analysis

Background Proton radiotherapy has a dosimetric advantage over photon radiotherapy. Many retrospective studies have shown promising results with proton radiotherapy for treating hepatocellular carcinoma (HCC). However, clinical evidence demonstrating the benefit of protons over photons is still limited. We therefore compared clinical outcomes for the two modalities using medical research databases from our medical foundation.Methods We conducted a propensity score-matched cohort study based on our multi-institution medical organization research database. From January 2007 to January 2018, a total of 413 patients (photon: 349; proton: 64) who were diagnosed with HCC and primarily treated with radiotherapy with curative intent were enrolled. Overall survival (OS) and radiation-induced liver disease (RILD) were assessed. Stratified analysis was also performed to evaluate the heterogeneous effects of the two arms.Results A total of 110 patients (photon: 55; proton: 55) were analyzed in the propensity-matched series. The matched groups were balanced for baseline tumor risk factors. Cox regression analysis revealed a significant survival benefit in the proton group (p = 0.032, HR 0.56, 95 CI 0.33–0.96). The median overall survival in the proton and photon group was not reached and 17.4 months, respectively. The biological equivalent dose for radiotherapy was significantly higher in the proton group than the photon group (median, 96.56 Gray vs. 62.5 Gray, p < 0.001). The risk of RILD was significantly lower in the proton group (11.8% vs. 36%, p = 0.004).Conclusions Proton radiotherapy could deliver a higher radiation dose without increasing the risk of RILD and result in a better overall survival rate for those diagnosed with HCC and treated with radiotherapy with curative intent.

RTHP-14. PSEUDOPROGRESSION IN HIGH GRADE GLIOMA PATIENTS AFTER PROTON OR PHOTON THERAPY

Pseudoprogression is defined as the appearance of false progression on MR imaging following radiation therapy. Proton therapy is thought to have increased relative biological effectiveness-the ratio of the doses required by two types of radiation to cause the same level of effect-near the edges of the high dose volume. This could lead to different rates of pseudoprogression for protons compared to photons. In our IRB approved study, a board-certified neuroradiologist reviewed serial imaging of 74 patients (photons: n=37, protons: n=37) treated from 2013–2018 with either proton or photon radiotherapy to 59.4–60 Gy in 30–33 fractions and temozolomide for high grade glioma. MR imaging was performed 1 month after completion of treatment and then every 3 months. True progression was scored based on updated RANO criteria. Pseudoprogression was determined if imaging improved without change in therapy. Cumulative incidences of these outcomes and survival were calculated utilizing Kaplan-Meier analyses. Patient and treatment factors were analyzed for their association with incidence of pseudoprogression. Median follow-up for alive patients in the proton and photon groups were 15 and 29 months, respectively. Median age was 49 years in the proton group and 54 years in the photon group (p=0.17). Among proton patients, 14 had grade III glioma and 23 had grade IV glioblastoma. Among photon patients, 1 had grade III glioma. Median survival was 23 and 35 months for the proton and photon groups, respectively (p=0.57). The cumulative incidence of pseudoprogression was 14.4% and 10.4% at 12 months for the proton and photon groups, respectively (p=0.53). Grade, extent of resection, age, and IDH status, were not significantly associated with development of pseudoprogression. MGMT methylated tumors showed a trend toward association with pseudoprogression compared to unmethylated tumors (p=0.058). We concluded that the incidence of pseudoprogression is similar regardless of whether proton or photon therapy was utilized.

A study of levels in 147Nd using the (d,t) reaction

The 148Nd(d,t)147Nd reaction has been studied using 12 MeV deuterons. The reaction products were analyzed with an Enge-type magnetic spectrograph and detected with photographic emulsions, giving peak widths (FWHM) of approximately 8 keV. The present results confirm previous indications that the highest energy proton group found in an early 146Nd(d,p) investigation does not correspond to the ground state transition, but to the level at an excitation energy of 50 keV. The (d,t) angular distributions were used to determine l-values for a number of transitions. A striking similarity is noted with the energy levels and spectroscopic strengths previously found in the isotones 149Sm and 151Gd. With the exception of the h11/2 state, it is possible to explain the observed strengths in terms of the spherical shell model, although there is fragmentation of the spherical states.

The transmutation of magnesium, aluminium and silicon by deuterons

A study has been made of the protons emitted by magnesium, aluminium and silicon targets when bombarded by deuterons of energy between 700 and 1000 keV. The Q values of these (d, p) reactions have been accurately determined. Observations of the induced radioactivity in the targets and comparisons with the Q values in analogous nuclei permit tentative assignments to the isotopes responsible. The Q values and assignments are: 24Mg (d, p) 2SMg 26Mg (d, p) 26Mg* 2®Mg (d, p) 27Mg 27A1 (d, p ) 28A1 28Si (d, p)2»Si “ Si (d, p)«Si Q = 5 03 MeV Q = 4-45 MeV (to excited state) Q = 4 05 MeV Q = 5-46 MeV = 4-46 MeVl = 3-98 MeV 1 (to excited states) = 3-31 MeV j Q = 6-16 MeV .= 4-87 MeV) .. .. , . , . = 3-75 MeV j The yield of the proton group attributed to 26 Mg (d, p ) 26 Mg* shows a resonance at 955 kV bombarding voltage, as does also the yield of radioactive 26 A1 formed in the reaction 26 Mg (d, n) 26 A1. This indicates a resonance level in the compound nucleus 27A1 at an excitation energy of 17 MeV. The maximum energy of the β+ rays from 26 A1 was measured as 2-8 MeV. The Q values listed above lead to a set of nuclear mass values, but these mass values are not always in satisfactory agreement with the published Q values for certain other reactions.

Experiments on the transmutation of fluorine by deuterons

The radioactive effects induced in fluorine by deuteron bombardment are supposed to be due to the formation of 20 F in accordance with the process 19 F + 2 H → 20 F + 1 H, (1) the radioactive body 20 F transforming into 20 Ne as a result of β -ray emission. Crane, Delsasso, Fowler and Lauritsen (1935, 1936) found the value 12 sec. for the half-period of the radioactive decay and the value 5.2 x 10 6 eV for the upper energy limit of the β -ray spectrum. Protons emitted during the bombardment of fluorine by deuterons have been detected by Burcham and Smith (1938) using an ionization chamber and linear amplifier. In these experiments an inhomogeneous group of protons of mean range 11.6 cm. was observed, and this proton emission was attributed to the formation of 20 F according to the process (1). The intensity of this proton group was found to be insufficient to account for the amount of radioactive 20 F which was observed. No proton group having a range greater than 11.6 cm. was detected but the emission of shorter range groups could not be excluded and it was thought that such shorter range groups might be sufficiently intense to account for the amount of radioactive fluorine produced in the transmutation. On the assumption that the total energy release in reaction (1) could be obtained from the energy of the 11.6 cm. group, a mass of 20.0087 was deduced for 20 F in its ground state. This led to the conclusion that the 20 Ne nucleus formed in accordance with the process 20 F → 20 Ne + β (2) must be left with an excitation energy of 4.1 x 10 6 eV which it might subsequently lose as a γ -ray, so that every β particle from 20 F should be followed by a γ -ray from 20 Ne. Some support for this view was obtained by the detection of a γ -ray activity decaying with a period of about 12 sec. from fluoride targets after deuteron bombardment. Measurements of the energy of these γ -rays are described and discussed in this paper.

Bombardment of the heavy isotope of hydrogen by α-particles

The constitution of the heavy isotope of hydrogen, of mass 2, raises a number of interesting questions on which there is at present considerable difference of opinion. We know that the nuclear charge of this element is 1, and its atomic mass has been accurately determined by Bainbridge as 2·0136, using his modified form of mass spectrograph. As regards the actual structure of the nucleus, a number of possibilities must be considered. In the first place the nucleus may be a primary unit or composite. And secondly, if the diplon is composite it may consist either of two protons and a negative electron, or, as seems more probable of a proton and a neutron closely combined. From a consideration of the general evidence of the transformations which give rise to neutrons, Chadwick concludes that the mass of the neutron in the free state is 1·0067. The sum of the masses of the neutron and hydrogen atom (1·0078) is 2·0145, while the observed mass of diplogen is 2·0136, indicating that the binding energy of the combination is somewhat less than 1 million electron volts. From other considerations Curie and Joliot have suggested that the neutron may have a mass a high as 1·012. On the other hand, Lawrence concludes that the mass of the neutron may be as low as 1·0006. This value is deduced from observations on the transformation of a number of elements by bombardment with fast diplons. With many elements he observed the ejection of a proton group of about 18cm. range, and considers that these are produced by the breaking up of the diplon, in the strong nuclear field of the transformed atom, into a neutron and a proton. In order to reconcile his observations with the principle of the conservation of energy, it is necessary to assume that the mass of the neutron is much smaller that the value deduced by Chadwick, and in fact very nearly equal to unity. On Lawrence's view, the diplon is a nucleus of an unusual type, for it possesses about 5 million volts of excess energy, which can be released under appropriate conditions.