Risk Of Second Cancer Research Articles

Second primary malignancies associated with radiation therapy in cervical cancer patients diagnosed between 1975 and 2011: a population-based competing-risk study.

BackgroundCervical cancer is a major health threat for women. Radiotherapy plays an important role in the treatment of cervical cancer. However, its overall benefit has been questioned due to the risk of second primary malignancies.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to search for cervical cancer patients diagnosed between January 1975 and November 2011. Factors that could possibly affect the occurrence of second primary malignancies included the year of diagnosis, gender, ethnicity, histologic type, SEER cancer stage, histology, grade, and whether surgery, chemotherapy, or radiotherapy were used. Age-adjusted and propensity scoring matching (PSM)—adjusted competing-risk analysis was applied for analysis.ResultsOf the 23,112 patients identified through SEER, 14,800 (64.0%) received radiotherapy. Second malignancies were diagnosed in 2,545 (11.0%) cases. PSM-adjusted competing analysis revealed that patients receiving radiotherapy had a significantly higher risk of developing a second cancer in the colon, rectum and anus [hazard ratio (HR): 1.43; 95% confidence interval (CI): 1.09–1.87; P=0.01], lung and bronchus (HR: 1.41; 95% CI: 1.13–1.76; P=0.002), corpus uteri (HR: 3.71; 95% CI: 1.71–8.06; P<0.001), ovary (HR: 2.79; 95% CI: 1.38–5.64; P=0.004), and urinary bladder (HR: 2.18; 95% CI: 1.35–3.54; P=0.002). However, radiotherapy significantly lowered the risk of second cancers in the female breast (HR: 0.67; 95% CI: 0.52–0.86; P=0.002). Age-adjusted competing-risk analysis showed generally consistent results.ConclusionsRadiotherapy increased the risk of second cancers among cervical cancer patients. Those who underwent radiotherapy had a significantly higher risk of developing a second cancer in the colon, rectum and anus, lung and bronchus, corpus uteri, ovary, and urinary bladder.

Anti-androgens in the treatment of prostate cancer and risk of secondary cancers: Overview of non clinical models and regulatory perspectives

Anti-androgens in the treatment of prostate cancer and risk of secondary cancers: Overview of non clinical models and regulatory perspectives

Neutron contamination in radiotherapy processes: a review study.

Using high-energy photon beams is one of the most practical methods in radiotherapy treatment of cases in deep site located tumors. In such treatments, neutron contamination induced through photoneutron interaction of high energy photons (>8MeV) with high Z materials of LINAC structures is the most crucial issue which should be considered. Generated neutrons will affect shielding calculations and cause extra doses to the patient and the probability of increase induced secondary cancer risks. In this study, different parameters of neutron production in radiotherapy processes will be reviewed.

PO-1784 On the Risk of Secondary Cancer from Thymoma Radiotherapy

PO-1784 On the Risk of Secondary Cancer from Thymoma Radiotherapy

Development and Implementation of Proton Therapy for Hodgkin Lymphoma: Challenges and Perspectives.

Simple SummaryHodgkin lymphoma (HL) is a highly curable disease; proton therapy for mediastinal HL irradiation might theoretically reduce late toxicities compared with classical radiotherapy techniques. However, optimal patient selection for this technique is subject to debate. While implementation at a larger scale of proton therapy for HL may face organizational, political, and societal challenges, new highly effective systematic drugs are being widely evaluated for this disease.Consolidative radiation therapy for early-stage Hodgkin lymphoma (HL) improves progression-free survival. Unfortunately, first-generation techniques, relying on large irradiation fields, were associated with an increased risk of secondary cancers, and of cardiac and lung toxicity. Fortunately, the use of smaller target volumes combined with technological advances in treatment techniques currently allows efficient organs-at-risk sparing without altering tumoral control. Recently, proton therapy has been evaluated for mediastinal HL treatment due to its potential to significantly reduce the dose to organs-at-risk, such as cardiac substructures. This is expected to limit late radiation-induced toxicity and possibly, second-neoplasm risk, compared with last-generation intensity-modulated radiation therapy. However, the democratization of this new technique faces multiple issues. Determination of which patient may benefit the most from proton therapy is subject to intense debate. The development of new effective systemic chemotherapy and organizational, societal, and political considerations might represent impediments to the larger-scale implementation of HL proton therapy. Based on the current literature, this critical review aims to discuss current challenges and controversies that may impede the larger-scale implementation of mediastinal HL proton therapy.

Secondary Cancer after Meningioma Diagnosis – an Israeli National Study

Background: There are limited data on whether primary diagnosis of meningioma may be associated with development of secondary primary cancer (SPC). Methods: All meningioma cases (ICD-O-3 morphology codes 9530/0-9539/3) diagnosed in Jewish Israelis ages 20 and over between 1990 to 2015 were located in the database of the Israel National Cancer Registry (INCR). All subsequent cancers occurring more than six months after meningioma diagnosis were identified. Risk of secondary cancer (SPC) was compared to cancer risk in the general population through the calculation of standardized incidence ratios (SIRs) and excess absolute risks (EARs). SIRs were stratified by type of second cancer, sex, and age group. Cox regression models were used to estimate hazard ratios of developing SPC. Findings: Overall, 8044 eligible meningioma cases were identified: mean age at diagnosis was 64.0 years (standard deviation=14.1). Of these, 927 (11.5%) were diagnosed with SPC (SIR 1.6, 95% Confidence Interval, CI 1.5–1.7). Secondary cancer risk was found to be elevated in both men (SIR 1.6, 95% CI 1.5–1.9) and women (SIR 1.6, 95%CI 1.5–1.8) diagnosed with meningioma. Cancers most commonly encountered as secondary cancers in persons previously diagnosed with meningioma were breast (17.6%), colorectal (13.4%), lung (8.1%), prostate (5%), and bladder (4.6%) cancer. Interpretation: Meningioma diagnosis is associated with an increased risk for developing secondary cancers. This risk should be discussed with patients treated for meningioma. Funding: There was no funding for this research project. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Sheba Medical Center ethics committee.

Investigating the out-of-field doses and estimating the risk of secondary thyroid cancer in high-grade gliomas radiation therapy with modulated intensity and 3D-conformal: a phantom study

Investigating the out-of-field doses and estimating the risk of secondary thyroid cancer in high-grade gliomas radiation therapy with modulated intensity and 3D-conformal: a phantom study

Investigating the out-of-field doses and estimating the risk of secondary thyroid cancer in high-grade gliomas radiation therapy with modulated intensity and 3D-conformal: a phantom study

Investigating the out-of-field doses and estimating the risk of secondary thyroid cancer in high-grade gliomas radiation therapy with modulated intensity and 3D-conformal: a phantom study

Risk of second cancer among young prostate cancer survivors.

PurposeAbout 40% of men diagnosed with prostate cancer (Pca) are ≤65 years of age. This study evaluates the risk of second cancer among young Pca patients treated with surgery or radiation.Materials and Methods This is a retrospective review of 150,915 men aged ≤65 years at Pca diagnosis treated with surgery or radiation registered in the Surveillance, Epidemiology, and End Results (SEER) database between 1973 and 2014. Incidence rates of second rectum/rectosigmoid junction (RJ), bladder, and lung cancer in each treatment group were reported with adjustment for potential confounders. Cumulative incidence functions were used to summarize the risk of second cancer after completing initial treatment. ResultsMen treated with external beam radiation (BEAM), brachytherapy (SEED), or combined radiation all exhibited a statistically significant increased incidence of second bladder cancer compared to men treated with surgery (adjusted incidence rate ratio [IRR]: 2.09, 1.91, and 2.04, respectively). Incidence of rectum/RJ cancer was also significantly increased in men receiving BEAM and combined radiation (adjusted IRR: 1.58 and 1.98, respectively). There were also significant differences in the cumulative incidence of second bladder cancer after receiving any form of radiation compared to surgery. ConclusionPca survivors ≤65 years of age at Pca diagnosis had an increased risk of second bladder and rectum/RJ cancer after BEAM and combined radiation treatment after adjusting for confounding factors. Second bladder cancer incidence after either form of radiation treatment was increased even at 5 years after a Pca diagnosis.

Secondary Solid Cancers after Allogeneic Hematopoietic Stem Cell Transplantation: A Single Center Experience of 1374 Patients Including 812 Cord Blood Transplant Recipients

Background: Secondary solid cancer is one of the most important late complications among long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Although age at HSCT, total body irradiation (TBI) as part of the conditioning regimens and chronic graft-versus-host diseases (GVHD) have been already reported as risk factors for secondary solid cancers, the impact of stem cell source has not been fully evaluated.Patients and Methods: We reviewed the medical records of Japanese adult patients who underwent allogeneic HSCT for the first time at the Toranomon Hospital between 1993 and 2015. Cumulative incidences of secondary solid cancers or GVHD were estimated, with death without developing secondary cancers or GVHD treated as a competing risk. The date of the first cancer in patients developing multiple metachronous secondary cancers was used in calculations of cumulative incidence. A step-wise multivariate approach was used to identify risk factors for secondary cancers. The variables considered were age at HSCT, sex, primary diseases, donor-type, conditioning regimens, TBI as part of the conditioning, grade II-IV acute GVHD and extensive chronic GVHD. Acute GVHD and chronic GVHD were considered as time-dependent covariates.Results: A total of 1374 patients were included in the analysis, with the median age of 54 years (16-82). Approximately two-thirds (64%) of the patients were male and were diagnosed with Acute leukemia/Myelodysplastic syndrome, respectively. Eight-hundred twelve (59.1%) patients underwent unrelated cord blood transplantation (UCBT), 313 (22.8%) underwent unrelated bone marrow transplantation (UBMT) and the remaining 249 (18.1%) underwent transplantation from a related donor. Half of the patients received reduced-intensity conditioning, and about 60% had any dose of total body irradiation. Cumulative incidence of grade II-IV acute GVHD at day 100 and extensive chronic GVHD at 2 years were 47.7% and 22.4%, respectively.Thirty-two patients developed secondary cancers at a median of 4.1 years (1.1months-14.8 years), four of who had two (2) or three (2) cancers in different organs. Overall, 38 cancers were identified. The most common sites of cancers were esophagus (9) and stomach (9), followed by oral (6), colon (3), skin (2), lung (2) and bladder (2). Cumulative incidence of secondary cancers at 5, 10, and 15 years after transplantation were 2.4%, 4.6%, and 10.8%, respectively. Compared with UBMT recipients, the risk of secondary cancers tended to be lower in transplant recipients from a related donor (HR 0.41, P=0.075) and was significantly lower in UCBT recipients (HR 0.45, P=0.035, Figure). Multivariate analysis revealed age ≥ 40 years (HR 9.3, P=0.027) and extensive chronic GVHD (HR 4.9, P<0.001) were identified as significant risk factors for secondary cancers.We also compared the incidence and risk factors for secondary cancers between UCBT (671) and UBMT (217) recipients who aged ≥ 40 years and underwent transplantation after 2002, because UCBT was introduced in 2002 at our hospital and only one case of secondary cancer was identified in transplant recipients from a related donor thereafter. The median age of UCBT recipients was higher than that of UBMT recipients (60 years vs. 56 years, P<0.001). Cumulative incidence of secondary cancers was 9.6%, which was significantly lower after UCBT compared to UBMT (5.2% vs. 18.4%, P=0.014). Extensive chronic GVHD was identified as a significant risk factor for secondary cancers (HR 3.38, P=0.04). Cumulative incidence of extensive chronic GVHD at 2 years was significantly lower after UCBT than after UBMT (12.3% vs. 39.1%, P<0.001), and extensive chronic GVHD had no significant impact on the risk of secondary cancers after UCBT (HR 2.8, P=0.134), in contrast with a strong association between extensive chronic GVHD and the development of secondary cancers after UBMT (HR 5.6, P=0.025).Conclusions: Endscopic screening is important as part of lifelong follow-up, especially for patients who are aged 40 and older or have extensive chronic GVHD. Despite the limitation of relatively shorter follow-up, the use of cord blood may have potential for reducing the risk of secondary solid cancers, probably because of lower frequency of extensive chronic GVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

No Excess Risk of Second Malignancies in Chronic Myeloid Leukemia (CML) Patients Treated with Tyrosine Kinase Inhibitors (TKIs)

Introduction With the introduction of tyrosine kinase inhibitors (TKI), the outcomes of patients with chronic myeloid leukemia (CML) has improved dramatically, with the majority of patients in chronic phase achieving near normal life expectancy. As pts live longer on TKIs, they may be more susceptible to subsequent malignancies either as late effects of TKI treatment, or due to genomic instability from having an established hematologic malignancy. Theoretical mechanisms of TKI carcinogenesis include impaired DNA repair mechanisms, inhibition of T-lymphocytes or impaired differentiation of peripheral blood progenitor cells. In this study, we evaluated the risk of subsequent cancers in CML pts at the population level and compared the effect of treatment period (pre- and post-TKI era) on that risk. Methods We used the April 2017 release of all 18 registries of the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute to assemble the study cohort. Only patients with CML, not otherwise specified or BCR/ ABL-positive CML were included in the analysis. Patients aged >20 years who had CML as a first cancer diagnosed between January 1973 and December 2013 who developed second cancers (excluding myeloid neoplasms and acute lymphocytic leukemia [to avoid misclassification with CML in blast crisis] and non-melanoma skin cancer) were studied. CML pts with third and subsequent cancers were excluded. Pt and disease characteristics including sex, race and ethnicity, age at diagnosis, year of diagnosis, and year of last follow-up or death were collected. Standardized incidence ratios (SIR) were calculated to assess the risk of a second malignancy by dividing the number of observed second malignancies in CML pts with the number of expected malignancies in the US population, using SEER*Stat. SIRs for the five most common second cancer types were analyzed by treatment eras (1973-1985 [era 1, in which busulfan and hydroxyurea predominated], 1986-2000 [era 2, in which interferon and hematopoietic cell transplantation predominated] and 2001-2014 [era 3, the TKI era] per Blood. 2011; 117(3):755-63 and by age groups (20-39 yrs; 40 -60 yrs and > 60 yrs). Results Of 26,810 patients diagnosed with CML between 1973 and 2014, 1,324 (4.94%) developed a subsequent cancer. The prevalence of second malignancies was 4.59% in era 1, 5.35% in era 2, and 4.84% in era 3 (with the increase from era 1 to 2 likely due to improved capture of cancers and possible transplant effects (BBMT 2007: 13(10):1121-1134)). The most common second cancers in the study period were prostate (17.98%), lung and bronchus (16.01%), breast (8.31%), urinary bladder (5.36%) and non-Hodgkin lymphoma (4.38%) with distribution by treatment era shown in Figure 1. The majority of subsequent malignancies occurred in Caucasians (85.95%), males (61.25%) and in pts > 60 years (68.43%). Table 1 shows SIR of second cancers by treatment eras. In era 1, an excess risk for bladder cancer was observed compared to matched population controls without CML (SIR 2.04, 95% CI 1.14-3.37). In era 2, SIRs for lung cancer and non-Hodgkin lymphoma were marginally elevated [1.34 (95% CI 1.03-1.72) and 1.81 (95% CI 1.01-2.98)], respectively. No excess risk of subsequent cancers was detected in the TKI era. Differences in excess risk of second cancers compared to matched population controls without CML were observed in the study period (1973-2014) when analyzed by age groups, as shown in table 2. Excess risk of oral (SIR 28.46, 95% CI 5.87-83.18) and cervical cancers (SIR 7.61, 95% CI 2.47-17.75) was observed in 20-39 yr age group, melanoma (SIR 1.83, 95% CI 1.02-3.02) in 40-59 yr age cohort, and lung and bronchus (SIR 1.31, 95% CI 1.07-1.58) and non-Hodgkin lymphoma (SIR 2.13, 95% CI 1.43-3.06) in patients >60 yrs. Conclusions In the TKI era of treatment for CML, there does not appear to be an excess risk of second cancers compared to what is seen in matched population controls without CML. Types of second cancers differ by age group. The paucity of second cancers may contribute to the survival of CML patients treated with TKIs approaching that of the general population. Download : Download high-res image (278KB) Download : Download full-size image Disclosures Advani: Pfizer: Consultancy; Takeda/ Millenium: Research Funding. Gerds: CTI BioPharma: Consultancy; Incyte: Consultancy. Maciejewski: Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy; Ra Pharma: Consultancy. Majhail: Sanofi: Honoraria; Anthem, Inc.: Consultancy. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees.

The Role of Radiation Therapy and Risk of Developing Secondary Gastric Cancer in Patients Presenting with Early Stage Gastric Lymphoma

▪Background: Gastric lymphoma is one of the most common extranodal lymphomas. Stage I/II disease is commonly treated with chemotherapy with or without radiation (RT). Although the development of secondary gastric cancers after treatment is a concern, the risk is not well described, and the role of histologic subtype and treatment remain unclear.Patients and Methods: TheSurveillance, Epidemiology and End Results (SEER) database was used to estimate cumulative incidence (CI) of secondary gastric cancer among adult (≥18 yrs) patients diagnosed with stage I/II gastric lymphoma between 1983 and 2014. We excluded patients who had history of gastric cancer prior to the diagnosis of lymphoma. Cumulative incidence (CI) of gastric cancer was calculated using competing risk regression analysis and death without having gastric cancer was defined as competing event.Results: A total of 10,192 patients were diagnosed with stage I/II gastic lymphoma of whom we excluded 321 patients with prior gastric neoplasm and 258 patients diagnosed with gastric cancer concurrently with lymphoma. The median age of the patients was 69 years (range, 18-104). Marginal zone lymphoma (MZL, N=3,981) was the most common histology followed by diffuse large B-cell lymphoma (DLBCL, N=3,944). After a median follow up of 76 months (range: 0-381 months), 417 patients developed secondary gastric cancer, and 173 (41%) died of gastric cancer. The 5-year and 10-year CI of gastric cancer was 4.1% (95%CI: 3.7-4.6%) and 4.8% (95%CI: 4.3-5.2%), respectively, 87% of secondary gastric cancer was diagnosed within 5 years after diagnosis of gastric lymphoma (Figure A).Patients with MZL had a higher risk of secondary gastric cancer compared to patients with DLBCL (SHR: 1.55, 95%CI: 1.26-1.92, Figure B). RT was associated with higher risk of second gastric cancer in earlier priod (1983-2000, SHR 2.06, 95%CI: 1.20-3.51) but not in recent period (2001-2014, SHR: 1.04, 95%CI: 0.81-1.34). RT for the treatment of gastric lymphoma was associated with significant longer overall survival for both patients with MZL (HR: 0.83, 95%CI: 0.74-0.92) and DLBCL (HR: 0.60, 95%CI: 0.53-0.69).Summary: Patients with gastric lymphoma have a low risk of developing secondary gastric cancers, though patients with MZL have a higher risk than those with DLBCL. RT is associated with significantly longer survival without increasing risk of secondary gastric cancer. [Display omitted] DisclosuresWestin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Neelapu:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida Therapeutics, Inc: Research Funding; Cellectis Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karus: Research Funding. Fanale:MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GENENTECH: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; ONYX: Research Funding; MOLECULAR TEMPLATES: Research Funding; ADC THERAPEUTICS: Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Karus Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Incidence of Infections and Second Cancers in Philadelphia Chromosome-Negative Patients with Myeloproliferative Neoplasms Treated with Ruxolitinib

Introduction:This is a retrospective, case-control study evaluating the incidence of infections and second cancers in Philadelphia-chromosome negative (Ph-) myeloproliferative neoplasm (MPN) patients treated with ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor approved for treating patients with polycythemia vera (PV), primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (PET-MF), and post-polycythemia vera myelofibrosis (PPV-MF) [1]. These patients are at significant risk for infections and second cancers when treated with long-term ruxolitinib. Similar observations have been reported in the COMFORT-II clinical trial findings, which studied ruxolitinib use in myelofibrosis (MF) patients [2], and have real-world clinical implications.Methods:128 MPN patients treated with ruxolitinib were studied and matched with 122 control patients based on gender, disease subtype, and age at the beginning of an MPN treatment (± 5 years). All evidence of infections and second cancers during this treatment regimen were recorded.Results:MPN patients whose mean age was 67.2±11.2 years when starting ruxolitinib treatment were studied, among whom myelofibrosis (38.3%) and PV (33.6%) were the leading subtypes. Of patients in the ruxolitnib cohort, 60/128 (46.9%) presented with ≥1 infection and a second cancer occurred in 13/128 (10.2%) patients. Of patients in the control cohort, 37/122 (30.3%) presented with ≥1 infection and a second cancer occurred in 6/122 (4.9%) patients. The difference of these proportions was significant for both infections (p=0.0072, RR=1.5456) and second cancers (p=0.0006, RR=2.0651) (Graph 1). Types of infections and cancers are summarized in Table 1a, Table 1b, and Table 2 . Of note, 2 patients treated with ruxolitinib had tuberculosis (TB) reactivations and 1 patient had pulmonary aspergillosis. All 13 of the patients that were diagnosed with a second cancer after being treated with ruxolitinib were found to have ≥1 skin cancer.Stratification of the incidence of these events by gender shows a trend for females treated with ruxolitinib with a higher relative risk (RR) of developing cancer than males of the same cohort (RR: 6.8971 for females, 0.4385 for males) (Table 3) . Serial upper respiratory infections (URIs) and urinary tract infections (UTIs) were of higher incidence in the ruxolitinib cohort than in the control cohort. In the ruxolitinib cohort, 7/21 (33.3%) and 5/12 (41.7%) experienced serial URIs and UTIs, respectively. In the control cohort, 1/9 (11.1%) and 0/8 (0.0%) experienced serial URIs and UTIs, respectively. 29/128 (22.7%) of the ruxolitinib cohort and 14/123 (11.4%) of the control cohort developed ≥2 different types of infections (p=0.0217, RR=1.9905).When compared to the control cohort, patients in the ruxolitinib cohort were found to have a higher incidence of recurring neutropenia (ruxolitinib: 35/128 (27.3%), control: 22/123 (17.9%), p=0.0782, RR=1.5288). The ruxolitnib cohort had a higher incidence of elevated ferritin than the control cohort (ruxolitinib: 26/128 (20.3%), control: 6/123 (4.9%), p=0.0010, RR=4.1641). Elevated ferritin could be a factor contributing to the increased risk of developing certain types of infections owing to iron overload [3].Conclusions:Long-term ruxolitinib treatment in Ph- MPN patients has resulted in an increased risk of infections and second cancers when compared to a matched control cohort. Those patients also had significantly higher ferritin levels which may contribute to the increased risk of certain infections. The risk of secondary cancer was much higher in the ruxolitinib group and especially in females. The significant proportion of ruxolitinib-treated patients who developed skin cancer (13/128, 10.2%) emphasizes the importance of skin cancer screening in these patients. [Display omitted] DisclosuresRitchie:Astellas Pharma: Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution; Bristol-Myers Squibb: Other: Research funding to my institution; Celgene: Consultancy, Other: Travel, Speakers Bureau; Pfizer: Consultancy, Other: Research funding to my institution; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau. Roboz:Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy. Lee:Amgen: Consultancy; Baxalta: Consultancy; Alexion Pharmaceuticals: Consultancy; Clinipace: Consultancy.

TP53 Germline Variations Influence the Predisposition and Prognosis of Acute Lymphoblastic Leukemia in Children

Germline TP53 mutations is the genetic basis of Li-Fraumeni syndrome (LFS), a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in children with hypodiploid acute lymphoblastic leukemia (ALL) suggest that childhood leukemia is another manifestation of LFS. However, the pattern, prevalence, and clinical relevance of pathogenic variants in TP53 in childhood ALL remain unknown.To comprehensively characterize genetic variants in TP53 in childhood ALL, we performed targeted sequencing of TP53 coding regions in 3858 children from the Children's Oncology Group front-line ALL clinical trials (COG AALL0232 and P9900). In total, 49 different non-silent coding rare TP53 variants were identifiedin 77 (2.0%) patients sequenced, including 40 missense, 1 nonsense, 6 frameshift, and 2 inframe deletion variants. To determine which TP53 variants are potentially pathogenic and related to ALL risk, we examined their experimentally-validated p53 transcriptional activity, bioinformatically-predicted damaging effects on TP53 function, and also the variant frequency in non-ALL populations. Twenty-two TP53 variants were classified as ALL risk-related (VAR), including 7 protein-truncating and 15 missense variants, all of which were either absent or exceedingly rare in non-ALL populations (i.e., allele frequency < 0.006% in the ExAC dataset). Fourteen missense VAR reside in the p53 core DNA-binding domain, with two affecting residues essential for DNA contact and seven located at residues that are important for the overall architecture of the DNA-binding surface. The 27 remaining TP53 variants were classified as “variants of unknown significance” (VUS). Together, of 3858 children in this ALL cohort, 26 (0.67%) patients had a predicted VAR and 51 (1.3%) had a VUS in the TP53 gene.We next evaluated the association of germline TP53 variants with patient demographics and ALL tumor genetic characteristics. Children with a TP53 VAR were significantly older at diagnosis (P < 0.0001), and had significantly lower leukocyte count at presentation than those with a VUS or wild-type (WT) genotype (P= 0.006). Of 26 patients carrying a germline TP53 VAR, 17 (65.4%) exhibited hypodiploidy in ALL blasts (mostly low hypoploidy or masked hypoploidy). In contrast, hypodiploid ALL was only present in 3.9% and 1.2% of children with TP53 VUS or WT genotype, respectively. The prevalence of TP53 VAR did not differ by genetic ancestry (P= 0.9). We also examined the relationship between germline TP53 variants and treatment outcomes of ALL therapy. In the COG AALL0232 cohort, the presence of a TP53 VAR was associated with a significantly lower event free survival (EFS) and overall survival (OS) compared to patients without a risk variant (hazard ratio [HR] of 2.84, P= 0.0007 for EFS; and HR of 3.13, P= 0.003 for OS). In multivariate analyses, TP53 VAR remained prognostic after adjusting for ancestry, age, leukocyte count at diagnosis, and minimal residual disease at the end of remission induction therapy (HR of 3.36, P= 0.0002 for EFS; HR of 2.88, P= 0.007 for OS). Importantly, there was a markedly higher risk of second cancers among patients with TP53 VARs compared to those with TP53 VUS or WT TP53: 5-year cumulative incidence of 25.1% vs. 0.7%, P= 5.4 × 10-11. In the COG P9900 cohort, only 4 patients harbored TP53 VAR, of whom 3 cases experienced adverse events (one patient each with ALL relapse, second cancer, or death in remission), and both EFS and OS were significantly worse than patients with TP53 VUS or WT genotype (HR of 7.14, P= 0.0008 for EFS; HR of 14.19, P= 1.1 x 10-5 for OS). Taken together, 14 of 26 patients with a TP53 VAR experienced adverse events, with 5 ALL relapses (36% of all events) and 5 second cancers (36%). This pattern of adverse events was dramatically different from those in patients with WT TP53 or VUS, for whom ALL relapse accounted for 75% of all events with only 4% as second cancers (P= 1.2 × 10-7). In fact, even within hypodiploid ALL patients who experienced adverse events, the frequency of second cancer was significantly higher in those with a TP53 VAR than those without (50% vs 5%, P= 0.01), further suggesting that germline TP53 variation was the underlying cause of second cancers in these cases.In conclusion, our findings identified germline TP53 variants as an important determinant of ALL predisposition and adverse treatment outcomes, particularly the risk of second malignant neoplasms. DisclosuresBorowitz:Beckman Coulter: Honoraria; Becton-Dickinson Biosciences: Research Funding; HTG Molecular: Honoraria. Mullighan:Loxo Oncology: Research Funding; Amgen: Consultancy. Hunger:Jazz Pharmaceuticals: Honoraria; Novartis: Consultancy; Erytech Pharmaceuticals: Consultancy; Amgen: Consultancy, Equity Ownership.

Incidence, Treatment Patterns, and Outcomes of Histiocytic Disorders in the United States: A Forty-Year Population Study

BackgroundLangerhans cell histiocytosis (LCH) is an orphan disease of clonal dendritic cells, which can affect any organ of the body. There is paucity of data on treatment patterns and outcomes of adult LCH pts, who are usually treated with pediatric-based therapies. No prospective clinical trial has been conducted to date to identify optimal therapeutic strategies in adult LCH. Uncertainty of the natural history of LCH in adults including its pathogenesis, treatment patterns, and outcomes have limited development of novel treatments. Here, we used the Surveillance Epidemiology and End Results (SEER) to describe the epidemiology of LCH, trends in treatment practices over time, and survival outcomes over a forty-year period.MethodsAll 18 registries of SEER covering a period from 1973 to 2014 was used to assemble LCH cohort. LCH cases included in the study had a diagnosis of malignant histiocytosis or LCH (unifocal, multifocal, disseminated, or not otherwise specified). Descriptive data on incidence, demographics, and treatment were collected. Relative survival (RS) was stratified by 5-year (yr) time increments, four age groups [< 20 years (yrs) - pediatric; 20-39 yrs; 40-59 yrs, and > 60 yrs - elderly], and treatment type was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. As LCH pts tend to live longer, we calculated RS probabilities, which compares survival in the pt cohort with the expected survival of the general population having the same characteristics with respect to age, sex, race, and calendar period. Survival probabilities were calculated using the SEER Survival System (SEER*Stat). RS estimates (proportion of cancer pts surviving for a specified period) were calculated by the life table method. Analysis was performed using SEER*Stat.ResultsA total of 1480 LCH pts were identified who met the inclusion criteria. Of these, 55% were male, 82% Caucasians, and 58% of cases were diagnosed in the pediatric age group (age <18). The incidence rate remained stable from 1973 to 2009 with an average of 17 new cases per year at an age-adjusted incidence rate of 0.3 per 1,000,000. However, introduction in 2010 of a new International Classification of Diseases code resulted in a significant increase in recorded cases from that year going forth. A variety of treatment modalities were used including 47.8% receiving chemotherapy, 26.2% receiving surgery, and 10.3% receiving radiation therapy. Survival analysis of available SEER data on 705 LCH pts showed a median RS of 16.2 years with 52% of pts alive at 25 yrs. Survival rates have steadily improved since 1973 when assessed in 5-yr increments and since 2003, survival rates have remained steady at 90% (Figure 1). When analyzed by age groups, survival rates successively worsened with advancing age groups with 80% of pediatric pts alive two decades from diagnosis compared to no survivors in the elderly group (Figure 2). In treated pts, receipt of chemotherapy or radiation therapy at diagnosis conferred no survival benefit over those not receiving such treatments (Figures 3 and 4). Likewise, pts receiving surgery at diagnosis did not have significant survival benefit over those not treated with surgery (Figure 5). Notably, 34.1% of the 1480 pts died due to a hematologic malignancy, while 13.1% died due to a solid tumor malignancy. In those who later developed second cancers, there was a significant risk of solid tumor (Odds ratio (OR) 1.69, 95% CI 1.08-2.51, P < 0.05) and hematologic malignancies (OR 4.89, 95% CI 1.96-10.07, P < 0.05).ConclusionTo our knowledge, this is the first population based study to examine treatment and survival trends in histiocytic disorders, which remain rare and poorly characterized. Notable observations from this study show no relative survival benefit with chemotherapy, radiation therapy, or surgery indicating these treatments were mainly to control local or systemic disease. As such, novel therapeutic approaches are needed to improve outcomes. Although this study shows consistent survival gains since 1973, this is likely due to improvements in supportive care practices. Unfortunately, outcomes in the elderly are dismal compared to pediatric pts. While pts with histiocytic disorders generally have a long duration of remission, we demonstrate that they are at risk for second cancers, particularly hematologic malignancies. [Display omitted] DisclosuresGerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Advani:Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Development of clinical application program for radiotherapy induced cancer risk calculation using Monte Carlo engine in volumetric-modulated arc therapy

BackgroundThe purpose of this study is to develop a clinical application program that automatically calculates the effect for secondary cancer risk (SCR) of individual patient. The program was designed based on accurate dose calculations using patient computed tomography (CT) data and Monte Carlo engine. Automated patient-specific evaluation program was configured to calculate SCR.MethodsThe application program is designed to re-calculate the beam sequence of treatment plan using the Monte Carlo engine and patient CT data, so it is possible to accurately calculate and evaluate scatter and leakage radiation, difficult to calculate in TPS. The Monte Carlo dose calculation system was performed through stoichiometric calibration using patient CT data. The automatic SCR evaluation program in application program created with a MATLAB was set to analyze the results to calculate SCR. The SCR for organ of patient was calculated based on Biological Effects of Ionizing Radiation (BEIR) VII models. The program is designed to sequentially calculate organ equivalent dose (OED), excess absolute risk (EAR), excess relative risk (ERR), and the lifetime attributable risk (LAR) in consideration of 3D dose distribution analysis. In order to confirm the usefulness of the developed clinical application program, the result values from clinical application program were compared with the manual calculation method used in the previous study.ResultsThe OED values calculated in program were calculated to be at most approximately 13.3% higher than results in TPS. The SCR result calculated by the developed clinical application program showed a maximum difference of 1.24% compared to the result of the conventional manual calculation method. And it was confirmed that EAR, ERR and LAR values can be easily calculated by changing the biological parameters.ConclusionsWe have developed a patient-specific SCR evaluation program that can be used conveniently in the clinic. The program consists of a Monte Carlo dose calculation system for accurate calculation of scatter and leakage radiation and a patient-specific automatic SCR evaluation program using 3D dose distribution. The clinical application program that improved the disadvantages of the existing process can be used as an index for evaluating a patient treatment plan.

Secondary Neutron Dose in Carbon-ion Radiotherapy: Investigations in QST–NIRS

Background: The National Institutes for Quantum and Radiological Science and Technology–National Institute of Radiological Sciences (QST–NIRS) has continuously investigated the undesired radiation exposure in ion beam radiotherapy mainly in carbon-ion radiotherapy (CIRT). This review introduces our investigations on the secondary neutron dose in CIRT with the broad and scanning beam methods.Materials and Methods: The neutron ambient dose equivalents in CIRT are evaluated based on rem meter (WENDI-II) measurements. The out-of-field organ doses assuming prostate cancer and pediatric brain tumor treatments are also evaluated through the Monte Carlo simulation. This evaluation of the out-of-field dose includes contributions from secondary neutrons and secondary charged particles.Results and Discussion: The measurements of the neutron ambient dose equivalents at a 90° angle to the beam axis in CIRT with the broad beam method show that the neutron dose per treatment dose in CIRT is lower than that in proton radiotherapy (PRT). For the scanning beam with the energy scanning technique, the neutron dose per treatment dose in CIRT is lower than that in PRT. Moreover, the out-of-field organ doses in CIRT decreased with distance to the target and are less than the lower bound in intensity-modulated radiotherapy (IMRT) shown in AAPM TG-158 (American Association of Physicists in Medicine Task Group).Conclusion: The evaluation of the out-of-field doses is important from the viewpoint of secondary cancer risk after radiotherapy. Secondary neutrons are the major source in CIRT, especially in the distant area from the target volume. However, the dose level in CIRT is similar or lower than that in PRT and IMRT, even if the contributions from all radiation species are included in the evaluation.

Understanding Competing Risks

You are debating with a urologist about the relative merits and harms of primary radiation therapy (RT) versus prostatectomy for high-risk prostate cancer. The urologist warns all of her patients about the risks of late effects from both RT and androgen deprivation therapy (ADT) and the secondary cancer risk after RT. In the absence of randomized trials, to inform this debate using an evidence-based approach, you have collected detailed, longitudinal data on the outcomes of several hundred patients with up to 10 years of follow-up.

CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation.

Simple SummarySome patients carry a mutated copy of the CDH1 gene that can lead to a very rare form of hereditary gastric cancer called signet-ring cell adenocarcinoma (SRCC). SRCCs rarely form visible tumors prior to spreading. Hence, patients are recommended to have prophylactic gastrectomies at a young age. Many patients wish to avoid surgery and thus have regular checks with upper endoscopy with biopsies to rule out cancer. Further, these patients may also be at risk of other cancers beyond the already known breast cancer risks, but this is not known. In this study, we show that despite systematic biopsy protocols, many early cancers might be missed on endoscopy. Therefore, patients should not rely on endoscopy to delay surgery. These patients may also be at increased risk of colorectal SRCC, which has very poor survival outcomes. To confirm this, we need a central database that captures outcomes for this patient population.Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data banking.

Oncologists’ (ONCs) perceptions of tumor genomic profiling (TGP) and barriers to communicating secondary hereditary risk to African American (AA) patients.

10592 Background: TGP identifies targets for precision cancer treatments. TGP may also identify secondary hereditary cancer risks, necessitating complex decision support during informed consent. ONCs are poorly trained in the communication of genetic information, particularly for patients with low health literacy, poor knowledge of genetics, and high medical mistrust. AA patients are especially vulnerable in this setting. Methods: We conducted semi-structured interviews with 10 ONCs to assess perceived barriers related to communication of secondary hereditary risks of TGP, probing barriers unique to AA patients. Informed by results, an Internet-based survey was developed/distributed to a convenience sample of 50 ONCs nationwide to assess TGP knowledge, genomics confidence, and perceptions related to communication of secondary hereditary risk. Results: Six themes emerged from interviews: risk/benefits of TGP, knowledge of genetics, discussing hereditary risk, value/harm of TGP, unique risks in AA, and training needs. Most ONCs felt uncomfortable discussing hereditary risks of TGP w/patients. Seven out of 10 identified socio-economic status, medical mistrust, discrimination, genetic counseling non-compliance, low health literacy and family relationships as factors important to consider with AA patients. Online survey participants were 52% White, 66% male, with median age of 42 years. Education in the interpretation/communication of TGP was largely informal (56% reported only informal training) and 46% reported perceived gaps in their education. Genomic confidence was associated w/higher use of TGP (p = 0.05), but was not associated w/knowledge or years in practice; however, low knowledge was associated w/more perceived barriers to TGP and w/negative attitudes toward the value of TGP and the challenge of communication of possible hereditary risks (p = 0.05). Early-career ONCs were more likely to endorse perceived barriers to communication of genetic risk information from TGP to AA patients. Overall 86% ONCs felt additional online training in communication of secondary hereditary risks of TGP would be useful. Conclusions: ONCs recognize unique needs and barriers for AAs related to communication of secondary hereditary genetic information from TGP. Many feel uncertain about how/whether to address barriers and recognize the need to improve their skillset to do so. Training is critical to ensure informed decision making in vulnerable populations.