Risk Of Second Cancer Research Articles

TP53 and the Ultimate Biological Optimization Steps of Curative Radiation Oncology.

The new biological interaction cross-section-based repairable-homologically repairable (RHR) damage formulation for radiation-induced cellular inactivation, repair, misrepair, and apoptosis was applied to optimize radiation therapy. This new formulation implies renewed thinking about biologically optimized radiation therapy, suggesting that most TP53 intact normal tissues are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA). This generates a fractionation window in LDHS normal tissues, indicating that the maximum dose to organs at risk should be ≤2.3 Gy/Fr, preferably of low LET. This calls for biologically optimized treatments using a few high tumor dose-intensity-modulated light ion beams, thereby avoiding secondary cancer risks and generating a real tumor cure without a caspase-3-induced accelerated tumor cell repopulation. Light ions with the lowest possible LET in normal tissues and high LET only in the tumor imply the use of the lightest ions, from lithium to boron. The high microscopic heterogeneity in the tumor will cause local microscopic cold spots; thus, in the last week of curative ion therapy, when there are few remaining viable tumor clonogens randomly spread in the target volume, the patient should preferably receive the last 10 GyE via low LET, ensuring perfect tumor coverage, a high cure probability, and a reduced risk for adverse normal tissue reactions. Interestingly, such an approach would also ensure a steeper rise in tumor cure probability and a higher complication-free cure, as the few remaining clonogens are often fairly well oxygenated, eliminating a shallower tumor response due to inherent ion beam heterogeneity. With the improved fractionation proposal, these approaches may improve the complication-free cure probability by about 10-25% or even more.

Expression of Stem Cell Markers in High-LET Space Radiation-Induced Intestinal Tumors in Apc1638N/+ Mouse Intestine.

Estimation of cancer risk among astronauts planning to undertake future deep-space missions requires understanding the quantitative and qualitative differences in radiogenic cancers after low- and high-LET radiation exposures. Previously, we reported a multifold higher RBE for high-LET radiation-induced gastrointestinal (GI) tumorigenesis in Apc1638N/+ mice. Using the same model system, i.e., Apc1638N/+ mice, here, we report qualitative differences in the cellular phenotype of low- and high-LET radiation-induced GI tumors. Stem cell (SC) phenotypes were identified using BMI1, ALDH1, CD133, DCLK1, MSI1, and LGR5 markers in low (γ-rays)- and high (56Fe)-LET radiation-induced and spontaneous tumors. We also assessed the expression of these markers in the adjacent normal mucosa. All six of these putative SC markers were shown to be overexpressed in tumors compared to the adjacent normal intestinal tissue. A differential SC phenotype for spontaneous and radiogenic intestinal tumors in Apc1638N/+ mice was observed, where the ALDH1, BMI1, CD133, MSI1, and DCLK1 expressing cells were increased, while LGR5 expressing cells were decreased in 56Fe-induced tumors compared to γ-ray-induced and spontaneous tumors. Furthermore, higher β-catenin activation (marked by nuclear localization) was observed in 56Fe-induced tumors compared to γ and spontaneous tumors. Since differential tumor cell phenotype along with activated β-catenin may very well affect malignant progression, our findings are relevant to understanding the higher carcinogenic risk of high-LET radiation. This study has implications for the assessment of GI-cancer risk among astronauts, as well as for the estimation of secondary cancer risk among patients receiving hadron therapy, considering that our results indicate increased stemness properties after radiation.

BIG data analysis of secondary cancer risk according to thyroid cancer in patients with lipid metabolic disease

BIG data analysis of secondary cancer risk according to thyroid cancer in patients with lipid metabolic disease

Recent advances progress in radiotherapy for breast cancer after breast-conserving surgery: a review.

Adjuvant radiotherapy after breast-conserving surgery has become an integral part of the treatment of breast cancer. In recent years, the development of radiotherapy technology has made great progress in this field, including the comparison of the curative effects of various radiotherapy techniques and the performance of the segmentation times. The choice of radiotherapy technology needs to be co-determined by clinical evidence practice and evaluated for each individual patient to achieve precision radiotherapy. This article discusses the treatment effects of different radiotherapy, techniques, the risk of second cancers and short-range radiation therapy techniques after breast-conserving surgery such as hypo fractionated whole breast irradiation and accelerated partial breast irradiation. The choice of radiotherapy regimen needs to be based on the individual condition of the patient, and the general principle is to focus on the target area and reduce the irradiation of the normal tissues and organs. Short-range radiotherapy and hypofractionated are superior to conventional radiotherapy and are expected to become the mainstream treatment after breast-conserving surgery.

Radiation Therapy Changed the Second Malignancy Pattern in Rectal Cancer Survivors.

Background and Objectives: Radiotherapy (RT) plays an important role in the treatment for locally advanced rectal cancer patients. It can bring radio exposure together with the survival benefit. Cancer survivors are generally at an increased risk for second malignancies, and survivors receiving RT may have higher risks than survivors not receiving RT. Whether the risk of an all-site second malignancy may increase after RT is still debated. This study aims to compare the second malignancy pattern in rectal cancer survivors after RT. Materials and Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used for analysis. In total, 49,961 rectal cancer patients (20-84 years of age) were identified between 2000 and 2012 from 18 SEER registries. All patients underwent surgery. The occurrence of second malignancies diagnosed after rectal cancer diagnosis was compared in patients who received and did not receive RT. The standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were used. SEER*Stat was used to generate the 95% CIs for the SIR statistics using the exact method. Results: Of the total 49,961 patients, 5582 developed second malignancies. For all-site second primary malignancies, the age-adjusted SIRs were 1.14 (95% CI 1.1-1.18) and 1.00 (95% CI 0.96-1.04) in the no RT and RT groups, respectively. In 23,192 patients from the surgery-only group, 2604 had second malignancies, and in 26,769 patients who received RT, 2978 developed second malignancies. With respect to every site, the risk of secondary prostate cancer was significantly lower in the RT group (SIR = 0.39, 95% CI 0.33-0.46) than that in the surgery-only group (SIR = 1.04, 95% CI 0.96-1.12). Moreover, the risk of thyroid cancer was significantly higher in the RT group (SIR = 2.80, 95% CI 2.2-3.51) than that in the surgery-only group (SIR = 1.29, 95% CI 0.99-1.66). Conclusions: RT may change the second malignancy pattern in rectal cancer survivors; the risk of prostate cancer decreased, and the risk of thyroid cancer increased most significantly.

Incidence risk assessment of secondary cancer due to radiotherapy of women with rectal cancer using BEIR VII, EPA, and ICRP models.

Radiotherapy has a significant side effect known as radiation-induced secondary cancer. This study aims to evaluate the dose and secondary cancer risk for women with rectal cancer treated with three-dimensional conformal radiation therapy (3D-CRT) to the organs at risk (OARs) and some sensitive organs using different types of radiation-induced cancer risk prediction models, including Biological Effects of Ionizing Radiation (BEIRVII), Environmental Protection Agency (EPA) and International Commission on Radiological Protection (ICRP), and compare the results of the different models for same organs. Thirty female patients with rectal cancer were considered and dose calculations were based on the PCRT-3D treatment planning system, while the radiotherapy of the patients had been performed using Shinva linear accelerator with a total dose of 45 Gy at 25 fractions. Planning target volume (PTV), OARs, and some sensitive organs were contoured, three models were used to evaluate secondary cancer risk (SCR) using the excess relative risk (ERR) and excess absolute risk (EAR). The bladder presents the highest risk, in terms of ERR, and the femur head and uterus in terms of EAR from the three models (BEIR VII, EPA, and ICRP). Based on the obtained results, radiotherapy of rectal cancer is relatively higher for the bladder and femur head, compared to the risk for other organs, the kidney risk is significantly lower. It was observed that the SCR from the ICRP model was higher compared to BEIR VII and EPA models.

Studies of dose distribution to Lung and Stomach and Estimation of Second Cancer Risk due to Outfeld Dose in Radiotherapy with 60Co Teletherapy Beam

A critical component of the radiation regimen for treating cancer patients is the precise dose delivery to the treatment organ while minimizing the dose to the healthy tissue. This study aims to evaluate in-field organ dose and dose distribution outside the target organs to estimate the excess lifetime risk of second cancer. The study was carried out with a male Alderson Rando Phantom. 20 sets of thermoluminescence dosimeters (MTS-100) were used in this study. The in-field organs absorbed dose was measured by inserting TLDs at different geometrical depths of the left lung, right lung, and stomach, and for peripheral organs skin dose TLDs were placed at the surface of the corresponding organs. Target organs were irradiated at 100 cGy and 200 cGy by a 60Co teletherapy unit, and irradiated TLDs were read out by a RE-2000 TLD reader. For precise dose delivery to the cancerous organs by 60Co teletherapy, the depth dose correction factor for lung cancer treatment is 0.8667 ± 0.01, and for the stomach is 0.7856 ± 0.017. In the case of the treatment for the lung and stomach, the closest organs received significant doses compared to the other distant organs. Thus, the risk of second cancer due to the peripheral dose is obtained. The stomach is at the highest risk when the lung is the target and the liver is at the highest risk when the stomach is the targeted organ.

The Role of Radiation Therapy in Adult and Pediatric Keloid Management: A National Survey of Radiation Oncologists.

Radiation therapy is a promising modality for treating keloids after surgical excision. However, it is currently not standard practice among physicians because of concern surrounding the risk of radiation-induced secondary cancers, especially among pediatric patients. There is minimal research assessing the complications for radiation therapy in keloid management. The goal of this study was to determine radiation oncologists' perspectives about the utility and appropriateness of radiation therapy for keloid management in both adult and pediatric patients. This study also aimed to characterize radiation modality, dose, fractionation, and secondary complications observed by providers. An electronic survey was delivered to 3102 members of the American Society for Radiation Oncology. The survey subjects were radiation oncologists who are currently practicing in the United States. Rates of responses were analyzed. A total of 114 responses from practicing radiation oncologists were received. Of these, 113 providers (99.1%) supported radiation therapy for keloid management in adults, whereas only 54.9% supported radiation therapy for pediatric patients. Of 101 providers that treated adults in the past year, the majority used external beam: electrons (84.2%), applied 3 fraction regimens (54.4%), and delivered radiation within 24 hours postexcision (45.5%). In pediatric patients, only 42 providers reported treating at least 1 patient. The majority used electron beam radiation (76.2%), applied 3 faction regimens (65%), and delivered radiation on the same day of keloid excision (50.0%) The main concern when treating pediatric patients were risk of secondary malignancy (92.1%). Although radiation therapy appears to be a widely accepted adjuvant treatment option for adults with keloids, the use of radiation therapy for pediatric patients is less widely accepted because of concerns regarding secondary malignancy. The findings suggest additional studies need to be carried out to assess the risk of those complications.

Nivolumab plus Brentuximab vedotin +/- bendamustine combination therapy: a safe and effective treatment in pediatric recurrent and refractory classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is the most common pediatric lymphoma. Approximately 10% of patients develop refractory or recurrent disease. These patients are treated with intensive chemotherapy followed by consolidation with radiotherapy or high-dose chemotherapy and autologous stem cell reinfusion. Although this treatment is effective, it comes at the cost of severe long-term adverse events, such as reduced fertility and an increased risk of secondary cancers. Recently, promising results of inducing remission with the immune checkpoint inhibitor nivolumab (targeting PD-1) and the anti-CD30 antibody-drug conjugate Brentuximab vedotin (BV) +/- bendamustine were published. Here we describe a cohort of 10 relapsed and refractory pediatric cHL patients treated with nivolumab + BV +/- bendamustine to induce remission prior to consolidation with standard treatment. All patients achieved complete remission prior to consolidation treatment and are in ongoing complete remission with a median follow-up of 25 months (range: 12 to 42 months) after end-of-treatment. Only one adverse event of CTCAE grade 3 or higher due to nivolumab + BV was identified. Based on these results we conclude that immunotherapy with nivolumab + BV +/- bendamustine is an effective and safe treatment to induce remission in pediatric R/R cHL patients prior to standard consolidation treatment. We propose to evaluate this treatment further to study putative long-term toxicity and the possibility to reduce the intensity of consolidation treatment.

Hybrid planning techniques for early-stage left-sided breast cancer: dose distribution analysis and estimation of projected secondary cancer-relative risk

Purpose The purpose of this study was to evaluate three techniques of irradiation of left-sided breast cancer patients, three-dimensional conformal radiotherapy (3D-CRT), hybrid Intensity-Modulated Radiotherapy (h-IMRT), and hybrid Volumetric-Modulated Arc Therapy (h-VMAT, h-ARC), in terms of dose distribution in the planning target volume (PTV) and organs at risk (OARs). The second aim was to estimate the projected relative risk of radiation-induced secondary cancers for hybrid techniques. Materials and methods Three treatment plans were prepared in 3D-CRT, h-IMRT, and h-VMAT techniques for each of the 40 patients, who underwent CT simulation in deep inspiration breath-hold (DIBH). For hybrid techniques, plans were created by combining 3D-CRT and dynamic fields with an 80%/20% dose ratio for 3D-CRT and IMRT or VMAT. Cumulative dose–volume histograms were used to compare dose distributions within the PTV and OARs (heart, left anterior descending coronary artery [LAD], left and right lung [LL, RL], right breast [RB]). Projected risk ratios for secondary cancers were estimated relative to 3D-CRT using the organ equivalent dose (OED) concept for the Schneider’s linear exponential, plateau, and full mechanistic dose–response model. Results All plans fulfilled the PTV criterium: V95%≥95%. Compared to 3D-CRT, both hybrid techniques showed significantly better target coverage (PTV: V95%>98%, p < 0.001), and the best conformality was achieved by h-ARC plans (CI: 1.18 ± 0.09, p < 0.001). Compared to 3D-CRT and h-ARC, h-IMRT increased the average sum of monitor units (MU) over 129.9% (p < 0.001). H-ARC increased the mean dose of contralateral organs and the LL V5Gy parameter (p < 0.001). Both hybrid techniques significantly reduced the D max of the heart by 5 Gy. Compared to h-IMRT, h-ARC increased secondary cancer projected relative risk ratios for LL, RL, and RB by 18, 152, and 81%, respectively. Conclusions The results confirmed that both hybrid techniques provide better target quality and OARs sparing than 3D-CRT. Hybrid VMAT delivers less MU compared to hybrid IMRT but may increase the risk of radiation-induced secondary malignancies.

Clinical characteristics of secondary bladder cancer developing after low-/high-dose-rate brachytherapy to treat localized prostate cancer.

To explore correlations between the clinical attributes of secondary bladder cancer and brachytherapy, we retrospectively reviewed our institutional database on patients with localized prostate cancer who underwent low-dose-rate brachytherapy (LDR-BT) or high-dose-rate brachytherapy (HDR-BT) with or without external beam radiation therapy (EBRT) or radical prostatectomy (RP). From October 2003 to December 2014, 2551 patients with localized prostate cancer were treated at our institution. Of these, data on 2163 were available (LDR-BT alone: n = 953; LDR-TB with EBRT: n = 181; HDR-BT with EBRT: n = 283; RP without EBRT: n = 746). The times of secondary bladder cancer development subsequent to radical treatment, and their clinical characteristics, were studied. Age-adjusted Cox's regression analyses indicated that brachytherapy did not significantly impact the incidence of secondary bladder cancer. However, the pathological characteristics of such cancer differed between patients treated via brachytherapy and RP without EBRT; invasive bladder cancer was more common in such patients. The risk for secondary bladder cancer was not significantly increased after brachytherapy compared to non-irradiation therapy. However, brachytherapy patients exhibited a higher incidence of invasive bladder cancer. Therefore, meticulous follow-up is crucial for early detection and treatment of bladder cancer in such patients.

Effect of a one-year personalized intensive dietary intervention on body composition in colorectal cancer patients: Results from a randomized controlled trial

Changes in body composition may affect colorectal cancer (CRC) patient's risk of cancer recurrence, secondary cancer, and other chronic diseases. The suggested interventions for changes in body composition such as low muscle mass or high fat mass, are diet and physical activity. Nevertheless, there is limited evidence of how dietary intervention alone can impact body composition. This study aimed to investigate the effect of a 6 and 12 month dietary intervention with a focus on healthy eating according to Norwegian food-based dietary guidelines on weight and body composition in patients with CRC stage I-III, post-surgery. This study included participants from the randomized controlled trial CRC-NORDIET study 2-9 months after surgery. The intervention group received an intensive dietary intervention, while the control group underwent similar measurements, but no dietary intervention. Body composition was measured with Lunar iDXA, and the results were analyzed using linear mixed models. A total of 383 participants were included, 192 in the intervention group and 191 in the control group. After 6 months, the intervention group showed a 0.7kg lower mean weight gain (p=0.020) and 0.6kg lower fat mass gain (p=0.019) than the control group, but no difference at 12 months. Moreover, the fat mass increase was 0.5 percentage points lower at 6 months (p=0.012), and 0.7 percentage points lower at 12 months (p=0.011) in the intervention group compared to the controls. At 6 months, the intervention group had 63g lower gain of visceral adipose tissue compared to the control group (p=0.031). No differences were seen for fat-free mass or subcutaneous adipose tissue at any time point. The intervention group showed a lower increase in the ratio between fat mass and fat-free mass at both 6 months (p=0.025) and 12 months (p=0.021). The dietary intervention reduced the increases in total weight and fat masses, without changing fat-free mass. Although the individual changes are small, the dietary intervention may have resulted in an overall more favourable body composition profile. These findings suggest that dietary intervention may be part of a treatment strategy for prevention of weight and fat mass gain in CRC survivors.

Estimation of the risk of secondary cancer in rectum and bladder after radiation therapy for prostate cancer using a feasibility dose-volume histogram.

We investigated the risk of secondary cancers in rectum and bladder for prostate cancer radiotherapy using a feasibility assessment tool. We calculated the risk of secondary cancer by generating a dose-volume histogram based on an ideal dose falloff function (f-value). This study found a smaller f-value was associated with a lower secondary cancer risk in the rectum but a higher risk in the bladder. The study suggests setting the f-value at 0-0.1 as the optimization goal for the rectum and 0.4 for the bladder is reasonable and feasible for reducing the risk of secondary cancer and other adverse events.

Pre-diagnostic cigarette smoking and risk of second primary cancer: The Melbourne Collaborative Cohort Study

Enhanced survival following a diagnosis of cancer has led to a steep rise in the number of individuals diagnosed with a second primary cancer. We examined the association between pre-cancer cigarette smoking and risk of second cancer in 9785 participants diagnosed with first invasive cancer after enrolment in the Melbourne Collaborative Cohort Study. Follow-up was from date of first invasive cancer until diagnosis of second primary invasive cancer, death, or 31 July 2019, whichever came first. Data on cigarette smoking was collected at enrolment (1990–94) along with information on other lifestyle factors including body size, alcohol intake and diet. We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for incident second cancer with several smoking measures, adjusted for potential confounders. After a mean follow-up of 7.3 years, 1658 second cancers were identified. All measures of smoking were associated with increased risk of second cancer. We observed a 44 % higher risk of second cancer for smokers of ≥ 20 cigarettes/day (HR=1.44, 95 % CI: 1.18–1.76), compared with never smokers. We also observed dose-dependent associations with number of cigarettes smoked (HR=1.05 per 10 cigarettes/day, 95 % CI: 1.01–1.09) and duration of smoking (HR=1.07 per 10 years, 95 % CI: 1.03–1.10). The risk of second cancer increased by 4 % per 10 pack-years of smoking (HR=1.04, 95 % CI: 1.02–1.06; p < 0.001). There was suggestive evidence of stronger associations with number of cigarettes smoked and pack-years of smoking for women (pinteraction<0.05), particularly for the highest risk categories of both variables. These associations with pre-diagnostic smoking were markedly stronger for second cancers known to be smoking-related than for others (phomogeneity<0.001). Our findings for pre-diagnostic cigarette smoking indicated increased risk of second primary cancer for cancer sites considered smoking-related, highlighting the importance of assessing smoking habits in cancer survivors.

Reduced risk of secondary primary extra pulmonary cancer in advanced/metastatic lung cancer patients treated with immune checkpoint inhibitors

BackgroundLung cancer survivors are at high risk of developing a second primary cancer (SPC). We explored the Unicancer Epidemiology Strategy Medical-Economics for advanced or metastatic lung cancer (AMLC) database to assess the impact of immune checkpoint inhibitors (ICI) on the risk of SPC in patients with advanced/metastatic lung cancer. Patients and methodsThis retrospective study used data from patients with AMLC, with treatment initiated between January 1st 2015 and December 31st 2018. Patients with lung cancer as the second primary cancer were excluded and a 6-months landmark threshold was applied to exclude patients with synchronous SPC, patients dead without SPC or with a follow-up inferior to 6 months. A propensity score (PS) was calculated on the following baseline covariates: Age at locally advanced or metastatic diagnosis, sex, smoking status, metastatic status, performance status and histological type. The inverse probability of treatment weighting approach was used on the analyses aiming to assess the impact of ICI administered for AMLC, on the risk of occurrence of SPC. ResultsAmong the 10 796 patients, 148 (1.4%) patients had a diagnosis of SPC in a median interval of 22 (min–max: 7–173) months. All the patients (100%) with locally advanced or metastatic LC received at least one systemic treatment including (chemotherapy regimen (n = 9 851, 91.2%); ICI (n = 4 648, 43.0%); targeted treatment (n = 3 500; 32.4%). 40 (0.9%) SPC were reported in the 4 648 patients with metastatic LC treated with ICI vs 108 (1.7%) out of the 6 148 who did not receive immunotherapy (p < 0.0001). The multivariate analysis identified that treatment with ICI in patients with AMLC is associated with a reduced risk of SPC (HR = 0.40, 95% CI 0.27–0.58). ConclusionTreatment with ICI in AMLC patients was associated with a significantly reduced risk of SPC. Prospective studies are required to confirm these results.

Epidemiology and clinical trends of testicular cancer and secondary malignant tumors in a north Italian province.

e17024 Background: In Italy, 2.300 new testicular cancer (TCa) were estimated in the year 2020. The aim of this study was to examine the incidence and mortality trends, the 5-year relative survival by histopathology of tumours and the association with second neoplasms in TCa patients (pts) of Reggio Emilia (RE) Province. Methods: The population-based cohort study used data from the RE Cancer Registry (RE-CR) and all TCa recorded from 1996 to 2020 were included, evaluated by age ( &lt; 30; 30-40; 40+), histotype and year of diagnosis (1996-2000; 2001-2005; 2006-2010; 2011-2015; 2016-2020). Population estimates are represented by the general population of the RE Province recorded on January 1st of each year. The standardized incidence rate was calculated using the European population and the Annual Percent Change (APC) was reported. The 5-year relative survival was estimated using the Pohar Perme method. Trends over time were analysed by calculating the APC in age-standardized rates using Joinpoint Regression. Results: 385 pts with TCa were considered, 244 (63.4%) seminomas and 141 (36.6%) non-seminomas, 153 cases (39.7%) aged 30–40 years. There were differences according to age between the different histopathology groups: in the non-seminoma group there were more younger pts (44% aged less than 30 years) while in seminoma group there were 40.2% of pts older than 40 years. The 25-year recording trends showed an annual increase of 2.3% in the annual incidence in seminomas. The incidence of seminomas increased from 36 cases (14.8%) in the period 1996-2000 to 60 cases (24.6%) in the period 2016-2020. The non-seminoma cases remained almost constant during these years. Overall 5-years survival was 95%, 99% and 88% for seminoma and non-seminoma groups, respectively. In seminoma group 5-years survival was higher in all age groups. In patients over 40 years, the 5-years survival was 98% in seminoma group but 64% in non-seminoma group. An association with second tumours was documented in 19 pts (4.9%) after TCa diagnosis. The main second neoplasms were skin (4 pts), lung (4pts) and prostate cancer (3 pts). The median time of second tumors onset after TCa diagnosis was respectively 9.4, 8.5 and 6.7 years. After adjusting for age at diagnosis, logistic regression analysis showed an increased risk for second cancer, odds ratio (OR) = 1.9 (95% CI 0.7; 5.4) among seminoma pts. In addition, the OR was higher in pts aged 30 to 40 years and over 40 years, OR = 1.8 (95% CI 0.4; 9.3), OR = 8.3 (95% CI 1.8; 37.7) respectively. Conclusions: Our data confirm the increase of seminoma incidence, in particular in older ones. The non-seminoma cancers occurred rarely in pts aged over 40 yrs and this group had worst prognosis. This finding requires further studies to highlight emerging risk factors and improve the therapy in poor prognosis pts .

A novel risk assessment metric for antimyeloma therapies and drug interactions.

e24082 Background: New treatments for multiple myeloma (MM) improved both the clinical course and survival. These differ in their mode of action, safety profile, and adverse events (AEs). The goal of this study is to establish the benchmark for an integrated systematic investigation to assess the toxicity of different anti-MM drug regimens (AMDR). Methods: We curated 342,213 MM patient information from 2016–2022 from the FDA Adverse Event Reporting System. A total of 71 AMDR were evaluated in 7 different system organ classes when mapped to MedDRA. Drug-associated genes and AEs were also quantified as genetic evidence of a drug-AE combination. Gene-gene associations were then explored using the STRING database. We then developed a novel risk assessment metric that combined historical data from MM patients with drug-AE scores regarding the AE occurrence, the number of reported AE, and the genetic evidence of drug-gene and gene-AE associations (GAA). This likelihood-based rating metric includes (vH): (very) high MDR risk–(very) frequent AEs and mortality with (very) significant GAA evidence; and similarly computed for M: medium risk; and L: low risk. Results: Our risk assessment findings revealed single agents (carfilzomib (K), bortezomib (V), daratumumab (D), lenalidomide (R), melphalan (Mel), thalidomide (T), ixazomib (Ix), elotuzumab (El), isatuximab (Is) or dexamethasone (d)) illustrated very low profile of toxicity compared to combination regimens. Overall, we found that AMDR profiles showed higher toxicities in 4 different SyOCs (hepatobiliary, cardiac, nervous, renal) with nominal issues in 3 SyOCs (vascular, neoplasm, GI). AMDR toxicity significantly increased when d was added to the treatment compared to AMDR without d. Cardiac and vascular AEs were higher with K-based combinations. Hepatobiliary toxicities were higher with V, K, or T-based combinations. Secondary neoplasms were seen more frequently in patients who received high dose Mel followed by R. Conclusions: Our analysis of large data shows the association of SyOCs and graded toxicity profiles with unique AMDR. The single drug or doublets without dexamethasone seemed to show an improved AE profile compared to those with dexamethasone used as doublets, triplets, or quadruplets. Secondary cancer risk was much higher with high dose Mel followed by R compared with other AMDR. Our assessment system provides a framework for AMDR comparison toward future precision MM therapeutics based on unique drug doses, combination regimens, patient phenotypic risk profiles, secondary cancer surveillance and interplay of genetics and comorbidities. [Table: see text]

Comparison of Dose Distribution to Target Volume and Organs at Risk using 3D CRT, IMRT, and VMAT Techniques in Glioblastoma Cases

The average lifetime risk of secondary cancer after irradiating glioblastoma radiation therapy to healthy organs shows that the technique of volumetric modulated arc therapy (VMAT) has a smaller risk of developing secondary cancer compared to intensity modulated radiation therapy (IMRT) and three-dimensional radiation therapy (3DCRT). Parameters of dose distribution, namely the target volume and dose received by the organs at risk (OAR), are used to compare these three techniques. The distribution of doses from TPS results in the form of DVH and isodose in the 3D CRT, IMRT, and VMAT techniques shows that the distribution of doses to healthy organs around the glioblastoma irradiation area is in the safe category and is still within tolerance limits. With VMAT, the PTV and CTV dose results were more optimal compared to the 3D CRT and IMRT techniques. 3D CRT showed a PTV dose value of 5551.8 cGy and a CTV of 5515.3 cGy. IMRT shows a PTV dose value of 6035.0 cGy and a CTV of 6018.8 cGy. VMAT shows PTV dose values of 6101.8 cGy and CTV of 6044.7 cGy. It can be seen that the distribution of doses to healthy organs in general in the VMAT technique is more optimal than the IMRT and 3D CRT techniques in protecting OAR.

Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls

Familial adenomatous polyposis (FAP) is a hereditary disorder that predisposes patients to colorectal cancer (CRC). Prophylactic colectomy has greatly reduced the risk of CRC. However, new associations between FAP and the risk of other cancers have subsequently emerged. In this study, we assessed the risk of specific primary and secondary cancers among patients with FAP compared with matched controls. All known patients with FAP up until April 2021 were identified in the nationwide Danish Polyposis Register and paired with 4 unique controls matched by birth year, sex, and postal code. The risk of overall cancers, specific cancer types, and risk of a second primary cancer was assessed and compared with controls. The analysis included 565 patients with FAP and 1890 controls. The overall risk of cancer was significantly higher for patients with FAP than for controls (hazard ratio [HR], 4.12; 95% confidence interval [CI], 3.28-5.17; P < .001). The increased risk was mainly due to CRC (HR, 4.61; 95% CI, 2.58-8.22; P < .001), pancreatic cancer (HR, 6.45; 95% CI, 2.02-20.64; P= .002), and duodenal/small-bowel cancer (HR, 14.49; 95% CI, 1.76-119.47; P= .013), whereas no significant difference was observed for gastric cancer (HR, 3.29; 95% CI, 0.53-20.23; P= .20). Furthermore, the risk of a second primary cancer was significantly higher for patients with FAP (HR, 1.89; 95% CI, 1.02-3.50; P= .042). Between 1980 and 2020, the risk of cancer among patients with FAP decreased by ∼50%. Despite an absolute reduction in the risk of developing cancer among patients with FAP, the risk remained significantly higher than for the background population due to colorectal, pancreatic, and duodenal/small-bowel cancers.

Risk of second primary cancer among women in the Kaiser Permanente Breast Cancer Survivors Cohort

BackgroundBreast cancer survivors are living longer due to early detection and advances in treatment and are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decades is lacking.MethodsWe identified 16,004 females diagnosed with a first primary stage I-III breast cancer between 1990 and 2016 (followed through 2017) and survived ≥ 1 year at Kaiser Permanente (KP) Colorado, Northwest, and Washington. Second cancer was defined as an invasive primary cancer diagnosed ≥ 12 months after the first primary breast cancer. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast cancer) using standardized incidence ratios (SIRs), and a competing risk approach for cumulative incidence and hazard ratios (HRs) adjusted for KP center, treatment, age, and year of first cancer diagnosis.ResultsOver a median follow-up of 6.2 years, 1,562 women developed second cancer. Breast cancer survivors had a 70% higher risk of any cancer (95%CI = 1.62–1.79) and 45% higher risk of non-breast cancer (95%CI = 1.37–1.54) compared with the general population. SIRs were highest for malignancies of the peritoneum (SIR = 3.44, 95%CI = 1.65–6.33), soft tissue (SIR = 3.32, 95%CI = 2.51–4.30), contralateral breast (SIR = 3.10, 95%CI = 2.82–3.40), and acute myeloid leukemia (SIR = 2.11, 95%CI = 1.18–3.48)/myelodysplastic syndrome (SIR = 3.25, 95%CI = 1.89–5.20). Women also had elevated risks for oral, colon, pancreas, lung, and uterine corpus cancer, melanoma, and non-Hodgkin lymphoma (SIR range = 1.31–1.97). Radiotherapy was associated with increased risk for all second cancers (HR = 1.13, 95%CI = 1.01–1.25) and soft tissue sarcoma (HR = 2.36, 95%CI = 1.17–4.78), chemotherapy with decreased risk for all second cancers (HR = 0.87, 95%CI = 0.78–0.98) and increased myelodysplastic syndrome risk (HR = 3.01, 95%CI = 1.01–8.94), and endocrine therapy with lower contralateral breast cancer risk (HR = 0.48, 95%CI = 0.38–0.60). Approximately 1 in 9 women who survived ≥ 1 year developed second cancer, 1 in 13 developed second non-breast cancer, and 1 in 30 developed contralateral breast cancer by 10 years. Trends in cumulative incidence declined for contralateral breast cancer but not for second non-breast cancers.ConclusionsElevated risks of second cancer among breast cancer survivors treated in recent decades suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed.