Risk Of Second Cancer Research Articles

The Long‐Term Effects of Exercise Mitigate Deleterious Healthspan Changes and Cancer Incidence in Mice Following Diet‐Induced Obesity and Radiation Exposure

There are nearly 16 million cancer survivors living in the United States today, with two‐thirds of them having received radiation therapy as part of their treatment. Furthermore, there is a concurrent increase in obesity and physical inactivity among this population. Combined with the effects of ionizing radiation (IR), these host factors are increasing the risk of secondary, treatment‐induced cancers and may contribute to poor healthspan outcomes in cancer survivors. As such, a critical need exists to develop a better understanding of how these host factors interact with radiation exposure, such that we can provide cancer survivors with better lifestyle recommendations to enhance their overall quality of life and decrease their secondary cancer risk. Male CBA mice were randomly divided into a control diet group (CTRL) or a 45% high fat diet group (HFD) to induce obesity. At nine weeks of age, half of the mice in each dietary group began a treadmill exercise training intervention (EX), or remained sedentary (SED), and were then all exposed to ionizing radiation (3 Gy) at 13 weeks of age. Healthspan was measured in each group at 17 months of age by assessing: endurance performance, metabolic and locomotor activity, depression‐like behaviour, forelimb grip strength and plasma clinical chemistry. Endurance performance was significantly greater in CTRL/EX compared to both HFD groups 5 days pre‐IR and compared to both SED groups 5 months post‐IR (both p<0.05). Metabolic analysis revealed a significant increase in the respiratory exchange ratio in CTRL compared to HFD mice (p<0.05), but there were no significant differences in O2 consumption, CO2, or heat production (p>0.05). There was also a trend for an increase in locomotor activity in the CTRL/EX compared to CTRL/SED group during their light and dark cycle (p = 0.06 and p = 0.108, respectively). Further, there was a significant decrease in depression‐like behaviour among HFD compared to CTRL mice, and EX compared to SED mice (p<0.05), as well as a significant decrease in forelimb grip strength normalized to body weight among HFD compared to CTRL mice (p<0.05). Additionally, there was a significant increase in total cholesterol levels among HFD compared to CTRL mice (p<0.05). Interestingly, the CTRL/EX and HFD/EX groups had a 20% decrease in cancer incidence compared to the HFD/SED group, and EX mice had a 17.5% decrease in cancer incidence compared to SED mice, independent of diet (both p>0.05). Our current findings suggest that long‐term exercise and dietary interventions should be implemented in cancer survivors exposed to radiation therapy in order to improve healthspan and potentially protect against secondary cancer incidence.Support or Funding InformationThe American Institute of Cancer Research (AICR), The Natural Sciences and Engineering Research Council of Canada (NSERC), and The Canadian Institutes of Health Research (CIHR)

The risk of malignancies in patients receiving hematopoietic stem cell transplantation: a systematic review and meta-analysis.

Hematopoietic stem cell transplantation (HSCT) is widely used in the treatment of malignant and non-malignant diseases. Due to advances in the number of survivors of this treatment, the number of survivors is increasing, but the late complications of this therapeutic approach such as secondary cancers have been long term and have not been fully controlled. The present meta-analysis study was performed by considering English-language articles in the databases including Web of Science, Scopus and PubMed. This meta-analysis included cohort studies that reported an incidence of cancer following stem cell transplantation (SCT). Random/fixed effect size meta-analyses were used to standardize the incidence ratio for different cancers. 22 studies that evaluated patients receiving SCT (n = 270,063) were included in the study. The study found 9233 cases of cancer after transplantation. Meta-analysis showed that the risk of cancer after SCT was SIR = 1.66 (95% CI 1.47-1.86). The most common cancers observed in SCT recipients were bone tissue, head and neck cancers, and melanoma, with SIRs of 10.04 (3.48-16.61), 6.35 (4.76-7.93) and 3.52 (2.65-4.39), respectively. The meta-analysis findings showed that the risk of secondary cancers after HSCT was significantly increased in most types of cancers. Consequently, diagnostic tests for common cancers should be included in the screening program of these patients for the prevention and early detection of high-risk cancers.

AVM0703 as a novel stand alone or combination therapy for lymphoma.

42 Background: Chemotherapy remains a vital part of cancer treatment. There is an urgent need to reduce the toxicities associated with chemotherapy-based treatments especially in the pediatric and young adult population where the risk for chemo-induced secondary cancers is high. AVM0703 is a new treatment option that can be used as a stand-alone or in combination with chemo for relapsed/refractory lymphoma patients. AVM0703 is effective at lymphoablating while sparing red blood cells, platelets, and hematopoietic stem cells. AVM0703 is a novel patent-pending formulation of a repurposed drug without the toxic excipients unlike existing formulations. AVM0703 has anti-tumor activity in an immunocompetent mouse model of B-cell lymphoma (A20) as both a stand-alone treatment and in combinations with current therapeutics. Methods: Wild-type BALB/c mice were implanted with A20 tumor cells suspended in a 50% Matrigel mixture and implanted subcutaneously. Palpable tumors were visible within seven days. Mice were dosed with either high-dose AVM0703 alone, or in combination with intraperitoneal cyclophosphamide and fludarabine. Mice were then monitored for tumor growth and changes in body weight. Results: Mice dosed repeatedly with AVM0703 survived 20 days longer than mice dosed with placebo and displayed no significant toxicity or body weight loss. In a separate study, mice treated with 2 doses of Cy/Flu had a loss of tumors similar to 1 dose of AVM0703 + 1 dose of Cy/Flu. Additionally, when compared to standard treatments like CHOP, in the same A20 lymphoma model, the AVM0703 + Cy/Flu combination had better tumor efficacy than 2 cycles of CHOP. Unlike 2XCHOP treatment, which induced greater than 30% body weight loss and death of 18% of the mice due to drug toxicity, the AVM0703 + Cy/flu combination had no observed toxicity or body weight loss. Conclusions: AVM0703 can reduce the number of chemotherapy cycles without affecting efficacy and decrease the toxicities associated with chemo and will help to provide a better quality of life for patients.

The influence of radiotherapy techniques on the plan quality and on the risk of secondary tumors in patients with pituitary adenoma

BackgroundThis planning study compares different radiotherapy techniques for patients with pituitary adenoma, including flatness filter free mode (FFF), concerning plan quality and secondary malignancies for potentially young patients. The flatness filter has been described as main source of photon scatter.Material and methodsEleven patients with pituitary adenoma were included. An Elekta Synergy™ linac was used in the treatment planning system Oncentra® and for the measurements. 3D plans, IMRT, and VMAT plans and non-coplanar varieties were considered. The plan quality was evaluated regarding homogeneity, conformity, delivery time and dose to the organs at risk. The secondary malignancy risk was calculated from dose volume data and from measured dose to the periphery using different models for carcinoma and sarcoma risk.ResultsThe homogeneity and conformity were nearly unchanged with and without flattening filter, neither was the delivery time found substantively different. VMAT plans were more homogenous, conformal and faster in delivery than IMRT plans. The secondary cancer risk was reduced with FFF both in the treated region and in the periphery. VMAT plans resulted in a higher secondary brain cancer risk than IMRT plans, but the risk for secondary peripheral cancer was reduced. Secondary sarcoma risk plays a minor role. No advantage was found for non-coplanar techniques. The FFF delivery times were not shortened due to additional monitor units needed and technical limitations. The risk for secondary brain cancer seems to depend on the irradiated volume. Secondary sarcoma risk is much smaller than carcinoma risk in accordance to the results of the atomic bomb survivors. The reduction of the peripheral dose and resulting secondary malignancy risk for FFF is statistically significant. However, it is negligible in comparison to the risk in the treated region.ConclusionTreatments with FFF can reduce secondary malignancy risk while retaining similar quality as with flattening filter and should be preferred. VMAT plans show the best plan quality combined with lowest peripheral secondary malignancy risk, but highest level of second brain cancer risk. Taking this into account VMAT FFF seems the most advantageous technique for the treatment of pituitary adenomas with the given equipment.

Secondary cancer risk after radiation therapy for breast cancer with different radiotherapy techniques

The aim of this study was to estimate the radiation-related secondary cancer risks in organs during the treatment of breast cancer with different radiotherapy techniques, such as three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). The treatment plans for 26 patients with breast cancer who received whole-breast irradiation at a dose of 50 Gy included tangential field 3D-CRT with hard-wedges (W-TF), tangential field IMRT (2F-IMRT), multiple field IMRT (6F-IMRT), and double partial arcs (VMAT). Patients were divided into three groups according to the distance between the contralateral breast (CB) and the body of the sternum. Setup error was simulated by moving the isocenter, and the dose distribution was then recalculated without changing the field fluency distribution. Based on the linear-exponential, the plateau, and the full mechanistic dose-response models, the organ equivalent dose and excess absolute risk were calculated from dose-volume histograms to estimate the secondary cancer risks in organs. Compared with 3D-CRT, IMRT and VMAT showed excellent results regarding tumor conformity and homogeneity; however, the low dose volume to organs was considerably higher in 6F-IMRT and VMAT. Secondary cancer risks for 2F-IMRT were comparable or slightly lower than for W-TF, but considerably lower than for 6F-IMRT or VMAT. After setup error simulation, there was a small increase in secondary cancer risk for 2F-IMRT and an increase of 159% and 318% for 6F-IMRT and VMAT, respectively, compared with W-TF. Although these results were obtained in most patients, they did not necessarily apply to every individual. The secondary cancer risks in the CB decreased significantly in correlation with increased distance for all alternative techniques, although they were higher in VMAT and lower in 2F-IMRT regardless of the distance. After setup error simulation, the increased changes in secondary cancer risks in the CB were comparable between 2F-IMRT, 6F-IMRT, and VMAT, suggesting that the secondary cancer risks in the CB mainly depend on radiotherapy techniques and distance, although the effect of setup error cannot be ignored. In the contralateral lung (CL), the secondary cancer risks were almost independent from distance and depended mainly on radiotherapy techniques; they were rarely affected by setup error. VMAT was associated with a higher secondary cancer risk in the CL. For the ipsilateral lung (IL), the secondary cancer risks were higher than those in other organs because the IL receives high doses to achieve tumor control, and they were relatively lower in VMAT. This warrants special consideration when estimating the secondary cancer risk to the IL. The study results suggested that the optimal radiotherapy method for breast cancer should be determined on an individual basis and according to the balance between secondary cancer risks related to anatomic diversity and setup error, which can prevent blind selection of techniques.

Monte Carlo simulation of non-target organ doses and radiation-induced secondary cancer risk in Tanzania from radiotherapy of nasopharyngeal by using Co-60 source

A few studies have reported the risks of secondary cancer in patients after radiation therapy in Tanzanian hospitals. This study was designed to assess non-target organ doses from Co-60 teletherapy for patients with nasopharyngeal cancer and to estimate the risk of radiation-induced secondary cancer. Specific organ-absorbed doses were evaluated in anatomically realistic 15-year-old and adult male phantoms based on Monte Carlo simulation. The assessed organ doses were used to calculate the lifetime secondary cancer risks in non-target organs according to the BEIR VII risk models. Survival information and the baseline cancer risks were associated with statistical data for the Tanzanian population. The average absorbed doses in non-target organs depended heavily on the distance from the target isocentre and patient's age. Organs near the tumour target, such as the salivary glands, brain, thyroid glands, eye bulb and oesophagus, received very high absorbed doses. The absorbed doses decreased exponentially towards the testis and prostate which are far from the tumour target. The highest received absorbed doses in non-target organs were due to the leakage in the gantry head and scattered radiation from collimator and inside the patient body. The absorbed doses were higher for young patients than in adults because of the larger body area exposed to high-dose radiation. The lifetime attributed risks for all organs considered were relatively lower than the baseline cancer risks. Results can help provide future database about radiation-induced second primary cancer incidence after Co-60 external beam radiation therapy for nasopharyngeal cancer in Tanzania and in many other developing countries.

Monte Carlo study on the secondary cancer risk estimations for patients undergoing prostate radiotherapy: A humanoid phantom study.

The aim of this study was to estimate the secondary malignancy risk from the radiation in FFB prostate linac-based radiotherapy for different organs of the patient. Radiation therapy is one of the main procedures of cancer treatment. However, the application the radiation may impose dose to organs of the patient which can be the cause of some malignancies. Monte Carlo (MC) simulation was used to calculate radiation doses to patient organs in 18MV linear accelerator (linac) based radiotherapy. A humanoid MC phantom was used to calculate the equivalent dose s for different organs and probability of secondary cancer, fatal and nonfatal risk, and other risks and parameters related to megavoltage radiation therapy. In out-of-field radiation calculation, it could be seen that neutrons imparted a higher dose to distant organs, and the dose to surrounding organs was mainly due to absorbed scattered photons and electron contamination. Our results showed that the bladder and skin with 54.89×10-3mSv/Gy and 46.09×10-3mSv/Gy, respectively, absorbed the highest equivalent dose s from photoneutrons, while a lower dose was absorbed by the lung at 3.42×10-3mSv/Gy. The large intestine and bladder absorbed 55.00×10-3mSv/Gy and 49.08×10-3, respectively, which were the highest equivalent dose s due to photons. The brain absorbed the lowest out-of-field dose, at 1.87×10-3mSv/Gy. We concluded that secondary neutron portion was higher than other radiation. Then, we recommended more attention to neutrons in the radiation protection in linac based high energy radiotherapy.

Epidemiology of Hairy Cell Leukemia (HCL) and HCL-Like Disorders

Hairy cell leukemia (HCL) is a very rare and well-defined entity that is characterized by the presence of hairy cells expressing the characteristic markers CD11c, CD25, CD103 and CD123 and in most cases by the presence of the BRAFV600E mutation. The incidence rate, directly adjusted to the 2000 United States standard population is estimated at 0.62 per 100 000 person-years (PA) in white men, 0.21 in black men, 0.20 in Asian men and 0.06 American Indian or Alaska native men. Based on the estimated 2019 leukemia incidence, of 61,780 in the United States, approximately 1,240 new HCL cases are expected per year, with only 60–75 new patients having a variant form of HCL each year. In France, the median age of patients at diagnosis is 63 years in men and 59 years in women. There is a strong male predominance, with a sex ratio of 5:1. HCL is a malignant disorder with a good prognosis, with a standardized average survival at 1 year and 5 years of 95% (95% CI: 91-97 for both). The etiology of HCL remains unknown. The risk of secondary cancers is high, especially that of another malignant hematologic disorder. This high risk justifies the need for prolonged hematological monitoring. HCL must be distinguished from other HCL-like disorders, including the variant form of HCL (HCL-V) or splenic diffuse red pulp lymphoma (SDRPL), warranting the development of international epidemiologic studies.

Low-dose radiation therapy for coronavirus disease-2019 pneumonia: Is it time to look beyond apprehensions?

Coronavirus disease-2019 (COVID-19) has become a global health crisis. Mortality associated with COVID-19 is characterized mainly by acute respiratory distress syndrome (ARDS), sepsis, pneumonia, and respiratory failure. The pathogenesis of the disease is known to be associated with pro-inflammatory processes after virus infection. Hence, various therapeutic strategies are being developed to control the inflammation and cytokine storm in COVID-19 patients. Recently, low-dose radiation therapy (LDRT) has been suggested for the treatment of pneumonia/ADRS in COVID-19 patients through irradiation of lungs by gamma/X-ray. In this direction, a few clinical trials have also been initiated. However, a few recent publications have raised some concerns regarding LDRT, especially about possibilities of activation/aggressiveness of virus (severe acute respiratory syndrome coronavirus 2 in case of COVID-19), lung injury and risk of second cancer after low-dose therapy. The present manuscript is an attempt to analyze these apprehensions based on cited references and other available literature, including some from our laboratory. At this point, LDRT may be not the first line of therapy. However, based on existing anti-inflammatory evidence of LDRT, it needs encouragement as an adjuvant therapy and for more multi-centric clinical trials. In addition, it would be worth combining LDRT with other anti-inflammatory therapies, which would open avenues for multi-modal therapy of pneumonia/ARDS in COVID-19 patients. The mode of irradiation (local lung irradiation or whole-body irradiation) and the window period after infection of the virus, need to be optimized using suitable animal studies for effective clinical outcomes of LDRT. However, considering ample evidence, it is time to look beyond the apprehensions if a low dose of radiation could be exploited for better management of COVID-19 patients.

Does muscle invasive bladder cancer following pelvic radiotherapy portend worse prognosis? A seer-based study

BackgroundAlthough emerging evidence demonstrates increased risk of secondary bladder cancer following pelvic radiotherapy, the aggressiveness of these tumors is not well-characterized. Materials and MethodsA search of the Surveillance, Epidemiology, and End Results (SEER) 18 Database, identified 25,734 patients diagnosed with bladder cancer following definitive therapy for previous pelvic malignancy. Kaplan-Meier curve analyses were utilized to determine overall survival with significance set at p<0.05. ResultsOf the 25,734 patients, 11,376 (44.2%) received radiation treatment for their first cancer. Overall survival of bladder cancer was found to be 80%, 69.5%, and 49.2% at 1,2 and 5 years, respectively. There was no significant survival difference between groups whose first cancer was treated with or without radiation (p=0.8). A survival advantage was seen for the bladder cancer patients not treated with radiation for cervical (p=0.004), uterine (p=0.0006), and vaginal cancers (p<0.0001). Bladder cancer patients treated with radiation for prostate cancer showed a survival advantage (p=0.002). The average time to second cancer diagnosis was 6.5±6.1 years. Patients treated with radiation for first primary cancer showed a longer time to second cancer (7.2±6.0 years) compared to those treated without radiation (5.9±6.0 years) (p<0.01). ConclusionPatients with prior history of female cancers treated without radiation demonstrated significant survival advantage in second primary bladder cancer. A small significant survival advantage was seen in bladder cancer patients previously treated for prostate cancer with radiation. This data suggests that second primary bladder cancer following pelvic radiotherapy has similar biologic aggressiveness to urothelial carcinoma developing without a history of radiotherapy. MicroabstractThe overall survival of 25,734 patients diagnosed with bladder cancer following definitive therapy for a previous pelvic malignancy was 49.2% at 5 years. There was no significant survival difference between groups whose first cancer was treated with or without radiation. Second primary bladder cancer following pelvic radiotherapy has similar biologic aggressiveness to urothelial carcinoma developing without a history of radiotherapy.

Does radiotherapy increase the risk of colorectal cancer among prostate cancer patients? A large population-based study.

Objective: The survival of prostate cancer (PC) patients after radiotherapy (RT) has improved over time, but it raises the debate of increased risk of secondary colorectal cancer (SCRC). This study aimed to assess whether RT for PC treatment increases the risk of SCRC in comparison with radical prostatectomy (RP).Methods: A population-based cohort of PC patients treated only with RT or only with RP between January 2007 and December 2015 was identified from the Taiwan Cancer Registry. The incidence rate of SCRC development was estimated using Cox regression model.Results: In this study, total 8,797 PC patients treated with either RT (n = 3,219) or RP (n =5,578). Patients subjected to RT were elder (higher percentage of 70≧years, p < 0.0001) and more advanced clinically (stage III: 22.90% vs. 11.87%; stage IV: 22.15% vs. 13.80%, p < 0.0001), compared to those subjected to RP. More patients subjected to RT had a much higher percentage of autoimmune disease (22.34% vs. 18.75%, p < 0.0001) and osteoarthritis and allied disorders (16.31% vs. 12.98%, p < 0.0001). Besides, RT patients had a higher percentage of underlying Crohn's disease (0.25% vs. 0.05%, p = 0.0230). Although almost all selected factors were not statistically significant, they presented the positive risk of SCRC for those under RP compared with those among RT. Besides, for PC patients in clinical stage I and II, patients with RP may have borderline significantly protective effects of SCRC compared with those under RT (stage I, HR: 0.14; 95% C.I.:0.01-1.39; p = 0.0929; stage II, HR: 1.92; 95% C.I.:0.93-3.95; p = 0.0775). Kaplan-Meier curves for a 3-year-period, which demonstrated no statistical difference in the risk of SCRC free between PC patients undergoing RT and RP (p = 0.9766).Conclusion: Whether or not pelvic RT for PC is associated with an increased risk for SCRC on a population-based level remains a matter of considerable debate. From a clinical perspective, these PC survivors should be counseled accordingly and received continued cancer surveillance with regular colonoscopy follow-up.

Intravascular Colonization of Kaposi Sarcoma: Expanding the Spectrum of Specific Infiltrates of B-Cell Chronic Lymphocytic Leukemia

B-cell chronic lymphocytic leukemia (CLL), a low-grade malignancy consisting of CD5(+), CD23(+), and CD43(+) small B lymphocytes, is the most frequent leukemia in the western world. Patients with CLL may exhibit skin changes characterized by histopathologic evidence of infiltration by atypical B lymphocytes, also known as "specific cutaneous infiltrates of CLL"; in addition, CLL is known to be associated with an increased risk of second cancers, including Kaposi sarcoma (KS). The combination of KS and CLL within the same cutaneous biopsy specimen has only rarely been described. We report a peculiar case of KS occurring in a patient with CLL, in which histopathological evaluation of KS lesions revealed prominent accumulation of CLL lymphocytes within neoplastic vascular spaces. We believe that our findings represent a novel example of intravascular colonization of vascular neoplasms by neoplastic lymphoid cells, further expanding the evergrowing spectrum of specific cutaneous infiltrates of CLL.

Second Cancers in Patients With Locally Advanced Prostate Cancer Randomized to Lifelong Endocrine Treatment With or Without Radical Radiation Therapy: Long-Term Follow-up of the Scandinavian Prostate Cancer Group-7 Trial

Curative radiation therapy (RT) constitutes a cornerstone in prostate cancer (PC) treatment. We present long-term follow-up estimates for second cancer (SC) risk and overall survival (OS) in patients randomized to hormone therapy (ET) alone or combined with 70 Gy prostatic RT in the Scandinavian Prostate Cancer Group-7 (SPCG-7) study. We explored the effect of salvage RT (≥60 Gy to the ET group) and reported causes of death. The SPCG-7 study (1996-2002) was a randomized controlled trial that included 875 men with locally advanced nonmetastatic PC. In this analysis, including data from the Norwegian and Swedish Cancer and Cause of Death registries for 651 Norwegian and 209 Swedish study patients, we estimated hazard ratios (HRs) for SC and death, and cumulative incidences of SC. Median follow-up of the 860 (431 ET and 429) ET + RT patients was 12.2 years for SC risk analysis and 12.6 years for the OS analysis. Eighty-three of the Norwegian ET patients received salvage RT, and median time to salvage RT was 5.9 years. We found 125 and 168 SCs in the ET and ET + RT patients, respectively. With ET alone as reference, ET + RT patients had an HR of 1.19 (95% confidence interval [CI], 0.92-1.54) for all SCs and 2.54 (95% CI, 1.14-5.69) for urinary bladder cancer (UBC). The total number of UBC was 31 (23 in ET + RT; 8 in ET), and the vast majority (85%) were superficial. The HR for SC in salvage RT patients was 0.48 (95% CI, 0.24-0.94). Median OS was 12.8 (95% CI, 11.8-13.8) and 15.3 (95%, CI 14.3-16.4) years in the ET and ET + RT groups, respectively. Compared with ET alone, the risk of death was reduced in ET + RT patients (HR, 0.73; 95% CI, 0.62-0.86) and in ET patients receiving salvage RT (HR, 0.44; 95% CI, 0.30-0.65). Although the risk of UBC was increased in PC patients who received RT in addition to ET, this disadvantage is outweighed by the OS benefit of RT confirmed in our study. The risk of SC, and especially UBC, should be discussed with patients and be reflected in follow-up programs.

Hot Topic: Should all Women with Breast Cancer Undergo Genetic Testing?

Panel testing for germline mutations in cancer patients has advanced rapidly in recent years. In breast cancer, these advances have raised questions about the indications for testing, with some groups advocating testing of all patients with breast cancer. Studies uniformly demonstrate that expanded scope of genetic testing will result in identification of more women with germline mutations. However, many challenges remain in interpretation of such broad panel testing, including limited information about the risks of second cancers conferred by most of these germline mutations and the high rates of VUS that risk causing anxiety and driving decisions towards unwarranted CPM. These challenges limit the utility of panel testing and are further compounded by lack of sufficient genetic counseling support to facilitate discussion with patients around these complex issues. For most women, the benefits of broad panel testing are limited. A tailored approach to genetic testing, based on detailed family history and tumor phenotype, remains the preferred approach.

Dosimetry calculations of involved and noninvolved organs in proton therapy of liver cancer: a simulation study

Radiation for targeting liver tumors can be challenging because of the damage that it can cause to sensitive organs such as heart and kidney. To calculate the dose received by noninvolved organs, a modeling of the patient’s entire body is necessary. Therefore, in this study, a human Oak Ridge National Laboratory-Medical Internal Radiation Dose phantom was used for liver proton therapy simulation. The results show that the optimum proton energy interval covering the whole tumor was in the range of 90–120 MeV. A spread-out Bragg peak was built by adding Bragg peaks to cover the liver tumor volume, and beam parameters recommended by the International Commission on Radiation Units and Measurements (ICRU) were evaluated. The flux of secondary particles was calculated on the surface of the tumor, and two-dimensional dose distributions for protons, neutrons and photons were shown. Finally, the total doses of protons, photons and neutrons in tumor and 14 noninvolved organs were calculated. The results indicated that the ratio of received dose to the normal tissue of the liver concerning the spherical tumor of 2 cm in radius was approximately 0.01. This ratio for organs such as gall bladder, heart and kidney was approximately 8.4 × 10−5, 5.1 × 10−5 and 2.34 × 10−5. Secondary particles such as neutrons and photons deposit their energies to organs located far from the treatment volume, thus increasing the risk of secondary cancers. The research results indicated that the secondary particles dose was quite small in liver proton therapy. All the calculations were performed using Monte Carlo N-Particle Transport Code (MCNP).

AVM0703, a New Treatment Option for Lymphoma Patients

AVM0703 is a new treatment option for lymphoma patients that can eliminate or reduce the dose of standard chemotherapy in the overall treatment plan. Radiation and chemotherapy have dramatically improved survival for patients with cancer. However, the American Cancer Society has reported that chemotherapy and radiation increase the chances of secondary cancers. In fact, the report states that chemotherapy is known to be a higher risk factor than radiation in causing leukemia. The need to decrease chemotherapy administration in young adults and pediatric populations becomes even more essential considering the risk for secondary cancers. Therefore, there is an urgent need for new therapies that are as efficacious as chemotherapy and are without the harmful side effects. AVM0703 is a repurposed small molecule that has significantly extended survival in a mouse model with aggressive B cell lymphoma (A20 mouse model). In addition to being a standalone treatment, AVM0703 can also be administered as a preconditioning agent before CART cell infusion. Two FDA approved breakthrough therapies, Kymriah and Yescarta are not yet available for 33% of patients who are frail and elderly, as they are too weak to undergo the required chemotherapy preconditioning. AVM0703 can have the same preconditioning effect as chemotherapy without the toxic side effects of chemo while sparing red blood cells, stem cells and platelets. AVM0703 demonstrated a significant improvement of the effect of CART cells in a mouse model of melanoma (data not shown). Preconditioning with AVM0703 before CART administration will allow frail and elderly patients access to FDA approved cell therapy treatments. To demonstrate the efficacy of AVM0703 in a lymphoma model, A20 tumor cells were inoculated subcutaneously into the right flank in a cohort of BALB/c mice. When the tumors reached ~ 100mm3, the mice were randomized into two cohorts, control and AVM0703-treated. The control group were vehicle-treated while AVM0703-treated group were administered the active drug on day 7, 10, 17, 23, 24, 28 and 35. Tumor volumes and body weights were measured thrice weekly. Overall the treatment was very well tolerated with no treatment related deaths or toxicity observed. Dramatic body weight loss defined as greater than 20 % decrease from baseline is a frequent concern with chemo treatment, however, it was not observed in any AVM0703-treated mice. The median survival time for the control group was 16 days where as the AVM0703-treated group had a median survival time of 34 days. Therefore, this data suggests that AVM0703 treatment almost doubled the survival time of mice bearing A20 tumors (Figure 1), a fast growing B cell lymphoma model. Most interestingly, when the data was compared to the CHOP regimen, a combination of 4 therapies in the same A20 model, the efficacy results were better than 1 cycle CHOP without the extremely toxic effects observed with CHOP cycles (Figure 2). As mentioned previously AVM0703 is a repurposed molecule with decades of clinical information available on safety and toxicity, allowing a rapid clinical development program. AVM0703 is a novel high-volume formulation with a target dose that is 25 times what is used currently. It has a unique mechanism of action targeting only cancer cells, lymphocytes and monocytes while sparing platelets, RBCs and stem cells. Due to its unique profile, AVM0703 can replace chemotherapy and reduce the financial and physical toxicities associated with it. AVM0703 presents a new treatment option for lymphoma patients that is safe and effective. Disclosures No relevant conflicts of interest to declare.

Comparative Effectiveness of Lenalidomide, Bortezomib, and Their Combinations As First-Line Treatment of Older Patients with Myeloma

Background: In the S0777 phase 3 trial (Durie et al., Lancet. 2017), the lenalidomide, bortezomib, and dexamethasone (RVD) triplet showed survival advantage over lenalidomide/dexamethasone (RD) as initial therapy for myeloma. However, older transplant-ineligible patients often receive doublet regimens (RD or bortezomib/dexamethasone [VD]), or VD plus cyclophosphamide (VCD). In this setting, RVD has not been directly compared with doublets, or RD compared with VD, leaving an important gap in evidence. Our objective was to compare these regimens based on real-life data from older patients receiving first-line therapy for myeloma in the United States (US), using a causal inference approach. Methods: We identified Medicare beneficiaries with myeloma receiving first-line RD, VD, RVD, or VCD in 2007-2015, using Medicare claims linked to data from cancer registry (SEER-Medicare) covering ~35% of the US population, with successful linkage of &gt;95% individuals aged 65 or over. Patients had to have complete Medicare claims, including outpatient prescriptions (Part D), and we excluded cases with amyloidosis or end-stage renal disease. We used propensity score analysis to generate pseudo-randomized cohorts balancing multiple baseline factors, including socio-economic and performance status, time from diagnosis, presence of baseline hypercalcemia, renal disease, anemia, neuropathy, venous thromboembolism (VTE), and other comorbidities. In each comparative analysis, we fitted a separate propensity score, aiming at confounder balance measured by standardized difference of means &lt;0.10. After generating adequately balanced cohorts to minimize indication bias, we analyzed two survival endpoints (measured from start of first-line therapy): event-free survival (EFS, defined as start of a 2nd-line agent, hospice enrollment, or death, censored in case of an autologous transplant) and overall survival (OS), reporting hazard ratios (HR) with 95% confidence intervals (CI). We also compared select identifiable toxicities occurring within 6 months of starting therapy: hospitalization, anemia, neuropathy, and VTE, reporting relative risk (RR), as well as cumulative incidence function (CIF) for secondary solid tumors, reporting subhazard ratio (SHR). Results: We identified 6,076 eligible myeloma patients receiving first-line therapy between 2007 and 2015. Median age was 76 years [y], and there were 50% women. Between 2007 and 2015, the proportion of Medicare beneficiaries receiving RD increased from 18% to 25% (total N = 1,541; Fig. A), VD from 17% to 26% (N = 1,672), and RVD from 1% to 26% (N = 891). Median EFS in the study population was 0.88 y (95%CI, 0.83-0.93), and median OS was 2.7 y (95%CI, 2.6-2.8 y). Lenalidomide was dosed at 25mg in 58%. Bortezomib was dosed weekly in 57%. Detailed results of comparative models are shown in the Table. In the analysis of RVD versus (vs.) doublets, RVD showed better EFS (median 1.7 vs 0.8y; Fig. B) and OS (median 3.4 vs 2.7y). RVD resulted in higher rates of hospitalization (RR, 1.17; 95%CI 1.03-1.32), anemia (RR, 1.16; 95%CI 1.09-1.23), and neuropathy (RR, 1.49; 95%CI, 1.14-1.96), but no increased risk of VTE (RR, 1.06; 95%CI, 0.79-1.44). A higher proportion of patients treated with RVD underwent consolidative transplant (26% vs 6%). There was no significant difference in the risk of secondary cancers. Consistent findings were observed in the more specific comparison of RVD vs. RD (Table). In the analysis of RD vs. VD, RD demonstrated better EFS (median 1.0 vs 0.6y; Fig. C) and marginally better OS (median 2.7 vs 2.3y). RD resulted in more frequent VTE (RR, 1.44; 95%CI, 1.13-1.83), but less neuropathy (RR, 0.39; 95%CI, 0.29-0.53), without significant difference in hospitalization (RR, 0.96; 95%CI, 0.87-1.06) or anemia (RR, 0.95; 95%CI, 0.89-1.00). In the comparison of VCD vs. VD, there were no significant differences in EFS (Fig. D), OS, or observed toxicities. Conclusions: In this large, population-based study, first-line RVD shows EFS and OS advantage for older patients with myeloma who can tolerate higher potential short-term toxicity. RVD (or "RVD-lite" to minimize toxicity) should be the preferred regimen, but it is applied in only a minority of Medicare beneficiaries. For patients not eligible for the RVD triplet, an unexpected advantage of RD over VD was observed, suggesting that RD may be the preferred doublet. VCD appears to offer no benefit over the VD doublet. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding.

Personalised Follow-up Program after Acute Phase of Treatment in Oncology/Hematology Patients Towards Early Intervention, Better Care and Quality of Life Improvement: Results from Pasca Pilot Study

Advances in diagnosis and treatment have helped increase cure rates for many cancers. However, the disease and its treatments are often accompanied by short-, mid- and long-term organic and psychosocial sequelae and increased risk of second cancer, adding to that, all pre-existing comorbidities, lifestyle risks and hereditary factors. At the Centre Leon Berard Cancer center, we launched a project named PASCA (Parcours de Sante au cours du Cancer) that aims at structuring and optimizing a follow-up schedule for patients suffering from breast cancer, testicular germ tumor, acute leukemia, lymphoma or myeloma, as well as patients who received hematopoietic stem cell transplantations (HSCT). The main objective of the program is the early detection and specific management of risk factors for second cancer as well as sequelae management after the acute treatment phase with the final objective of quality of life improvement. Follow-up and evaluation are done through the establishment of a multidisciplinary organic assessment, anthropometric and physical fitness, psychic and socio-professional evaluation, the aim is to establish a score for each assessment, complementary to the specific oncology and hematology monitoring, that allows later to establish a personalized and adapted sequelae management and prevention of complications that could significantly impact the patient quality of life but also compromise the optimal management of the malignant disease. Patients were referred to PASCA by the oncologist/hematologist after being discharged from the acute phase of treatment, an information sheet about the program was given as well as a package containing different questionnaires to capture information about risk factors, general health, social status, quality of life and others. At the same time a series of medical laboratory requests were ordered to get a full medical assessment. Based on the questionnaires/medical evaluation a score was given for each type of assessment. Score 0 means the patients needs only a simple follow-up, score 1 means the patient needs to be followed by the family doctor for the specific issue, and score 2 means there is a need for specialist intervention. We put together a network of internal medicine or organ specific doctors in addition to fitness-physiotherapy specialist as well as many other specialists available to intervene for patients with score 2. We started in Hematology a pilot phase that included non-Hodgkin lymphomas (NHL, N=27) and multiple myelomas (MM, N=27) patients, 15 (28%) females and 39 (72%) males. Median age at evaluation was 60 years (range: 56-65), all patients except 8 (all NHL) received autologous HSCT. Here we present some of the most relevant PASCA assessments with the different scores: nephrology (0: 94%, 1:6%), cardiology (0:27%, 1:63%, 2:10%), hepatology (0:49%, 1:42%, 2:9%), pneumology (0:41%, 1:39%, 2:20%), sexual (0:67%, 1:14%, 2:9%), dermatology (0:78%, 1:13%, 2:9%), pain (0:43%, 1:31%, 2:26%), gynecology (0:56%, 2:44%), endocrinology (0:67%, 1:31%, 2:2%), malnutrition (0:75%, 1:8%, 2:17%), obesity (0:54%, 1:20%, 2:26%), flexibility (0:46%, 1:27%, 2:27%), employment (0:76%, 2:24%), fatigue (0:24%, 1:2%, 2:73%), anxiety (0:56%, 1:22%, 2:22%), and depression (0:80%, 1:10%, 2:10%). In addition, a list of FACT questionnaires was collected for all patients as baseline evaluation and will be compared later during follow-up. During the PASCA consult visit, patient was informed about his different assessment results and in case of any score 1 or 2, a referral to the family doctor or a specialist was requested. Planned 6- and 12-months evaluation are ongoing to evaluate the potential improvement after PASCA program. Our results from this pilot study showed a real need for specific follow-up on the medical level but also on social/well being level that is in most of the cases given less priority when the patient is seen in oncology/hematology clinic. We noticed a significant positive feedback from patients included in this program and we expect to see a drastic improvement on the medical, psychological and social level as well as on quality of life. We are starting the full PASCA program that will include also patients with breast cancers, germ cells cancers and sarcoma. A protocol for a randomized multicentric study is in preparation and will allow to evaluate the impact and the importance of such program in patients with malignant diseases. Disclosures No relevant conflicts of interest to declare.

Frontline Treatment with Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hypercvad/MTX Is Extremely Potent and Safe in Patients (age ≤ 65 years) with Mantle Cell Lymphoma (MCL) - Results of Phase-II Window-1 Clinical Trial

Frontline Treatment with Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hypercvad/MTX Is Extremely Potent and Safe in Patients (age ≤ 65 years) with Mantle Cell Lymphoma (MCL) - Results of Phase-II Window-1 Clinical Trial

French National Retrospective Cohort of Hairy-Cell Leukemias: Risk of Second Malignancies after 10 Years of Follow-up

Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients. Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second 'solid' cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR). Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with 'other' treatments (log rank test, p &amp;lt; 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p &amp;lt; 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67). Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies. Figure Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.