Second Malignant Neoplasms Research Articles

Second Malignant Neoplasms (SMN) in Myeloma Patients Post Stem Cell Transplant (SCT)

Introduction: Recent developments in management of patients with myeloma have resulted in longer survival. Availability of newer class of agents for treatment has prolonged survival, improved quality of life and achieved better disease control. Use of SCT, either autologous (AutoSCT) and to a lesser extent allogeneic (AlloSCT) still forms an important aspect of myeloma treatment pathway. Improved survivorship mandates evaluation of long term consequences and risk of SMN is one of the most important long-term consequences affecting overall outcome.Aim: Estimate the risk of SMN post SCT in patients with Myeloma.Methods and Materials: Analysis includes 779 patients who received SCT for myeloma from January 2002 to December 2019. Data was collected using case records, electronic patient records, transplant database and information from referring hospitals. Follow-up was updated to June 2020.Results: Analysis includes 779 patients with myeloma (M: 488, F:291; median age:59yr, range: 26-75) receiving AutoSCT (n=716) or AlloSCT (n=63). Conditioning for AutoSCT was high dose melphalan in majority (n=714, 99.7%). AlloSCT conditioning was RIC (n=40/63, 63.5%) or MAC (n=23/63, 36.5%). TBI was part of conditioning in 51/779 (6.5%). There was no difference in demographics between two groups.Results: Median follow-up was 46 mo (range: 0.2-220). Second malignancy was identified in 48 of 779 cases (6.0%). SMN developed in 6/63 (10%) AlloSCT and 42/716 (6%) AutoSCT patents (p=0.25). SMN types were haematological (n=21), lymphoma (n=6) and solid tumours (n=21). MDS was the only haematological SMN in this series. Secondary MDS developed in 20/21 of AutoSCT as compared to 1/63 in AlloSCT (p=0.01). Non-haematological SMN were breast (n=3), upper GI (n=3), lower GI (n=2), hepato-billiary (n=2), prostate (n=3), skin (n=5), and unknown primary (n=1). SMN incidence was higher with increasing follow-up (2002-2014, 8%; 2015-2017, 2.8%, 2018-2019, 0%, p=0.002). There was no association with development of SMN and gender, age at transplant, type of stem cell source or transplant conditioning. Incidence of SMN was significantly higher for all sites as compared to general population. Cumulative incidence of SMN was 5% at 5 yr, and 15% at 10 yr for AutoSCT patients.Conclusion: Myeloma patients are at increased risk of SMN and need monitoring for long term side effects. Development of MDS post AutoSCT is the commonest SMN post AutoSCT but there is increased incidence of solid tumours as well. Impact of new modalities of treatment needs long term monitoring. DisclosuresBloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria.

A Systematic Review on Intensity Modulated Radiation Therapy for Mediastinal Hodgkin's Lymphoma.

Secondary malignant neoplasms (SMNs) and cardiovascular diseases induced by chemotherapy and radiotherapy represent the main cause of excess mortality for early-stage Hodgkin lymphoma patients, especially when the mediastinum is involved. Conformal radiotherapy techniques such as Intensity-Modulated Radiation Therapy (IMRT) could allow a reduction of the dose to the organs-at-risk (OARs) and therefore limit long-term toxicity. We performed a systematic review of the current literature regarding comparisons between IMRT and conventional photon beam radiotherapy, or between different IMRT techniques, for the treatment of mediastinal lymphoma. IMRT allows a substantial reduction of the volumes of OARs exposed to high doses, reducing the risk of long-term toxicity. This benefit is conterbalanced by the increase of volumes receiving low doses, that could potentially increase the risk of SMNs. Treatment planning should be personalized on patient and disease characteristics. Dedicated techniques such as "butterfly" VMAT often provide the best trade-off.

Advances in radiation therapy in malignant brain tumors

Radiation therapy (RT) plays a key role in the optimal management of a range of primary and secondary brain tumors. RT has evolved from conventional radiotherapy to three-dimensional (3D) conformal, intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), stereotactic techniques such as stereotactic radiosurgery or fractionated stereotactic radiotherapy to particle beam therapies such as the proton beam therapy (PBT) and carbon ion therapy. Further, there is increased evidence of molecular-based approach in the treatment of malignant brain tumors. Tumors such as the high-grade gliomas tend to have inferior outcomes as compared to the low-grade gliomas. Pediatric brain tumors tend to do better, in terms of local control, progression-free survival, and overall survival. In such scenarios, sparing of critical structures is essential as it tends to reduce the dose to the normal brain tissue, thereby improving neurocognitive outcomes, reduces hormonal impairment and risk of secondary malignant neoplasms. Modern techniques such as the IMRT, VMAT, and PBT, especially image-guided intensity-modulated proton therapy, spare the critical structures to bare minimum, which in turn leads to superior dose distribution without any low dose spillage to the nearby areas. These advanced techniques not only behave therapeutically but are also cost-effective, resulting in improved quality of life.

Second Cancer Risk in Childhood Cancer Survivors Treated with Intensity-Modulated Radiation Therapy (IMRT): An Updated Analysis of More Than 10 Years of Follow-Up

It is unclear how treatment with intensity-modulated radiation therapy (IMRT) impacts long-term risk of second malignant neoplasms (SMNs) in pediatric patients. A preliminary report from our institution published in 2015 by Casey et al. demonstrated a 10-year cumulative incidence (CI) of 3.3%, which we sought to update with now a median follow-up of over 10 years.Pediatric patients < = 21 years of age treated with IMRT at our institution between December 1998 and February 2009 and who survived with follow-up data > = 5 years after IMRT were included. The total dose of IMRT to any field was calculated and adjusted for contribution of conventional radiotherapy. Exposure to chemotherapy was recorded and noted if exposed to alkylating agents, anthracyclines, and/or epidodophyllotoxins. Treatment plans were evaluated to assess whether SMNs occurred within the treatment field. CI estimates of all SMN and second solid malignancies were calculated using the CI method of competing risks with death considered a competing event.A total of 326 patients were included with a median follow-up of 11 years from IMRT initiation (IQR, 8.6-14.0). The most common primary diagnosis was soft tissue sarcoma (n = 109, 33.4%) followed by neuroblastoma (n = 64, 19.6%). Most (n = 282, 86.5%) received chemotherapy. Most (n = 200, 61.3%) patients had > 10 years of follow-up and 285 (87.4%) patients were alive at the time of this analysis. At a median time of 8.2 years from IMRT (range, 3.2-19.2), 17 developed SMNs (11 solid, 6 hematologic) with a 10-year and 15-year CI of 1.8% (95% confidence interval [CI] 0.8-4.3) and 3.6% (95% CI 1.5-8.3), respectively. Six of these patients (35.3%) are still alive. Of the 11 solid SMNs, most (7, 63.6%) had received IMRT to the head and neck, 3 to the CNS, and 1 to the abdomen/pelvis. The mean and median doses to the IMRT field were 5360cGy (standard deviation, 2433) and 5580cGy (range, 2100-9640), respectively. Median time to solid SMN was 11.0 years (range, 6.8-19.2) and cancers included 2 colon adenocarcinomas, 3 osteosarcomas, 1 high grade astrocytoma, 2 glioblastomas, 1 papillary thyroid cancer, 1 widely metastatic cancer of unknown primary, and 1 presumed soft tissue sarcoma. 2 patients with SMNs had hereditary retinoblastoma. 5 solid SMNs developed within the 100% isodose line (IDL) of the IMRT field, 1 within 80% IDL, 1 within 50% IDL, and 1 within 40% IDL. A colon cancer is estimated to have developed within the 70-80% IDL of the conventional posteroanterior field as part of craniospinal irradiation. The papillary thyroid carcinoma was out of the IMRT field. The metastatic cancer of unknown primary could not be categorized or attributable to IMRT.With a median follow-up of 11 years, there was an increased CI of solid SMNs after IMRT in childhood cancer survivors. SMNs developed both in and out of the high dose region. These data serve as a foundation for comparison with other modalities of radiation treatment, namely proton therapy.

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia

AbstractThe effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP–related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.

To X-ray diagnostics of malignant neoplasms in patients with operated stomach

The decisive method for the treatment of malignant neoplasms of the stomach is surgical intervention. The successes achieved in this direction are limited mainly to surgery for primary cancer of the stomach. Patients with recurrent tumors in the stomach stump, as well as with secondary malignant neoplasms in this area after surgery for peptic ulcer, polyps and other diseases, were considered doomed and hopeless until recently.

Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors’ late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy’s long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines’ possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect’s vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

Second Malignant Neoplasms in Patients With Rhabdomyosarcoma.

ObjectiveRhabdomyosarcoma (RMS) is a rare malignant tumor. The main treatment modality is comprehensive with chemotherapy, radiotherapy, and surgery. With the advancement in recent decades, patient survival has been prolonged, and long-term complications are attracting increasing attention among both physicians and patients. This study aimed to present the survival of patients with RMS and analyze the risk factors for the development of a second malignant neoplasm (SMN).MethodsThe Surveillance, Epidemiology, and End Results (SEER) Program 18 registry database from 1973 to 2015 of the National Cancer Institute of the United States was used for the survival analyses, and the SEER 9 for the SMN analysis.ResultsThe 5-, 10-, and 20-year overall survival rates of the patients with RMS were 45%, 43%, and 33%, respectively. The risk of SMN was significantly higher in patients with RMS compared to the general population (SIR=1.95, 95% CI: 1.44 – 2.57, p < 0.001). The risk of developing SMN was increased in multiple locations, including the bones and joints (SIR = 35.25) soft tissues including the heart (SIR = 22.5), breasts (SIR = 2.10), male genital organs (SIR = 118.14), urinary system (SIR = 2.36), brain (SIR = 9.21), and all nervous system organs (SIR = 8.59). The multivariate analysis indicated that RMS in the limbs and earlier diagnosis time were independent risk factors for the development of SMN. Patients with head and neck (OR = 0.546, 95% CI: 0.313 – 0.952, p = 0.033) and trunk RMS (OR = 0.322, 95% CI: 0.184 – 0.564. p < 0.001) and a later diagnosis time were less likely to develop SMN (OR = 0.496, 95% CI: 0.421 – 0.585, p < 0.001).ConclusionThis study describes the risk factors associated with the development of SMN in patients with RMS, which is helpful for the personalized screening of high-risk patients with RMS.

Estimated Risk of Radiation-Induced Cancer after Thymoma Treatments with Proton- or X-ray Beams.

Simple SummaryThymic tumors, i.e., thymomas and thymic carcinomas, are rare tumors that derive from the remnant of the thymus gland. Although surgery is the first treatment of choice, some patients will be treated with radiotherapy. For many patients the prognosis is good, hence it is important to avoid treatment related complications such as radiation-induced secondary malignancies. Radiotherapy can be delivered with different techniques and with different particles. In the present study, we compare the calculated (estimated) risks for secondary malignancies after treatment of thymic tumors with two different photon (x-ray) radiotherapy techniques or with proton beam therapy. We use a commonly used radiobiological model to calculate the risks for radiation induced secondary malignancies for each treatment modality. In conclusion, proton beam therapy was shown to provide the potential for reducing the risk of secondary malignancies, compared to photon radiotherapy, after treatment of thymic tumors.We compared the calculated risks of radiation-induced secondary malignant neoplasms (SMNs) for patients treated for thymic tumors with 3D-CRT, IMRT, or single-field uniform dose (SFUD) proton beam therapy (PBT) using the pencil beam scanning (PBS) technique. A cancer-induction model based on the organ equivalent dose (OED) concept was used. For twelve patients, treated with 3D-CRT for thymic tumors, alternative IMRT and SFUD plans were retrospectively prepared. The resulting DVHs for organs at risk (OARs) were extracted and used to estimate the risk of SMNs. The OED was calculated using a mechanistic model for carcinoma induction. Two limit cases were considered; the linear-exponential model, in which the repopulation/repair of the cells is neglected, and the plateau model, in which full repopulation/repair of the irradiated cells is assumed. The calculated risks for SMNs for the different radiation modalities and dose-relation models were used to calculate relative risks, which were compared pairwise. The risks for developing SMNs were reduced for all OARs, and for both dose-relation models, if SFUD was used, compared to 3D-CRT and IMRT. In conclusion, PBS shows a potential benefit to reduce the risk of SMNs compared to 3D-CRT and IMRT in the treatment of thymic tumors.

Cisplatin Reduces the Frequencies of Radiotherapy-Induced Micronuclei in Peripheral Blood Lymphocytes of Patients with Gynaecological Cancer: Possible Implications for the Risk of Second Malignant Neoplasms.

Gynaecologic cancers are common among women and treatment includes surgery, radiotherapy or chemotherapy, where the last two methods induce DNA damage in non-targeted cells like peripheral blood lymphocytes (PBL). Damaged normal cells can transform leading to second malignant neoplasms (SMN) but the level of risk and impact of risk modifiers is not well defined. We investigated how radiotherapy alone or in combination with chemotherapy induce DNA damage in PBL of cervix and endometrial cancer patients during therapy. Blood samples were collected from nine endometrial cancer patients (treatment with radiotherapy + chemotherapy—RC) and nine cervical cancer patients (treatment with radiotherapy alone—R) before radiotherapy, 3 weeks after onset of radiotherapy and at the end of radiotherapy. Half of each blood sample was irradiated ex vivo with 2 Gy of gamma radiation in order to check how therapy influenced the sensitivity of PBL to radiation. Analysed endpoints were micronucleus (MN) frequencies, apoptosis frequencies and cell proliferation index. The results were characterised by strong individual variation, especially the MN frequencies and proliferation index. On average, despite higher total dose and larger fields, therapy alone induced the same level of MN in PBL of RC patients as compared to R. This result was accompanied by a higher level of apoptosis and stronger inhibition of cell proliferation in RC patients. The ex vivo dose induced fewer MN, more apoptosis and more strongly inhibited proliferation of PBL of RC as compared to R patients. These results are interpreted as evidence for a sensitizing effect of chemotherapy on radiation cytotoxicity. The possible implications for the risk of second malignant neoplasms are discussed.

MP40-18 IDENTIFICATION OF A NOVEL PROGNOSIS MODEL FOR SECONDARY MALIGNANT NEOPLASMS (SMNs) FREE SURVIVAL IN TESTICULAR CANCER SURVIVORS: A SEER-BASED STUDY

INTRODUCTION AND OBJECTIVE:This study aims to identify the significant demographic factors and pathologic factors associated with diagnosis of secondary malignant neoplasms (SMNs) in testicular can...

An Analysis of the Social and Economic Costs of Breast Cancer in Italy.

Background: Breast cancer is the most prevalent cancer affecting women and it represents an important economic burden. The aim of this study was to estimate the socio-economic burden of breast cancer (BC) in Italy both from the National Health Service (NHS) and the government perspectives (costs borne by the social security system). Methods: The economic analysis was based on the costs incurred by the NHS from 2008 to 2016 (direct costs related to hospitalizations) and by the National Social Security Institute (INPS) from 2009 to 2015 (costs of social security benefits) for patients with breast cancer. The analysis was based on the Hospital Information System (HIS) and Disability Insurance Awards databases. For both databases, patients affected by a malignant neoplasm of the female breast, carcinoma in situ, or secondary malignant neoplasm of the breast were considered. Results: Results show that more than 75,000 women were hospitalized for breast cancer every year, with an overall cost for hospitalization of about €300 million per year. From the Social Security analysis, a number of 29,000 beneficiaries each year was estimated. Considering per patient social costs, breast cancer at the primary stage cost €8828 per year, while secondary neoplasms cost €9780, with an average total economic burden of €257 million per year. Conclusions: This analysis focused on the economic impact of breast cancer in Italy, showing that an advanced stage of the disease was associated with a higher cost.

Late effects in pediatric Hodgkin lymphoma survivors after uniform treatment with ABVD with or without radiotherapy.

ABVD (doxorubicin, bleomycin,vinblastine, and dacarbazine) is not a standard regimen in children due to concerns regarding late effects. However, no studies have evaluated long-term toxicities of ABVD in children. Total 154 pediatric Hodgkin lymphoma (HL) survivors uniformly treated with ABVD were clinically followed up as per institutional protocol. All participants were evaluated for cardiac, pulmonary, and thyroid function abnormalities by multigated acquisition scan (MUGA) scan, spirometry with diffusion capacity of lung for the uptake of carbon monoxide (DLCO), and thyroid profile test, respectively, at a single time point. Predictors of toxicity were also analyzed. The median duration of follow-up of the cohort was 10.3years (6.04-16.8). No secondary malignant neoplasm (SMN) or symptomatic cardiac/pulmonary toxicities were detected. Nine patients (5.9%) had left ventricular ejection fraction (LVEF) <55%. Subclinical and overt hypothyroidism were observed in 78 (50.6%) and 16 (10.4%) survivors, respectively. Abnormal spirometry and reduced DLCO was observed in 43.2% and 42.0% survivors, respectively. Receiving neck radiation was significantly associated with thyroid dysfunction (odds ratio [OR] 16.04, p<.001); age ≥10years predicted reduced DLCO (OR 4.12, p=.001). Sixty-three and 33 patients had one and two late adverse effects, respectively; receiving neck radiation predicted development of multiple late effects (proportional OR 4.72, p<0.001). Cumulative dose of chemotherapy did not predict toxicity. Overall, ABVD appears safe in children at a relatively short follow-up. Long-term safety data are required before it can be adopted for treating pediatric HL patients. Children receiving neck radiation require close follow-up.

Health care utilisation preceding relapse or second malignant neoplasm after childhood acute lymphoblastic leukaemia: a population-based matched cohort study

ObjectivesTo investigate health care utilisation including both primary and secondary health care 6 months before the diagnosis of a relapse or a second malignant neoplasm (SMN) in survivors of childhood...

Overall survival and secondary malignant neoplasms in children receiving passively scattered proton or photon craniospinal irradiation for medulloblastoma.

Both intensity-modulated radiotherapy (RT) and passively scattered proton therapy have a risk of secondary malignant neoplasm (SMN) in children. To determine the influence of RT modality on the incidence of SMN after craniospinal irradiation (CSI), the authors compared the incidence of SMN in children who had medulloblastoma treated with either photon CSI plus an intensity-modulated RT boost (group I) or passively scattered proton CSI plus a boost (group II). From 1996 to 2014, 115 children with medulloblastoma (group I, n = 63; group II, n = 52) received CSI followed by a boost to the tumor bed. Most patients had standard-risk disease (63.5%). The median follow-up was 12.8 years for group I and 8.7 years for group II. The 5-year and 10-year overall survival (OS) rates were 88.8% and 85.1%, respectively, for standard-risk patients and 63.1% and 57.3%, respectively, for high-risk patients, with no OS difference by RT modality (P = .81). Six SMNs were identified (4 in group I, 2 in group II). The 5-year and 10-year SMN incidence rates were 1.0% and 6.9%, respectively (0.0% and 8.0%, respectively, in group I; 2.2% and 4.9%, respectively, in group II; P = .74). Two SMNs occurred in the clinical target volume in the brain, 2 occurred in the exit dose region from the photon spinal field, 1 occurred in the entrance path of a proton beam, and 1 occurred outside the radiation field. There were no reported cases of secondary leukemia. This analysis demonstrates no difference in OS or SMN incidence between patients in groups I and II 10 years after RT. One hundred fifteen children with medulloblastoma received radiotherapy (RT) with either photon craniospinal irradiation (CSI) and an intensity-modulated RT boost (group I; n = 63) or passively scattered proton CSI and a boost (group II;, n = 52). The majority of children had standard-risk disease (63.5%). The 5-year and 10-year overall survival rates were 88.8% and 85.1% for standard-risk patients, respectively, and 63.1% and 57.3% for high-risk patients, respectively, with no difference in overall survival by RT group (P = .81). The 5-year and 10-year second malignant neoplasm incidence rates were 1.0% and 6.9%, respectively, with no difference in second malignant neoplasm incidence according to RT group (P = .74).

Health Care Utilization and Costs Associated With Systemic First-Line Metastatic Melanoma Therapies in the United States.

US Food and Drug Administration approvals of immune checkpoint inhibitors and targeted therapies revolutionized the treatment of metastatic melanoma. Our aim was to assess health care resource utilization and costs for patients with metastatic melanoma treated with systemic therapies in first line between January 2012 and December 2017. We conducted a retrospective cohort study of patients with metastatic melanoma using MarketScan data. We included patients diagnosed with melanoma and secondary malignant neoplasm who used pembrolizumab, nivolumab, ipilimumab, ipilimumab plus nivolumab, BRAF-inhibitor (BRAF-i) plus MEK inhibitor (MEK-i), BRAF-i or MEK-i monotherapy, or chemotherapy in first line. We compared health care utilization and costs per patient per month (PPPM) using two-part and generalized linear models. We identified 1,870 patients, including 185 pembrolizumab, 103 nivolumab, 689 ipilimumab, 185 nivolumab plus ipilimumab, 214 BRAF-i plus MEK-i, 240 BRAF-i or MEK-i monotherapy, and 254 chemotherapy users. Highest PPPM rates of hospitalizations, emergency room visits, and outpatient visits were observed in patients with ipilimumab plus nivolumab therapy (adjusted difference v pembrolizumab [aDiff], 0.18, 0.12, and 0.88, respectively; all P < .001). Ipilimumab monotherapy users (aDiff, 0.07 and 0.93; all P < .001) and chemotherapy users (aDiff, 0.10 and 2.63; all P < .001) showed higher PPPM rates of hospitalizations and outpatient visits compared with pembrolizumab users, respectively. Utilization rates in nivolumab, BRAF-i plus MEK-i, and BRAF-i or MEK-i groups were similar to the pembrolizumab group. Highest PPPM total costs and drug-related costs were observed in the ipilimumab group ($80,139 US dollars [USD] and $70,051 USD; all P < .001), followed by the ipilimumab plus nivolumab ($71,689 USD and $56,217 USD; all P < .001) and the BRAF-i plus MEK-i group ($31,184 USD and $19,648 USD; all P < .001). PPPM costs in the nivolumab group were similar to the pembrolizumab group. Significant differences in health care resource utilization and costs were found across first-line metastatic melanoma regimens. Utilization rates were highest in patients using ipilimumab-containing therapies. High drug costs constituted a major fraction of total PPPM health care costs.

Risk of radiation-induced second malignant neoplasms from photon and proton radiotherapy in paediatric abdominal neuroblastoma.

Background and PurposeState-of-the-art radiotherapy modalities have the potential of reducing late effects of treatment in childhood cancer survivors. Our aim was to investigate the carcinogenic risk associated with 3D conformal (photon) radiation (3D-CRT), intensity modulated arc therapy (IMAT) and pencil beam scanning proton therapy (PBS-PT) in the treatment of paediatric abdominal neuroblastoma.Materials and MethodsThe risk of radiation-induced second malignant neoplasm (SMN) was estimated using the concept of organ equivalent dose (OED) for eleven organs (lungs, rectum, colon, stomach, small intestine, liver, bladder, skin, central nervous system (CNS), bone, and soft tissues). The risk ratio (RR) between radiotherapy modalities and lifetime absolute risks (LAR) were reported for twenty abdominal neuroblastoma patients (median, 4y; range, 1-9y) historically treated with 3D-CRT that were also retrospectively replanned for IMAT and PBS-PT.ResultsThe risk of SMN due to primary radiation was reduced in PBS-PT against 3D-CRT and IMAT for most patients and organs. The RR across all organs ranged from 0.38 ± 0.22 (bladder) to 0.98 ± 0.04 (CNS) between PBS-PT and IMAT, and 0.12 ± 0.06 (rectum and bladder) to 1.06 ± 0.43 (bone) between PBS-PT and 3D-CRT. The LAR for most organs was within 0.01–1% (except the colon) with a cumulative risk of 21 ± 13%, 35 ± 14% and 35 ± 16% for PBS-PT, IMAT and 3D-CRT, respectively.ConclusionsPBS-PT was associated with the lowest risk of radiation-induced SMN compared to IMAT and 3D-CRT in abdominal neuroblastoma treatment. Other clinical endpoints and plan robustness should also be considered for optimal plan selection.

Risk and Outcomes of Second Malignant Neoplasms in Chronic Myeloid Leukemia Survivors

BACKGROUND: The introduction of tyrosine kinase inhibitors (TKIs) has significantly improved the long term survival of patients with chronic myeloid leukemia (CML). Patients in cytogenetic remission have life expectancy that approaches that of the general population. The majority of patients with CML remain on TKIs indefinitely. It is unclear whether prolonged exposure to TKIs increases the risk of second malignant neoplasms (SMN) and if malignancies developing in CML survivors harbor similar prognosis to malignancies in non-CML patients. METHODS: We utilized the Surveillance, Epidemiology and End Results 18 (SEER 18) registries to evaluate SMN in adult patients diagnosed with BCR-ABL1 positive CML as first malignant neoplasm between 2001 (introduction of TKIs) and 2014(most recent year with available data). Follow up is current to the end of 2014 (November 2016 submission). Using the multiple primary standardized incidence ratio (SIR) session of the SEER*stat software (version 8.1.5), we calculated the SIR of SMNs for CML survivors. Cases diagnosed at autopsy and by death certificate only were excluded. SMN was defined as a metachronous non-leukemia malignancy that developed at least 6 months after the diagnosis of CML. Survival rates for the most common malignancies in CML survivors were compared with tumor site, age, gender, race/ethnicity, histology, grade and stage-matched cases developing in individuals without a prior diagnosis of CML. RESULTS: There were 3,407 patients included in the analysis with a median follow up of 41 months. The median age at diagnoses was 53 years (range 20-98) and 56% were men. Of these patients, 170 (4.99%) developed a SMN after a median of 36.5 months from diagnosis of CML (range 6-160) with a SIR of 1.40 (95%C.I. 1.19-1.62) and excess risk of 34.92 per 10,000 persons* year. The most commonly occurring SMNs were lung (n=30), prostate (n=28) and colorectal (n=19). A significantly increased risk was noted for cancers of the respiratory tract (n=32, SIR 1.69, 95%C.I. 1.15-2.4), genitourinary (GU) tract (n=54, SIR 1.39, 95%C.I. 1.04-1.81) and skin excluding basal cell and squamous cell carcinoma (n=13, SIR 1.94, 95%C.I. 1.04-3.32). There was no significant increase in risk of gastrointestinal (GI) tract (n=32, SIR 1.36, 95%C.I. 0.93-1.92), head and neck (n=5, SIR 1.51, 95%C.I. 0.49-3.52) and breast cancer (n=13, SIR 0.85, 95%C.I. 0.45-1.46). Using 3:1 matching (3 de novo malignancies to 1 post-CML SMN case), we compared survival data for cancers of the respiratory, GU and GI tract. Patients with GU malignancies developing after CML had worse overall survival than matched patients without prior CML diagnosis (P=0.018). There was no survival difference between post-CML and non-post-CML patients with respiratory or GI malignancies (Figure). CONCLUSION: CML survivors have an increased risk of developing subsequent malignancies as compared to the general population. The increase in risk is more evident for GU, respiratory and non-basal cell, non-squamous cell carcinoma skin cancer. GU malignancies in CML survivors have worse outcomes than in non-CML patients. Future investigation should focus on the biologic mechanism of increased susceptibility of CML survivors to solid tumors. Download : Download high-res image (60KB) Download : Download full-size image Figure . Disclosures No relevant conflicts of interest to declare.

Dexrazoxane decreases the cardiotoxic effects of doxorubicin in osteosarcoma patients without increasing mortality from secondary malignant neoplasms

A clinical decision report appraising: Schwartz CL, Wexler LH, Krailo MD, et al. Intensified chemotherapy with dexrazoxane cardioprotection in newly diagnosed nonmetastatic osteosarcoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer. 2016;63(1):54-615. https://doi.org/10.1002/pbc.25753 for a patient with osteosarcoma and concerns about the risk of secondary malignant neoplasms that attend use of dexarazoxane.

Treatment-specific risk of second malignancies in five-year survivors of diffuse large B-cell lymphoma.

12072 Background: Due to the historically less favorable prognosis of diffuse large B cell lymphoma (DLBCL), the burden of second malignant neoplasms (SMNs) has been rarely studied in DLBCL survivors. However, radiotherapy and chemotherapy may increase SMN risk among DLBCL patients. Anthracyclines may increase the risk of hematological malignancies, but it is not clear whether they also increase solid cancer risk. Methods: We established a multicenter cohort of 2,384 5-year DLBCL survivors treated at ages 15-60 years with radiotherapy and/or immuno-chemotherapy between 1989 and 2012. Observed numbers of SMNs were compared with expected cancer incidence in the general population to compute standardized incidence ratios (SIRs), absolute excess risks (AERs, per 10.000 person-years) and cumulative incidence. Treatment specific incidence was compared with general population rates and assessed within the cohort using Cox regression. Results: Most DLBCL patients received alkylating agents (95%), anthracycline-containing chemotherapy (95%) or radiotherapy (61%); 46% received rituximab. Median follow-up was 13.3 years; 17% of patients was followed ≥20 years. In total, 308 5-year survivors developed an invasive SMN (SIR 1.6; 95% confidence interval (CI), 1.4 to 1.8), translating into 56.2 excess cancers per 10.000 person-years (see Table for specific sites). In 20-year survivors of DLBCL, the SIR was 1.8 (95% CI 1.3-2.6). The 20-year cumulative incidence of any SMN was 18.7% (95% CI 16.5-21.0%). The SIR for any SMN was higher in patients &lt;40 years at first treatment (SIR ≤40 years: 2.8, SIR &gt;40 years: 1.4; p&lt;0.001). Treatment specific results will be presented at ASCO21. Conclusions: DLBCL survivors experience higher risk of SMNs than the general population. Identification of patients at increased risk could improve follow-up care.[Table: see text]