Incidence Of Second Malignancies Research Articles

Li-Fraumeni-associated osteosarcomas: The French experience.

Describe clinical characteristics and outcome of Li-Fraumeni syndrome (LFS)-associated osteosarcomas. TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) for patients of the same age group. Median age at first osteosarcoma diagnosis was 13.7years (range: 5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients less than 10years of age (23% vs. 9%), and when compared with osteosarcomas in patients less than 25years were characterized by an excess of axial (16% vs. 10%) and jaw sites (15% vs. 3%) and histology with predominant chondroblastic component and periosteal subtypes (17% vs. 1%). Metastases incidence (25%) was as expected in osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5-year progression-free survival (55%, 95% confidence interval [CI]: 42.6-71.1) were as expected in unselected series of osteosarcomas, whereas the 5-year event-free survival was 36.5% [95% CI: 25.3-52.7] due to the high incidence of second malignancies reaching a 10-year cumulative risk of 43.4% [95% CI: 28.5-57.5]. In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype, and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up.

Long-term efficacy and safety of dose-dense and dose-intense ABVD without consolidation radiotherapy in patients with advanced Hodgkin lymphoma: A 15-year follow-up of the ABVDDD-DI phase II study.

We demonstrated that dose-densified and dose-intensified ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; ABVDDD-DI) was safe and effective. Here, we present a post hoc long-term analysis of the 82 patients enrolled in the original study. The median observation time was 175 months (IQR 159-197). At 15 years, progression-free and overall survival rates were 81.2% (95% CI, 69.9%-88.7%) and 92.7% (95% CI, 82.6%-97.0%), respectively. Four patients with multiple cardiovascular risk factors experienced delayed G3 cardiac events. The cumulative incidence of second malignancies at 20 years was 6.1%. Fertility and childbearing potential were unaffected. Data support an ongoing benefit for ABVDDD-DI without uneven late toxicities.

Abstract 7449: Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients

Abstract Introduction: The incidence of colorectal cancer in the younger population (20-49) continues to rise at a rapid pace. EOCRC patients are potentially at risk for developing additional secondary malignancies. There is a lack of reported data in the EOCRC space. In this analysis, we seek to examine the incidence, trends, and outcomes of secondary malignancies in EOCRC patients. Methods: The surveillance, epidemiology, and end-result (SEER) database was utilized to assess and compare the incidence and factors associated with development of secondary malignancies among EOCRC patients. Patient characteristics were summarized by secondary cancer status and compared using the Pearson chi-square test. Further OS was assessed using Kaplan- -Meier methods and compared across groups using the log-rank test. Multivariable Logistic regression models using backward selection approach were used to evaluate the association between patient characteristics and risk of secondary cancers. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: Of the 53,891 patients analyzed, 2578 (4.8%) patients with EOCRC developed a secondary malignancy in the SEER database from 2000-2019. The mean age for developing a secondary malignancy was 47.6 yo (median 48 yo; range 20-69). There was a higher likelihood of second cancers among men(56%), white patients (61.4%), those with stage II (25.5%). and III (32.8%) CRC. The patients who most commonly developed a secondary malignancy were in the age group 40-49(p <.001). Of the patients who developed a secondary malignancy, 1843 (71.5%) initially had a primary colon cancer compared to 920 (22.6%) having rectal cancer, with the remainder having a rectosigmoid cancer. Of the patients who developed secondary malignancies, a majority had received prior chemotherapy (58.5%), and a minority of patients received radiation therapy (20.6%) Patients who had a partner had a higher incidence of secondary malignancy (59.5%) and they were more likely to have resided in a metropolitan area compared to a nonmetropolitan area (86.6 versus 13.2% respectively). The most common sites of secondary malignancy were: an additional colorectal cancer (47.7%), followed by breast cancer (8.2%) urinary tract cancer (7.1%), thyroid cancer (7%) and prostate cancer (5%). Patients who developed a secondary cancer were found to have an improved disease specific survival (DSS) compared to those who did not develop a secondary malignancy (3 year mDSS 89% vs 74%; p <.001)The overall survival of patients who developed a secondary malignancy was worse than those who did not develop one (mOS 208 months vs 229 mos respectively). Conclusion: EOCRC patients are likely to develop secondary malignancies. Long-term screening should be recommended for these patients and integrated into their survivorship plans. Citation Format: Deepak Vadehra, Kristopher Attwood, Anthony George, Shailesh Advani, Sahithi Sonti, Sarbajit Mukherjee. Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7449.

Incidence of second malignancies in patients with thymic carcinoma and thymic neuroendocrine tumor

ObjectivesThymic carcinoma and thymic neuroendocrine tumor (NET) are rare and are more likely to develop second malignancies. The purpose of this study was to explore the incidence and lifetime risk of second malignancies in thymic carcinoma and thymic NET.MethodsThe standardized incidence ratio (SIR) and the age-adjusted cancer incidence of the thymic carcinoma and thymic NET patients with second malignancies were retrospectively calculated by using the Surveillance, Epidemiology, and End Results (SEER) database. Prognosis results were also determined by Kaplan–Meier analysis and Cox regression.Results1130 patients with thymic carcinoma (73 patients had second malignancies) and 263 patients with thymic NET (19 patients had second malignancies) from 2000 to 2018 are included. Patients with thymic carcinoma (SIR: 1.36, 95% CI 1.08–1.69) and with thymic NET (SIR: 1.73, 95% CI 1.13–2.54) demonstrate an increased overall risk of developing second malignancies in various organ systems. The age-adjusted cancer incidence of second malignancies in patients with thymic carcinoma is 3058.48 per 100,000 persons (4178.46 per 100,000 persons in patients with thymic NET). Age at diagnosis is a significant risk factor for the development of second malignancies.ConclusionThe incidence of second malignancies in patients with thymic carcinoma and thymic NET is significantly higher than the patients in the normal population. The occurrence of second malignancies is not related to the use of different treatments. It is important to extend the follow-up period and add other screening methods.

Incidence and survival of secondary malignancies after external beam radiotherapy for prostate cancer in the SEER database.

We investigated the incidence of secondary bladder (BCa) and rectal cancers (RCa) after external beam radiotherapy (EBRT) for prostate cancer (PCa) compared to radical prostatectomy (RP) alone, and compared cancer-specific survival (CSS) of these secondary neoplasms to their primary counterparts. This retrospective cohort study included men in the SEER cancer registry with a diagnosis of non-metastatic, clinically node-negative PCa treated with either RP or EBRT from 1995-2011 and allowed a minimum five-year lag period for the development of secondary BCa or RCa. Patients were divided into two eras, 1995-2002 and 2003-2011, to examine differences in incidence of secondary malignancies over time. Univariable and multivariable competing risk analyses with Fine-Gray subdistribution hazard and cause-specific hazard models were used to examine the risk of developing a secondary BCa or RCa. Competing risks analyses were used to compare CSS of primary vs. secondary BCa and RCa. A total of 198 184 men underwent RP and 190 536 underwent EBRT for PCa. The cumulative incidence of secondary BCa at 10 years was 1.71% for RP, and 3.7% for EBRT (p<0.001), while that of RCa was 0.52% for RP and 0.99% for EBRT (p<0.001). EBRT was associated with almost twice the risk of developing a secondary BCa and RCa compared to RP. The hazard of secondary BCa following EBRT delivered during 2003-2011 was 20% less than from 1995-2002 (p<0.09, Fine-Gray model), while that of secondary RCa was 31% less (p<0.001) (hazard ratio 0.78, p<0.001) for Fine-Gray and cause-specific hazard models. In the Fine-Gray model, the risk of death from BCa was 27% lower for secondary BCa after RP compared to primary BCa, while the risk of death was 9% lower for secondary BCa after EBRT compared to primary BCa. There was no difference in RCa-specific survival between primary or secondary RCa after RP or EBRT. The risk of BCa and RCa is almost twice as high for men undergoing EBRT for localized PCa vs. RP, but that risk is declining, likely reflecting advances in radiation delivery. The development of secondary RCa or BCa does not confer elevated risk of death compared to their primary counterparts.

Similar Overall Survival and Event-Free Survival for Patients Under or over the Age of 14 Years, but More Chronic Graft Versus Host Disease and Non-Relapse Mortality in the “Older” Patients

Purpose: In the prospective, randomized, multinational FORUM trial, total body irradiation and etoposide were statistically more effective than chemoconditioning (Peters et al, JCO 2021; FORUM study; EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). The multivariate analysis in this cohort showed an inferior overall survival (OS) for patients (pts) over the age of 10 years, HR 1.8 (95% CI, p=0.048). To update these findings, we examine the impact of age at allogeneic hematopoietic stem cell transplantation (HSCT), we analyzed 791 FORUM pts who received TBI and etoposide as conditioning regimen between April 2012 and March 2022 and compared their outcomes according to different age categories. Patients and Methods: Almost all patients were transplanted in second or first complete remission (CR2) (47%, n=370; CR1: 46%, n=361, &amp;gt;CR3: 8%, n=59), from matched unrelated donors (MUD) 70%, n=552, HLA-identical sibling donors (MSD) 30%, n=239, bone marrow (BM) 70%, n=551, or cord blood (CB) 3%, n=26. Median age at HSCT was 10 years (4-21). Median observation time was 2.3 years (0.3 to 8) (Table 1: Basic Characteristics). The conditioning regimen consisted of total body irradiation (TBI) - 6 fractions of 2 Gy on 3 consecutive days followed by 60 mg/kg body weight etoposide (max 1800 mg/m2, total upper dose limit 3.6 g). GVHD prophylaxis was CSA only for MSD receiving bone marrow. ATG/CSA/MTX was used for the MUD HSCT group. Results: 127 evaluable pts were transplanted between 4-6 years (group 1), 249 between 6-10 years (group 2), 231 between 10-14 years (group 3), and &amp;gt; 14 years were 184 pts (group 4) (n.s.) By the 4 age groups, the 5-year OS was 0.83±0.04 (group 1), 0.75±0.04 (group 2), 0.75±0.04 (group 3), and 0.74±0.04 (group 4), respectively, p = 0.133. Five-year event-free survival (EFS) was also similar for all age groups: 0.71 ± 0.06, 0.72 ± 0.04, 0.66 ± 0.05, 0.69 ± 0.04 (p=0.611): Figure 1. The three-year cumulative relapse incidences (CIR) were 0.23±0.04, 0.19±0.03, 0.14±0.03, and 0.17±0.03, respectively (p=0.286). Non-relapse mortality (NRM) was significantly lower in the two younger age groups (0.02 ± 0.01 group 1 and 0.05 ± 0.02 group 2) compared to 0.11 ± 0.02 in both older age groups (p = 0.047). The primary causes of death in the 18/184 pts in group 4 were as follows: infections (fungal, viral, bacterial): n=8, acute and chronic graft versus host disease (aGVHD, cGVHD): n=3, sinusoidal obstruction syndrome, coagulopathies: n=4, multi-organ failure: n=3. Among the 767 evaluable pts, 503 (66%) had no or grade1 aGVHD, 188 (25%) had grade 2 aGVHD, and 76 pts (11%) had grade3 to 4 aGVHD; in patients &amp;gt; 14 years 22 (14%) had a grade 3 to 4 aGVHD (p = 0.624). The 3-year incidence of extensive cGVHD was significantly higher in pts older than 14 years (0.21±0.03 vs. 0.10±0.03, 0.11±0.02 and 0.14±0.03, respectively), which also translated into significantly better extensive cGVHD-free, relapse-free survival (cGRFS) for the younger cohorts (Table 1). To date, the overall incidence of secondary malignancies in this cohort is 0.01 (n = 11) with no significant differences in the 4 age categories. In the age group &amp;gt; 14 years, in 98 pts transplanted in first CR vs. &amp;gt; CR1 (n=86), 5-year OS is 0.83±0.04 and 0.63±0.06, respectively (p=0.005). Similarly, 5-year EFS was 0.79±0.05 and 0.56±0.07, respectively (p=0.002). In multivariate analysis, OS, EFS, CIR was not influenced by donor type and pts' age at transplant. However, NRM was higher in pts older than 14 years, the hazard ratio (HR) being 4.8 (1.4-16; p=0.012) as compared to patients aged 4-6 years. Remission status (CR1 vs. &amp;gt;CR1) had significant impact on EFS with HR of 1.6 (1.1-2.1; p= 0.004) and CIR (HR 1.7; 1.1-2.4; p= 0.012). Conclusions: In the FORUM trial, patients who underwent allogeneic HSCT from HLA-identical or HLA-matched unrelated donors older than 4 years and younger than 21 years who received myeloablative conditioning with TBI/etoposide had similar overall and event-free survival regardless of age at HSCT. The incidence of chronic GVHD and NRM was higher in patients &amp;gt; 14 years compared to younger patients.

A Single-center Experience of Synchronous and Metachronous Hematologic and Oncologic Tumors

The incidence of cancer is increasing in the world. With the developments in cancer treatment, the life expectancy of patients is prolonged and the incidence of secondary malignancies is increasing. We retrospetively patients with syncronous / metachronous oncological malignancies accompanying hematological malignancies in a newly established hematology center. Data were obtained from the medical records. Demographic data, treatments and overall survival of the patients were evaluated. Twenty eight (6%) of 433 patients hematological malignancies were included in the study. 12 patients (42.9) were diagnosed with syncronous and 16 (57.1%) patients with metachronous hematologic-oncologic tumors. Sixteen of the patients were male,twelve were female. In syncronous tumors, the most common hematologic malignancy was Non-hodgkın lymphoma (NHL), while the most common oncologic malignancies were thyroid papillary cancer and colon cancer. In metachronous tumors, the most common malignancies were NHL and breast cancer. The median time between diagnosis of metachronous tumors was 49.5 months (8-192 months). The median survival of patients with syncronous malignancies was 19 months (SE=12.19) (95% CI 0-42.89), with metachronous malignancies was 22 months (SE=14.0) (95% CI 0-49.44). There was no statistically significant difference in the comparison of survival curves of patients with syncronous and metachronous malignancies (p=0.382). Oncological malignancies accompanying hematological malignancies are not uncommon. There is no standart treatment for syncronous / metachronous hematologic malignancies. In the presence of syncronous multipl malignancies should be evaluated individually.

BRAFV600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis

AbstractIn this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

RITUXIMAB‐CONTAINING COMBINED MODALITY THERAPY IN LIMITED STAGE FOLLICULAR LYMPHOMA: MATURE FOLLOW UP AND DERIVATION OF A NOVEL PROGNOSTIC SCORE FROM THE TROG99.03 TRIAL

Introduction: The TROG99.03 represents the only randomised phase III trial of combined modality therapy (CMT) in limited-stage follicular lymphoma ‘LSFL’, reporting a prolonged progression-free survival (PFS) in the CMT arm (MacManus, JCO, 2018). Here, we report extended follow up of this study providing mature data of patients treated with a rituximab-containing CMT regimen and the development of a new gene-expression based prognostic score. Methods: Patients with LSFL, grade 1–3a were randomised (1:1) to either involved-field radiotherapy alone (IFRT) (30–36Gy) or to CMT consisting of identical IFRT followed by 6 cycles of CVP. Reflecting evolving clinical practice, from 2006 onwards (i.e., ‘modern-era’), PET staging was increasingly utilised, and rituximab added to the CMT arm. Digital multiplex gene expression by Nanostring was performed on diagnostic biopsies based on genes previously identified to differentiate LSFL from advanced stage FL ‘ASFL’ (AM Staiger, Blood, 2020). Results: 150 patients were recruited between 2000 and 2012 with 31/75 patients in each arm recruited in the ‘modern-era’. At median follow-up 11.3 years, PFS remained superior for CMT compared to RT (HR 0.6; p = 0.043). Although no significant difference in OS was observed (HR 0.45, p = 0.11), compared with IFRT, patients in the CMT arm experienced fewer composite (deaths and histological transformation ‘HT’) events (HR 0.25; p = 0.045). With additional follow up no new non-malignant late toxicities were observed and incidence of secondary malignancies were similar between both arms (11 IFRT vs. 10 CMT, p = 0.99). Patients treated with a rituximab regimen (i.e., IFRT+R-CVP) had a markedly superior PFS compared to those treated without rituximab (i.e., IFRT, or IFRT+CVP), 8 year PFS rates 81% versus 52%, HR 0.42 p = 0.013 (Figure 1). Amongst PET staged patients the difference between R-CVP/IFRT versus IFRT increased (HR 0.35 p =0.027) suggesting this effect was not due to stage migration. No clinical factors were significantly associated with PFS on multivariate analysis. Nor were prognostic associations found for expression level of any individual genes. However, by penalised Cox regression an 8-gene Lasso-weighted prognosticator was identified, termed the ‘Bio-LSFL-score’. Genes (CACNA2D2, CD69, GZMB, IL7R, MYCT1, SLP1, TNFRSF14, TNFRSF25) reflected both B-cells and the microenvironment. The Bio-LSFL-score was highly significant for PFS (HR 0.25, p < 0.0001) with 100% patients in the high-risk group relapsing before 8 years. Conclusions: Particularly when incorporating rituximab, LSFL patients demonstrated significant increases in PFS and reduction in the rates of death and/or HT when treated with CMT compared with IFRT alone. A novel gene expression prognosticator was identified which in this trial cohort showed ‘ASFL-like’ behaviour by identifying LSFL patients unlikely to experience durable remissions. Keywords: diagnostic and prognostic biomarkers, indolent non-Hodgkin lymphoma, radiation therapy Conflicts of interests pertinent to the abstract C. Cheah Consultant or advisory role: Roche, Janssen, Gilead, Astra Zeneca, Lilly, TG Therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab, BMS Research funding: BMS, Roche, Abbvie, MSD, Lilly J. F. Seymour Consultant or advisory role: Abbvie, Astra Zeneca, Celgene/BMS, Genentech, Genor Bio, Gilead, Janssen, Morphosys, Roche, Sunesis, TG Therapeutics Research funding: Celgene/BMS M. K. Gandhi Research funding: Beigene, Janssen

ESCALATED BEACOPP X 2 + ABVD X 4 IS SUPERIOR TO ABVD X 6 IN ADVANCE STAGE CLASSICAL HODGKIN LYMPHOMA: EXPERIENCE IN A TERTIARY CENTER

Introduction: Classical Hodgkin lymphoma (cHL) is a curable disease but results in advanced stages are suboptimal when treated with standard treatment ABVD with 10%–15% of primary refractoriness and 30% of relapses, although 5 years overall survival (OS) around 88%–90%. First-line treatment with more intensive schemes such as escalated BEACOPP has improved progression-free survival (PFS) in these patients, although associating greater toxicity. However, escalated BEACOPP did not improve OS when compared to ABVD due to the efficacy of rescue treatments, but assuming a high toxic cost. We present our experience to optimize first-line treatment in advanced cHL. Methods: We retrospectively analyzed patients with advanced stage cHL (IIB-IV) treated with curative intent in our center between December 2008 and December 2022 (Table 1). In the period 2008–2011, patients were treated with ABVD x 6. During the period 2011–2022, we implemented a strategy intermediate PET guided (PET2) after escalated BEACOPP (x 2). With PET2 negative, we continued with ABVD/AVD x 4; in PET2 positive patients we continued with escalated BEACOPP x 4. Both groups received radiotherapy on bulky masses. We evaluate the efficacy of this strategy by comparing results and toxicity in the two study periods. Results: In the 2008–11 period, 21 patients received standard treatment with ABVD and during the 2011–22 period, 60 the intensified one (S). In PET2, 55 (91.6%) of patients in the intensified group achieved CR and 5 (8.4%) PR versus 5 (23.8%) CR, 14 (66.7%) PR and 2 (9.52%) refractory patients in the ABVD group. At the end of treatment, 58 patients (96.6%) achieved CR in the intensified treatment group and 15 (71.4%) in the ABVD group. There where 4 (19%) refractory patients in ABVD group versus 2 (3.3%) in the intensified group. PFS for the intensified treatment group was 90.8% at 5 years versus 57.1% for the ABVD group (p = 0.00025). OS for the intensified treatment group was 98.1% versus 85.7% for the ABVD group at 5 years (p = 0.01). The incidence of admissions for febrile neutropenia tended to be higher in the intensified group (15% vs. 4.76%, p = 0.44) and no significant differences were observed in the incidence of secondary malignancies or infertility. There were no toxic deaths in any group. Keywords: Hodkin lymphoma, PET-CT No conflicts of interests pertinent to the abstract.

Therapy results in pediatric Hodgkin lymphoma — does less mean better? Experience from a single children’s oncology center

Therapy results in pediatric Hodgkin lymphoma reflect remarkable progress in pediatric oncology. In the last decade, relevant development of new therapeutic options for children with refractory or relapsed disease has been made. In this study, we retrospectively analyzed therapy results and risk factors in children treated in a single oncology center according to five therapeutic protocols. Data from 114 children treated by a single institution between 1997 and 2022 were analyzed. Classic Hodgkin lymphoma therapy results were divided into four therapeutic periods: 1997–2009, 2009–2014, 2014–2019, and 2019–2022. For nodular lymphocyte-predominant Hodgkin lymphoma, data from one therapeutic protocol was analyzed. For the entire group, the 5-year probability of overall survival was 93.5%. There were no statistically significant differences between therapeutic periods. The occurrence of B symptoms at diagnosis and incidence of relapse were risk factors for death (p = 0.018 and p < 0.001). Relapse occurred in 5 cases. The 5-year probability of relapse-free survival for the entire group was 95.2%, without significant differences between groups. Patients treated between 1997 and 2009 had over a sixfold higher risk for events, defined as primary progression, relapse, death, or incidence of secondary malignancies (OR = 6.25, p = 0.086). The 5-year probability of event-free survival for all patients was 91.3%. Five patients died, and the most common cause of death was relapse. Modern therapeutic protocols in pediatric Hodgkin lymphoma are marked by excellent outcomes. Patients with disease relapses have a notably high risk of death, and the development of new therapeutic options for this group remains one of the main goals of current trials.

Deciphering the Patterns of Dual Primary Cases Registered at the Hospital-Based Cancer Registry: First Experience from Rural Cancer Center in North India.

Objectives The objective is to present the patterns of dual primary malignancies diagnosed at the Pathology Laboratory of Cancer Hospital with the support from hospital-based cancer registry (HBCR), Sangrur, Punjab, India for the years 2018 and 2019. Methods HBCR abstracts data from electronic medical records. Trained cancer registry staff abstracts cases in standard pro forma. Dual primary was coded as per the International Agency for Research on Cancer rule and was rechecked by the pathologist. Statistical Analysis Data about multiple primary was entered and documented in an Excel sheet. Time interval was calculated by subtracting the date of diagnosis for second primary and first primary. Results A total of 6,933 cases were registered, 45 cases are dual primary (26 females, 19 males) of which 64.4% are synchronous and 35.6% metachronous cases. Seventy-nine percent received cancer-directed treatment for synchronous and 87% for metachronous. The most common sites of the primary tumor were breast (33%), head and neck (22.2%), gynecological sites (11%), prostate (9%), esophagus (4%), and remaining other tumors (20.8%). Most common sites for second malignancies were gastrointestinal (GI) tract (31%), gynecological sites (18%), head and neck (16%), hematological malignancies (7%), soft tissue sarcoma (4%), breast (2%), and other sites (22%). Conclusion More than 70% of cases of primary tumors were in breast, head and neck, gynecological, and prostate. Of these, more than 60% of the second malignancy was found in the GI tract, gynecological, and head and neck sites. Around two-thirds of dual tumors are synchronous. Breast cancer cases have higher incidence of second malignancy. Regular follow-up is necessary to assess the survival of the second primary.

Long-Term Analysis of an Open-Label, Multicentre, Randomized Phase 3 Trial Comparing Busulfan Plus Cyclophosphamide Versus Busulfan Plus Fludarabine As a Preparative Regimen for Allogeneic Stem-Cell Transplantation in Patients with Acute Myeloid Leukemia

Background In a previous randomized trial performed by the Gruppo Italiano Trapianto di Midollo Osseo in AML patients (GITMO, AML-R2 study, Clinical Trial.gov number NCT01191957, Rambaldi A et al.: Lancet Oncology, 2015), we compared the combination of busulfan (3.2 mg/kg/die for four days) and fludarabine (160 mg/sqm) (BuFlu) with the conventional combination of busulfan and cyclophosphamide (120 mg/kg) (BuCy2). In this study, 252 AML patients with a median age of 52, undergoing allogeneic transplantation in first (n=213) or second (n=37) remission, from a sibling (n=114) or unrelated (n=138) donor were randomly assigned 1:1 to BuCy2 (n=125) or BuFlu (n=127). GvHD prophylaxis was based on cyclosporine-A and methotrexate; in case of unrelated donors, anti Thymocyte Globulin was given at a total dose of 5 mg/kg (or 7.5 mg/kg in case of HLA acceptable disparity). The 1-year non-relapse mortality (NRM) (primary endpoint of the study) of patients assigned to BuFlu proved significantly lower (7.9% in the BuFlu arm vs. 17.2% in BuCy2 arm, Gray's test p=0.026). There was no difference between the two arms in terms of cumulative incidence of relapse (CIR), leukemia free survival (LFS), overall survival (OS) at 1 and 2 years after transplant. Grade III-IV acute graft versus host disease (GvHD) was significantly higher in BuCy2 group (12 patients [10%]) than BuFlu group (3 patients [2%]). Hereby we present the long-term analysis of this clinical trial. Methods We collected data about the last follow up (dead/alive), the causes of death (NRM/disease relapse), the incidence of chronic GvHD (cGvHD) and current cGvHD therapy, the occurrence of disease relapse with the type of subsequent treatment including a second allogeneic transplant. We also searched for long-term side effects including cardiovascular events, secondary malignancies, other relevant medical events (i.e. infections, neurological or pulmonary events etc.). The Endpoints of the current analysis were NRM, CIR, LFS, OS, cumulative incidence of cGvHD, cumulative incidence of moderate/severe cGvHD, cGvHD and leukemia-free survival (GLFS). Results With a median follow up time for the whole study population of 6 years (range 0.03-13), the 4-years NRM is 10% in BuFlu arm vs 20% in BuCy2 arm (P= 0.0388). The 4 and 10-years CIR was not statistically different in both arms (36% vs. 33% in in BuFlu and BuCy2, and 39% vs 37% in BuFlu vs. BuCy2 arm). Similarly, we did not observe any difference in terms of 4-years LFS (53% vs 47% in BuFlu and BuCy2 arm, respectively), OS (56% in both arms) and cumulative incidence of moderate/severe cGvHD (14% in BuFlu arm vs 19% in BuCy2 arm). The 4-years GLFS was 35% in BuFlu arm vs 24% in BuCy2 (P= 0.0602). The incidence of secondary malignancies was not different in the two study groups (16 events, 7 in BuCy2 arm and 9 in BuFlu arm). Conclusion: This long-term analysis confirms the benefit in terms of NRM associated with the BuFlu conditioning which was not associated to a higher incidence of late leukemia relapse. We found a better trend in GLFS in BuFlu arm, most likely due to a lower rate of grade III/IV acute GvHD in the experimental arm. Although we did not observe any difference between the two arms, CIR was stable and high (40% in both arms at 10 years) throughout the observation period. Therefore, AML relapse remains the major concern, urging the development of new therapeutic interventions driven by post-transplant MRD monitoring and pre-emptive therapies in high-risk patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Impact of Radiation Therapy on the Incidence of Second Malignant Neoplasm among Adolescent and Young Adult Cancer Survivors

<h3>Purpose/Objective(s)</h3> The risks of second malignancy, including radiation-associated malignancies, are well described in adult populations as well as among pediatric patients. Adolescents and young adults (AYA) are a vulnerable population in which the risks of late effects may be increased relative to older adult patients but are not fully characterized. We sought to investigate the incidence second malignant neoplasm among AYA patients and hypothesize that receiving radiation therapy is associated with increased risk of secondary cancers in this population. <h3>Materials/Methods</h3> The Surveillance, Epidemiology, and End Results (SEER) Research Plus database was queried for patients age 15-39 who survived at least 5 years after diagnosis of a solid-tumor primary malignancy between 1975-2017. Descriptive statistics were obtained and univariate comparisons were performed using ANOVA and chi-square test. The 15-year cumulative incidence of second malignant neoplasm (SMN) was calculated among AYA patients overall, among those who did vs did not receive radiation therapy, and across other significant variables. A multivariable model was created to assess the effect of receiving radiation therapy on the risk of SMN when adjusting for age, sex, decade of diagnosis, and disease. <h3>Results</h3> A total of 159,829 AYA patients with ≥5-year survival were included, 31.1% of whom received radiation therapy. Median follow up among the entire cohort was 17 years (range, 5-43 years). The cumulative incidence of SMN among all AYA patients at 15 years was 5.6%. The cumulative incidence of SMN at 15 years was significantly increased among AYA patients who received radiation therapy as part of their definitive treatment (6.6% with radiation therapy versus 5.1% without, p<0.001). Cumulative incidence of SMN was also affected by sex, age, decade of initial diagnosis, and AYA primary cancer diagnosis (see Table 1). On multivariable analysis, patients who received radiation therapy remained more likely to develop a second malignancy than those who did not (HR 1.4, p<0.001). <h3>Conclusion</h3> This study uses national data to report the incidence of second malignancy among adolescents and young adults diagnosed with cancer. Receiving radiation therapy was associated with an increase in SMN at 15 years, with an absolute increase of 1.5% and HR of 1.4 compared to those who did not receive radiation. These results provide an important reference for counseling patients regarding risks of treatment and should guide further efforts to improve treatment delivery and outcomes among this vulnerable population.

Incidence of Secondary Malignancy and Other Late Effects after Proton Radiotherapy for Retinoblastoma

<h3>Purpose/Objective(s)</h3> Radiotherapy is an important treatment modality for retinoblastoma (RB), an often-inherited pediatric cancer. Proton radiotherapy (PRT) is an infrequently used treatment modality for RB, and the late effects, particularly secondary malignancies, after PRT remain not well described. <h3>Materials/Methods</h3> We conducted an Institutional Review Board-approved retrospective cohort analysis of RB patients who received PRT from 1987-2011 at a major tertiary center. We recorded clinical and treatment characteristics, outcomes, and toxicities, including secondary malignancies. Follow-up time was calculated from the end of RT. Survival outcomes were analyzed using Kaplan-Meier method. <h3>Results</h3> We identified 60 patients who received PRT for RB, with 107 eyes diagnosed and 75 eyes receiving PRT. Median age was 0 years (range: 0.02-11) at diagnosis and 1 year (range: 0.2-12) at time of RT. International Classification for Intraocular Retinoblastoma (ICIR) Staging has 44.1% of patients in stages A-C, 37.3% of patients in stage D, and 18.6% of patients in stage E. Median follow-up time was 11.5 years (range: 0.02 - 34.4). No patients had follow-up beyond age 40. 10-year overall survival was 100%. 42 patients kept 50 irradiated eyes (67% of PRT-treated eyes) throughout follow-up. 3 (5%) patients were found to have secondary malignancies outside of the RT field: bladder cancer, localized melanoma on the left shoulder, and osteosarcoma in the left femur; none were found within the RT field. The patient with secondary osteosarcoma had a history of familial Rb1 mutation and ultimately passed due to her osteosarcoma after 14 years. Ocular changes were the most common side effects observed in follow-up. 13 patients developed cataracts (21%); 13 patients (21%) experienced considerable vision loss unrelated to cataracts. 5 patients (8.3%) were noted to have radiation retinopathy. 2 patients (3.2%) noted hearing decrease after completing treatment; notably both received carboplatin. No other non-ocular neurological sequelae were noted. <h3>Conclusion</h3> With a median follow-up of 11.4 years, we found no patients with secondary malignancies in the PRT field. Our findings suggest that PRT is effective and reasonably safe and that other factors, such as systemic chemotherapy and genetic Rb mutation, likely continue to contribute to secondary cancer risk. Patients remain at risk for development of cataracts and vision loss after PRT, though other components of treatment may also play a role. Prospective comparisons with photon cohorts with long-term follow-up are needed to determine the risks and benefits of PRT.

Risk of secondary malignancy after radiotherapy for breast cancer: long-term follow-up of Japanese patients with breast cancer

PurposeThere have been very few reports of secondary malignancies after breast cancer treatment in Asia, particularly in Japan. This study aimed to evaluate the risk of secondary malignancies after radiotherapy (RT) in Japanese breast cancer patients.MethodsThis single-center retrospective study included patients who underwent RT between July 1961 and September 2006 for postoperative breast cancer. A total of 702 patients with a follow-up period of more than 5 years were analyzed. All malignancies observed at more than 5 years after the start of RT were defined as secondary malignancies. To calculate the relative risk (RR) of secondary malignancies, we applied data from the National Cancer Center in Japan.ResultsThe median observation period was 9.7 (interquartile range 7.1–18.2) years. The cumulative person-years of observation were 6879.4. The RR of contralateral breast cancer increased by 1.85-fold (95% confidence interval [CI] 1.05–3.26) among patients compared with that among the general population; however, the difference was not significant (p = 0.053). The RR of secondary malignancies other than breast cancer increased by 2.71-fold (95% CI 1.99–3.70, p < 0.001) among the patients compared with the general population. Even when only malignancies detected more than 10 years after RT were defined as secondary malignancies, the RR of secondary malignancies other than breast cancer was 1.91 (95% CI 1.33–2.73, p < 0.001).ConclusionThe incidence of secondary malignancies after RT may be somewhat higher in Japanese patients with breast cancer than in the general population.

P1375: SECOND PRIMARY MALIGNANCY AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background: Hematopoietic stem cell transplantation is a curative treatment for a variety of hematologic malignancies and some benign hematologic diseases. Besides chronic GVHD, second primary malignancy is also one of long-term adverse effect. Aims: We analyze the incidence and type of second malignancy in a single institute in 20 years. Methods: We retrospectively searched our post-transplant patients long-term follow up data between 2001 and 2021 and analyzed the incidence and pattern of second primary malignancy in our cohort. Results: Between 2001 and 2021, in our 380 patients cohort (184 auto- and 196 allo-transplant) with long-term survival 126 (68%) in autologous and 100 (51%) in allogeneic transplant, we had 12 patients of second primary malignancy including 5 of head and neck squamous cell carcinoma, 3 of MDS/AML, 1 of ALL, 1 of esophageal squamous cell carcinoma, 1 of breast cancer, and 1 of papillary thyroid cancer. Eight of them underwent allogeneic hematopoietic stem cell transplant had head and neck SCC, esophageal cancer, breast cancer, and papillary thyroid cancer. Four of whom underwent autologous transplant are MDS/AML and ALL. All 5 patients with head and neck cancer and one esophageal cancer patients had extensive chronic GVHD. Ten of our patients survived with 8 free of disease and one low risk MDS and one AML undergoing treatment. One hypo-pharyngeal and one esophageal cancer passed away after definitive cancer treatment. The accumulative incidence of second malignancy was 6% in 10 years and 16% in 19 years and post-autologous and post-allogeneic transplant were 5% vs 7% and 15% vs 17% in 10 years and 19 years, repectively. Image:Summary/Conclusion: Second primary malignancy in 20-year follow-up in our post-transplant cohort was 6% and 16% in 10 years and 19 years, respectively, and extensive chronic GVHD is associated with head and neck and esophageal squamous cell carcinoma.

Effect of adjuvant chemotherapy on periosteal osteosarcoma: a systematic review.

The effects of adjuvant chemotherapy on periosteal osteosarcoma are controversial. Therefore, we conducted a systematic review of studies comparing mortality, local recurrence, distant metastasis and secondary malignancy incidence among patients who underwent surgery and (neo-) adjuvant chemotherapy or surgery alone for periosteal osteosarcoma without distant metastases at diagnosis. Of the 210 studies identified in the search, 13 were included in this study, involving 291 patients with periosteal osteosarcoma in total. The mortality rates in the surgery and (neo-) adjuvant chemotherapy and surgery alone groups were 11.3% (8/71) and 16.3% (16/98), respectively. The overall pooled odds ratio was 0.89 (P=0.800). The local recurrence rate in the surgery and (neo-) adjuvant chemotherapy group was 12.1% (8/66), while that in the surgery alone group was 17.6% (13/74). The overall pooled odds ratio was 1.31 (P=0.601). The distant metastasis rate in the surgery and (neo-) adjuvant chemotherapy group was 15.2% (10/66) and that in the surgery alone group was 10.8% (8/74). The overall pooled odds ratio was 1.51 (P=0.444). The incidence of secondary malignancy in the surgery and (neo-) adjuvant chemotherapy group was 7.6% (9/118) and that in the surgery alone group was 2.7% (2/74). The overall pooled odds ratio was 2.29 (P=0.187). Adjuvant chemotherapy did not appear to improve the prognosis of patients with periosteal osteosarcoma. No association was found between the use of adjuvant chemotherapy and development of secondary malignancies.

92 - Incidence of Secondary Malignancies after Total Body Irradiation-Based Allogeneic HSCT in Children with ALL – Long-Term Follow-up from the Prospective ALL-SCT 2003 Trial

92 - Incidence of Secondary Malignancies after Total Body Irradiation-Based Allogeneic HSCT in Children with ALL – Long-Term Follow-up from the Prospective ALL-SCT 2003 Trial

Second Cancers in Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma: A Systematic Review by the Fondazione Italiana Linfomi.

Simple SummaryWith the presented study, the FIL researchers aimed to fill a gap in the literature regarding long-lived lymphoma patients, at least 5 years after lymphoma. These patients can develop a series of late sequelae that affect their quality of life and overall survival, in particular cardiotoxicity and secondary malignancies. This systematic review conducted by FIL researchers aimed to understand the incidence of second malignancies, consider the impact of novel therapies, and examine the best follow-up policies for their early detection. On the basis of the evidence, individualized primary risk prevention strategies are suggested, depending on the dose and volume of radiation, chemotherapy, age at treatment, and predisposing factors. When evidence was either lacking or not definitive, expert opinion was used to identify a screening schedule. Background: The increase of lymphoma patient survival led to a modification of the incidence of long-term sequelae, including second malignancies (SM). Several groups have dealt with the incidence of SM, according to the primary treatment; however, a standardized approach for the early detection and screening of SM in the population of lymphoma survivors should be implemented. Methods: A systematic review was conducted by Fondazione Italiana Linfomi (FIL), in order to define the incidence of SM, the impact of modern radiotherapy on SM risk, and the usefulness of tailored follow-up and screening strategies for early diagnosis of SM. Classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) survivors were investigated. The MEDLINE, Embase, and Cochrane Library databases were checked for relevant reports published up to January 2020. The selection process was reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Results: A total of 27 full-text manuscripts resulted as eligible for the analysis. The incidence of SM in cHL patients treated with ABVD was higher compared to the general population and was even higher in patients treated with intensified regimens. The risk increased over time, as well as after 10–15 years from therapy, and was augmented by radiotherapy exposure. In DLBCL, more intensive regimens (i.e., R-CHOEP or R-MegaCHOEP) vs. R-CHOP were associated with a higher SM incidence. Salvage chemotherapy and autologous stem cell transplants increased the risk of SM in both cHL and DLBCL cohorts. A lower incidence of SM, particularly of breast cancer (BC), was shown in cohorts of cHL survivors treated with reduced radiation volumes and doses (involved fields vs. extended fields), but robust trials are still lacking. Considering the advantage of a structured screening for early detection of SM, all the included studies regarded cHL survivors and screening strategy for early BC detection. Moreover, the authors discuss additional papers, to guide the early diagnosis of lung, colorectal, skin, and thyroid cancer in patients at risk due to family history, drug or RT exposure, or unhealthy lifestyles. These screening strategies all passed through patient awareness. Conclusion: A modern approach to chemotherapy and radiotherapy led to a lower risk of SM, which should be confirmed over time. Early detection of secondary cancers could be achieved through a tailored screening program, according to the individual risk profile.