Development Of Second Primary Malignancies Research Articles

Exploring the risk of second primary malignancies in laryngeal cancer survivors: insights from the SEER database.

We intended to investigate the risk for second primary malignancy (SPM) development in Laryngeal Cancer (LC) survivors. We conducted a population-based analysis of SPM risk using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Data of selected LC survivors from the SEER database between 2000 and 2020 were examined. Standardized Incidence ratios (SIRs) for SPM development were calculated, followed by detailed stratification according to anatomical site and different latency periods. A total of 8413 SPMs were observed in our extracted cohort. The collective standardized incidence of SPMs was 2.12 (95% CI 2.07-2.17) compared to the US population, with an absolute excess risk (AER) of 201.73 per 10,000 individuals. The highest SPM risks were observed in patients with young age at diagnosis, females, and American Indians/Alaska natives. Increased SPM risks were reported in patients receiving all modalities of treatment including surgery, chemotherapy, and radiotherapy. Most SPMs were detected in solid organs such asthe lungs and bronchus, oral cavity and pharynx, and prostate. The highest increased risks of developing SPMs were observed in Trachea, larynx, oral cavity and pharynx, lung and bronchus, and esophagus. The risk of SPMs in LC survivors was significantly increased compared to the general US population. Accordingly, a more impactful cancer surveillance strategy for LC patients should be implemented.

Prognosis of Second Primary Malignancies in Pediatric Acute Lymphoblastic Leukemia Survivors: A Multicenter Study by the Turkish Pediatric Hematology Society.

The improved survival rates of childhood cancers raise the long-term risk of second primary malignancy (SPM) in childhood and adolescent cancer survivors. The intensity of the treatment protocol used, the use of some groups of chemotherapeutics, and radiotherapy were found to be risk factors for the development of second primary malignancies (SPMs). Forty-one patients who developed acute myelocytic leukemia or any solid organ cancer within 25 years of follow-up, after completion of pediatric acute lymphoblastic leukemia (ALL) treatment, were included in the study. The mean duration of initial ALL diagnosis to SPM was 9.3 ± 6.1 years. The 3 most common SPMs were acute myelocytic leukemia, glial tumors, and thyroid cancer. Thirteen (81%) of 16 patients exposed to cranial irradiation had cancer related to the radiation field. In total 13/41 (32%) patients died, and the 5-year overall survival rate was 70 ± 8%. Patients older than 5 years old at ALL diagnosis had significantly worse overall survival than cases younger than 5 years old. In conclusion, children and adolescents who survive ALL have an increased risk of developing SPM compared with healthy populations, and physicians following these patients should screen for SPMs at regular intervals.

Incidence, risk and prognosis of second primary malignancy of patients with gastric adenocarcinoma

Due to the long-term low survival rates of gastric adenocarcinoma (GAC) patients, the occurrence and prognosis of second primary malignancies (SPMs) are often underreported and overlooked as a significant concern.To date, only a few studies have addressed this issue in the context of GAC. These studies, however, are limited by their small patient cohorts and lack of substantial, meaningful findings. Our study aims to fill this gap by investigating the incidence, risk factors, and prognostic significance of SPMs among GAC survivors. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we analysed data from patients diagnosed with GAC between 2000 and 2020. The study employs the standardized incidence ratio (SIR) to assess the relative risk of SPMs, competing risk regression to identify risk factors for SPM development after GAC, and Kaplan-Meier and COX regression analyses for survival outcomes. Out of 44,041 GAC patients analyzed, 2,032 (4.3%) developed SPMs, with a median latency period of 36 months. The incidence of SPMs was significantly higher in GAC patients (SIR 1.36, 95% CI 1.32-1.4, EAR 53.57) compared to the general population. Key factors including older age, sex, tumor grade, summary stage, and history of surgical and radiation therapy were related to the higher risk of developing SPMs following GAC. Interestingly, GAC patients without SPMs exhibited poorer overall survival compared to those with SPMs. Age, summary stage, and surgical history were identified as independent prognostic factors for GAC patients with SPMs. This comprehensive analysis underscores the necessity of vigilant monitoring and tailored follow-up for SPMs in GAC survivors, highlighting the study's contribution to enhancing GAC survivors care strategies.

Assessment of second primary malignancies among treated and untreated patients with chronic lymphocytic leukemia using real-world data from the USA.

Aim: Improved management of chronic lymphocytic leukemia (CLL) has resulted in a growing population of CLL survivors; these patients have a higher risk of developing second primary malignancies (SPMs) versus the general population. This retrospective cohort study aims to assess the timing, frequency, incidence and types of SPMs in treated and untreated patients with CLL in the USA, using the Surveillance, Epidemiology, and End Results (SEER) Medicare database, which links a nationally representative cancer registry with Medicare claims data. Patients & methods: Patients aged ≥66years with newly diagnosed CLL between 1January2010 and 31December2016, who were enrolled in Parts A and B of Medicare for ≥12months pre-diagnosis of CLL were selected from the database. Patients were assessed for ≥36months until the end of continuous enrollment in Medicare Parts A, B and D, a switch to a health maintenance organization, death, or end of the study period (December2019). Results: Of 3053 patients included in the analyses, 620 (20.3%) were treated and 2433 (79.7%) were untreated within 36months of diagnosis. Overall, 638 (20.9%) patients developed a SPM, 26.8% of patients in the treated cohort and 19.4% of patients in the untreated cohort. The most common SPMs for both cohorts were squamous cell carcinoma and acute myeloid leukemia. Among the 166 treated patients who developed a SPM, a greater proportion developed their first SPM after treatment initiation versus those who developed their first SPM prior to treatment initiation (p<0.001). A significantly lower percentage of patients who received targeted therapy developed a SPM (p<0.05) versus patients treated with anti-CD20+ chemotherapy. Conclusion: Findings indicate that treatment type and timing can affect SPM development in patients with CLL. Combined with previous findings, this can help inform best practices in monitoring for SPM in patients with CLL.

Lifetime risks of second primary malignancies after pediatric Hodgkin lymphoma and non-Hodgkin lymphoma

ObjectivesSurvivors after pediatric Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are with lifetime risk for second primary malignancy (SPM). This necessitates a thorough analysis to better understand the potential long-term health implications for these individuals.MethodsWe used a US-wide population-based cancer registry data to quantify the SPM risk and identify its incidence patterns among pediatric lymphoma patients.ResultsWe observed 4.74-fold (95% CI 4.27–5.25) and 3.40-fold (95% CI 2.78–4.10) increased risks of SPM in survivors after pediatric HL and NHL, respectively. Through over 40 years’ follow-up, the cumulative incidence of SPM for pediatric lymphoma was persistently increasing, and here we firstly report the high 40-year cumulative incidence rates of SPM, 22.2% for HL and 12.6% for NHL, suggesting that SPM accounts for a great proportion of deaths among survivors. Of 6805 pediatric lymphomas, 462 (6.36%) developed a SPM, especially second breast and thyroid cancer, followed by hematologic neoplasms including leukemia and NHL. The competing risk analysis demonstrated gender, lymphoma subtype and radiotherapy were significantly associated with SPM. Different risk patterns of SPM were identified between pediatric HL and NHL. Chemotherapy accelerated SPM development but did not increase its incidence risk.ConclusionOverall, patients after pediatric lymphoma can be with high lifetime risk of SPM, and more attention should be paid to SPM-related signs for early detection and intervention.

IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.

Second primary malignancies: A clinicopathological study from a tertiary care centre

Abstract Background: Second primary malignancy (SPM) is defined as a second de novo malignant neoplasm arising in a patient with known primary malignancy. SPM is common and can occur synchronously or metachronously. Methods: We retrospectively studied the epidemiological factors, patterns of occurrence and common associations of SPMs seen in our Department of Pathology during the period January 2016 and December 2020. The case details were retrieved from the medical records. SPM were diagnosed as per the International Association of Cancer Registries and International Agency for Research on Cancer criteria. Results: During the study period, 22 cases were seen. Their age ranged from 36 to 80 years; females had outnumbered males (female:male = 3.4:1). The most common site for metachronous primary was breast and the most common site for SPMs was head and neck. The median age for diagnosis of metachronous SPM was 59.2 years (range 41–80 years). The time interval for development of metachronous SPMs ranged from 6 months to 9 years. Conclusions: Our observations suggest that increased awareness regarding the entity and regular follow-up of patients can aid in early diagnosis of SPMs.

The Impact of Epstein-Barr Virus Infection on Second Cancer Development in Newly Diagnosed Myeloma Patients Treated with Lenalidomide in the UK NCRI Myeloma XI Trial

Background Several factors have been linked to second primary malignancy (SPM) development in myeloma patients, including advanced age, immunocompromise and therapy, such as melphalan and lenalidomide (len). The impact of infection, including EBV is yet to be elucidated. Here we address this in the context of the UK NCRI Myeloma XI Trial for newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len maintenance treatment in TE and TNE patients. TE patients received high dose melphalan supported by autologous stem cell transplantation (ASCT). Patients in both pathways were randomised to maintenance with len or observation. In total, 4358 patients entered. Planned SPM analysis was conducted in May 2019, with 318 patients developing an SPM prior to that point. Median follow-up from trial entry was 60 months (IQ range 47-76). A nested cohort analysis was performed to determine EBV infection and immunity status in 170 SPM patients for which serum samples were available. Forty-two trial patients who did not develop an SPM were used as a control group. EBV assessment time-points included pre-induction, post induction, 4 months post ASCT (TE only) and 1 year post induction. Peripheral blood serum samples were tested for EBV EBNA IgG Antibody/index (LIAISON®), EBV VCA IgM Antibody/Index (LIAISON®) and EBV positivity was determined using the artus® EBV RG PCR Kit from Qiagen. Active or recent EBV infection was evidenced by a positive EBV IgM antibody and/or EBV PCR. Results Of the 170 patients, 208 SPM were noted with 147 patients developing 1 SPM and 23 patients developing ≥2. One hundred and five patients developed an SPM following maintenance randomisation, with 76 receiving len and 29 being observed. The remaining 65 patients developed an SPM prior to maintenance. Eighty-four SPMs were diagnosed in 68 TE patients and 124 SPMs in 102 TNE patients. Of the 170 SPM patients, 8 had evidence of recent or active infection at the time of testing, evidenced by either IgM EBV antibodies (n=5), positive EBV PCR (n=2) or both (n=1). The median EBV DNA copies/ml was 353 (range 337-428). The median IgM antibody titre was 71.5U/ml (26 - &amp;gt;160). No patients in the control group had evidence of recent EBV infection (p=0.36). Of the 8 patients with evidence of EBV infection, 6 developed &amp;gt;1 SPM, Table 1. Five had been treated in the TE pathway, with all developing post maintenance randomisation, and 4 of the 5 receiving len maintenance. None of the 3 TNE patients received len maintenance, with 2 developing an SPM prior to maintenance randomisation. The median time from EBV testing to SPM diagnosis was 17·9 months (0.5-51.7). Two of the EBV positive patients developed a haematological SPM: myelodysplastic syndrome and Hodgkin lymphoma. Four patients developed a solid malignancy: lung, breast, ovary, and colon. The remaining cases were non-melanoma skin cancers, Table 1. Immune status (EBV IgG) was also determined. In TE patients, the median EBV IgG titre was 65.3U/ml at diagnosis (&amp;lt;3 - 600, n=48), falling to 28.1U/ml following induction (&amp;lt;3 - 326, n=41) and recovering to 44.2U/ml one year post ASCT (&amp;lt;3 - 600, n=22). In TNE patients, the median IgG titre at diagnosis was 39.1U/ml (&amp;lt;3 to 517, n=72), falling to 31.2U/ml 4 months post induction (&amp;lt;3 - 287, n=42) and recovering to 51.3U/ml after 1 year (&amp;lt;3 - 554, n=41). In the SPM patients the IgG EBV titres were noted to be &amp;lt;20U/ml in 5 of the 8 patients. Three of the eight patients had no detectable EBV IgG level (&amp;lt;3U/ml) Conclusions These data suggest that EBV infection is unlikely to be a risk factor for SPM development in myeloma patients. This is supported by the finding that EBV IgG titres were consistent with immunity in most patients (&amp;gt;20U/ml) and even in the patients with possible EBV infection, EBV DNA was only identified in 3 patients, and at a low level. In addition, the SPM developed are not classically associated with EBV infection or reactivation. It is noted that EBV infection status was not always determined at the time of SPM development. Despite this, the data does show that EBV immunity recovers following therapy, even in the post ASCT setting. EBV monitoring is therefore not supported by this work, although in patients who develop ≥2 SPM, further clarification is required.

Maintenance lenalidomide in newly diagnosed transplant eligible and non-eligible myeloma patients; profiling second primary malignancies in 4358 patients treated in the Myeloma XI Trial

Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan. Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively. In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p=0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p=0.10).The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p=0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients.Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n=25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients.Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed. This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes. Primary financial support was from Cancer Research UK [C1298/A10410].

Impact of second primary malignancy post-autologous transplantation on outcomes of multiple myeloma: a CIBMTR analysis.

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n= 3948). At a median follow-up of 37months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P< .001 and HR 5.01, P< .001, respectively) and OS (HR 3.85, P< .001 and HR 8.13, P< .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.

The Effects of Second Primary Malignancies and Frailty on Overall Survival and Mortality in Geriatric Turkish Patients with Multiple Myeloma.

The study aims to investigate second primary malignancy (SPM) development and frailty in Turkish geriatric patients with multiple myeloma (MM) and to assess the relationship between overall survival (OS) and various characteristics including SPM and frailty. Seventy-two patients diagnosed with and treated for MM were enrolled in the study. Frailty was determined by the IMWG Frailty Score. Fifty-three participants (73.6%) were found to have clinically-relevant frailty. Seven patients (9.7%) had SPM. Median follow-up was 36.5 (22-48.5) months, and 17 patients died during the follow-up period. Overall (OS) was 49.40 (45.01-53.80) months. Shorter OS was found in patients with SPM (35.29 (19.66-50.91) months) compared to those without (51.05 (46.7-55.4) months) (Kaplan-Meier; p = 0.018). The multivariate cox proportional hazards model revealed that patients with SPM had 4.420-fold higher risk of death than those without (HR: 4.420, 95% CI: 1.371-14.246, p = 0.013). Higher ALT levels were also independently associated with mortality (p = 0.038). The prevalence of SPM and frailty was high in elderly patients with MM in our study. The development of SPM independently reduces survival in MM; however, frailty was not found to be independently associated with survival. Our results suggest the importance of individualized approaches in the management of patients with MM, particularly with regard to SPM development.

Time-varying association of second primary malignancy and long-term survival outcomes in patients with head and neck cancer.

A high risk of developing second primary malignancy (SPM) has been reported among head and neck cancer patients. Here, we aimed to statistically quantify the impact of SPM development on the survival of head and neck cancer patients. Our study was conducted using the Surveillance, Epidemiology and End Results database to collect the data of 48 316 patients who received curative surgical resection for initial primary head and neck squamous cell carcinoma (IP-HNSCC) in 1975 to 2019. SPM diagnosis was treated as a time-varying covariate and multivariable Cox regression analysis was conducted to estimate the association between SPM development and survival, overall or by the subsite of IP-HNSCC. Of the included patients, 11 238 patients (23.3%) developed SPM during the follow-up period. A significant reduction in survival was observed among patients with SPM (hazard ratio [HR] for overall survival, 3.30; 95% confidence interval [CI]: 3.20-3.41). The impact of SPM development on reduced survival was more significant in patients with localized IP-HNSCC vs regional IP-HNSCC (HROS , 3.41; 95% CI: 3.24-3.6 vs HROS , 3.18; 95% CI: 3.05-3.31; P for interaction <.001). The survival impact of SPM development was more evident in younger patients than in older patients. SPM in lung and bronchus was associated with the most pronounced reduction in survival, overall and across all subsites of HNSCC. Our results indicated that SPM development led to a significant reduction in survival. A greater survival benefit may be achieved through intensive surveillance for SPM in lung and bronchus targeting younger patients and those with localized HNSCC.

Incidence and risk outcomes of second primary malignancy of patients with post-operative colorectal cancer

This study aimed to investigate the incidence and the risk factors of incidence for second primary malignancies (SPMs) onset among survivors diagnosed with colorectal cancer (CRC). A large population-based cohort study was performed. Data of patients diagnosed with CRC was identified and extracted from 8 cancer registries of Surveillance, Epidemiology, and End Results database from January 1990 to December 2017. The outcome of interest was percentage and common sites of SPM onset after primary CRC diagnosis. The cumulative incidence and standardize incidence rates (SIRs) were also reported. Afterwards, we estimated sub-distribution hazards ratios (SHRs) and relative risks (RRs) for SPM occurrence using multivariable competing-risk and Poisson regression models, respectively. A total of 152,402 patients with CRC were included to analyze. Overall, 23,816 patients of all CRC survivors (15.6%) were reported SPM occurrence. The highest proportion of SPMs development after primary CRC diagnosis was second CRC, followed by lung and bronchus cancer among all survivors. Also, CRC survivors were more susceptible to develop second gastrointestinal cancers (GICs). Besides, pelvic cancers were analyzed with a relative high proportion among patients who received RT in comparison to those without RT. The cumulative incidence of all SPMs onset was 22.16% (95% CI: 21.82-22.49%) after near 30-year follow-up. Several factors including older age, male, married status, and localized stage of CRC were related to the high risk of SPMs onset. In treatment-specific analyses, RT was related to a higher cumulative incidence of SPMs occurrence (all SPMs: 14.08% vs. 8.72%; GICs: 2.67% vs. 2.04%; CRC: 1.01% vs. 1.57%; all p < 0.01). Furthermore, the increased risk of SPMs onset was found among patients who received RT than patients within the NRT group (SHR: 1.50, 95% CI: 1.32-1.71), p < 0.01; RR: 1.61, 95% CI: 1.45-1.79, p < 0.01). The present study described the incidence pattern of SPM among CRC survivors and identified the risk factors of the SPM onset. RT treatment for patients diagnosed with CRC may increase the risk of SPMs occurrence. The findings suggest the need for long-term follow-up surveillance for these patients.

Risk of second primary malignancies in patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019

The longevity of patients with chronic lymphocytic leukemia (CLL) has improved progressively over the past decades, making it essential to understand long-term health outcomes, such as second primary malignancies (SPMs). Therefore, this nationwide, population-based study assessed the risk of SPM development in CLL patients diagnosed during 1989-2019 in the Netherlands compared to the expected number of malignancies in an age-, sex-, and period-matched group from the general Dutch population. In 24,815 CLL patients followed for 162,698.49 person-years, 4369 SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.63 (95% confidence interval [CI] 1.59–1.68). This elevated risk was observed for solid (SIR, 1.67; 95% CI, 1.65–1.75) and hematological SPMs (SIR 1.42; 95% CI, 1.24–1.62). The highest risk for SPMs was noted beyond five years post-diagnosis (SIR, 1.70; 95% CI, 1.62–1.77), for male individuals (SIR, 1.70; 95% CI, 1.64–1.77), and patients aged 18–69 years (SIR, 1.92; 95% CI, 1.79–2.05). The risk of SPMs was higher in CLL patients who received anti-neoplastic therapy (SIR, 2.12; 95% CI, 1.96–2.28), as compared with those who did not (SIR, 1.58; 95% CI, 1.53–1.63). Routine surveillance activities and tailored interventions to counteract the increased morbidity and excess mortality associated with SPMs are essential for improving long-term outcomes in CLL patients.

Association between radiotherapy and risk of second primary malignancies in patients with resectable lung cancer: a population-based study

BackgroundThe most common form of treatment for non-metastatic lung cancer is surgery-based combination therapy, which may also include adjuvant radiotherapy or chemotherapy. Second primary malignancies (SPMs) are uncommon but significant radiation side effects in patients with resectable lung cancer, and SPMs have not been adequately investigated. Our study aims to assess the correlations of radiotherapy with the development of SPMs in patients with resectable lung cancer.MethodsWe screened for any primary malignancy that occurred more than five years after the diagnosis of resectable lung cancer. Based on the large cohort of the Surveillance, Epidemiology and End Results database, radiotherapy-correlated risks were estimated using the Poisson regression analysis and the cumulative incidence of SPMs was calculated using Fine-Gray competing risk regression analysis.ResultsAmong the 62,435 patients with non-metastatic lung cancer undergoing surgery, a total of 11,341 (18.16%) patients have received radiotherapy. Our findings indicated that radiotherapy was substantially related to a high risk of main second solid malignancies (RR = 1.21; 95%CI, 1.08 to 1.35) and a negligible risk of main second hematologic malignancies (RR = 1.08; 95%CI, 0.84 to 1.37). With the greatest number of patients, the risk of acquiring a second primary gastrointestinal cancer was the highest overall (RR = 1.77; 95 percent CI, 1.44 to 2.15). The cumulative incidence and standardized incidence ratios of SPMs revealed similar findings. Furthermore, the young and the elderly may be more vulnerable, and the highest risk of acquiring most SPMs was seen more than ten years after lung cancer diagnosis. Additionally, more attention should be paid to the second primary gastrointestinal cancer in young individuals with resectable lung cancer.ConclusionAfter receiving radiotherapy, an increased risk of developing second primary solid and gastrointestinal cancers was observed for patients with resectable lung cancer. The prevention of SPMs associated with radiotherapy requires further attention.

Second Primary Malignancies in Patients with Differentiated Thyroid Cancer after Radionuclide Therapy: A Retrospective Single-Centre Study.

Second primary malignancies (SPM) are described as any primary, not synchronous, malignancy arising in a different anatomical district, with confirmed histological diagnosis. Age at diagnosis, previous non-thyroidal primary malignancy, and radioactive iodine (RAI) therapy have been proposed as independent risk factors for SPM. RAI therapy is a standard treatment for moderate-high risk differentiated thyroid cancer (DTC), and its effect on the development of SPM has become a critical topic in DTC treatment. The purpose of this retrospective single-center study was to investigate the occurrence and the possible association of non-thyroidal SPM diagnosed after DTC and RAI therapy in a cohort of 1326 consecutive DTC patients referred at our Institution for RAI treatment from 1993 to 2009. Eighty-nine patients with ages ≤ 18 years at the time of DTC diagnosis or with a follow-up of ≤12 months were excluded from the final analysis. All patients underwent a complete clinical and hematological follow-up every 6 months for a minimum of 12 months. During follow-up (mean 89 ± 73 months), 25 patients (2%) had an SPM diagnosis (mean 133 ± 73 months). The most common site of the second malignancy was the breast, accounting for 32% of all SPM, followed by colon-rectal cancer (16%), leukemia, and gynecological and kidney cancer (4%). At Cox univariable regression analysis, age at DTC diagnosis (p < 0.001), age ≥55 years (p < 0.001) and follow-up duration (p < 0.004) were associated with SPM onset, while no significant association was observed with the administered activity of radioiodine. In conclusion, our data suggest that the older a person gets, the more sharply the likelihood of developing additional diseases, such as PMS, increases. Similarly, for follow-up, the more a patient is followed up clinically over time, the higher the risk of new diagnoses increases.

Clinical characteristics of second primary malignancies among first primary malignancy survivors: A single-center study, 2005-2020.

The cancer survivor population is growing due to advances in detection and treatment. For improved long-term patient management, it is critical to examine the clinical characteristics and outcomes of second primary malignancies (SPMs). An SPM is defined as a second distinct pathological diagnosis, with the same or different origin as the first primary malignancy (FPM). In the present retrospective study, categorical clinical variables were compared between subgroups and the impact on overall survival was evaluated. A total of 1,188 patients with an FPM were included, of which 102 experienced an SPM (8.59%). When compared with the patients who did not develop an SPM, patients with an SPM were significantly older at first diagnosis, had a higher pathological stage and higher rates of biliary tract disease and thyroid disease. In addition, patients with an SPM were more likely to have received postoperative chemotherapy (28.43 vs. 12.16%, P<0.0001) and to be long-term consumers of cigarettes and alcohol (25.00 vs. 8.95%, P<0.05). In addition, an increase in the number of regimens received but not in the number of courses of chemotherapy was associated with a reduction in the time interval to SPM development. Non-small cell lung cancer (NSCLC) was the most common type of FPM (18.27%). In patients with NSCLC the occurrence of SPMs was relatively low (5.07%) and the SPM-associated mortality rate was 2.30%. Breast cancer was the second common type of FPM (12.09%). Patients with breast cancer had a relatively high likelihood of developing an SPM (9.30%), for which family history of malignancy and postoperative chemotherapy were identified as potential risk factors. Patients with stomach cancer were the most vulnerable to SPM (17.95%) and patients with digestive tract cancer had the longest time interval between the FPM and SPM development. In addition, thyroid adenoma was identified as a potential risk factor for SCLC. The findings of the present study may provide valuable guidance for the short- and long-term monitoring of FPM survivors.

Incidence of Second Primary Malignancies in Lymphoma Survivors: A Prospective Cohort Study in the Modern Treatment Era

Background: Improved treatments for Hodgkin and non-Hodgkin lymphoma has resulted in a growing population of long-term survivors, many of whom are cured. A focus of long-term care of these patients (pts) has in turn moved toward optimizing survivorship, including identification and management of second primary malignancies (SPM). In this prospective cohort study initiated in the modern treatment era, we describe the incidence and factors associated with risk of SPM. Methods: Pts were identified from the Molecular Epidemiology Resource (MER) cohort of the University of Iowa/Mayo Clinic Lymphoma SPORE, which offers enrollment to all consecutive patients with newly diagnosed lymphoma aged 18+ years. Clinical and treatment data are abstracted from medical records using a standard protocol. Pts are prospectively contacted regularly to assess disease status and development of SPM. All reported SPM through 2021 were validated against medical records. For this analysis, SPM were defined as any cancer other than lymphoma diagnosed >90 days from lymphoma diagnosis. Cumulative incidence of SPM and 95% confidence intervals (CI) were calculated with death as a competing risk, and associations with patient and treatment characteristics were estimated with Cox models. To evaluate the incidence of SPM in the MER against expected population rates, we calculated the standardized incidence ratio (SIR) using the Iowa component of the Surveillance, Epidemiology and End Results (SEER) database, accounting for age, sex, calendar year and person-time. Results: Of 6929 pts enrolled into the MER from 9/2002 - 6/2015, 59% were male; median age at enrollment was 61 yrs (IQR: 51-70). 763 pts developed SPM through 2021, including 37 acute myeloid leukemia and myelodysplastic syndrome (AML/MDS), 341 non-melanoma skin, 133 genitourinary (GU), 57 gastrointestinal (GI), 49 breast, and 52 lung cancers. The 10-year cumulative incidence of SPM was 12% (CI: 11-13), and 31% (CI: 30-32) for the competing risk of death (Fig 1A). Skin cancers had highest 10-year cumulative incidence of 6.6% (CI: 5.9 -7.4), followed by GU 2.4% (CI: 2.0-2.9), breast 1.0% (CI: 0.8-1.4), lung 1.0% (CI: 0.8-1.3), GI 0.9% (CI: 0.7-1.3), and AML/MDS 0.7% (CI: 0.5-1.0)(Fig 1B). The MER cohort had a lower than expected rate of any SPM (excluding non-melanoma skin cancer, which SEER does not collect) compared to the general Iowa population (SIR=0.61, CI: 0.5-0.7), as well as lower than expected rates of GU (SIR=0.60, CI: 0.5-0.7), GI (SIR=0.45, CI: 0.3-0.6), breast (SIR=0.69, CI: 0.5-0.9), and lung (SIR=0.47, CI: 0.4-0.6) cancer. In contrast, the MER showed a 5-fold higher than expected rate of AML/MDS (SIR=5.2, CI: 3.6-7.1). Risk of SPM increased with age: compared to pts age 18-40 years, those 41-60 yrs had a 3-fold (CI: 1.9-4.5) and >60 yrs had a 6.3-fold (CI: 4.2-9.6) elevated risk of SPM. Females were at lower risk of SPM (HR=0.7, CI: 0.6-0.9). After adjustment for age and sex, there was no association with lymphoma subtype. For initial treatment class (adjusted for age, sex and subtype), risk of a SPM was associated with use of a systemic chemotherapy (HR=1.3, CI: 1.1-1.6); was inversely associated with initial observation (HR=0.8, CI: 0.6-0.9); and was not associated with use of local radiation (HR=0.9, CI: 0.7-1.2), an anthracycline (HR=1.0, CI: 0.8-1.3), alkylator (HR=1.2, CI: 1.0-1.4) or R-monotherapy (HR=1.0, CI: 0.7-1.3). In joint modeling of initial treatment adjusted for age, sex and subtype, compared to pts not receiving systemic chemotherapy, pts with systemic therapy including an alkylator but no anthracycline (HR=1.4, CI: 1.1-1.7) or systemic therapy without an alkylator or anthracycline (HR=1.3, CI:1.1-1.7) had increased risks of SPM, while those receiving both an alkylator/anthracycline were not at significantly elevated risk (HR=1.2, CI: 0.9-1.5). Conclusions: In the rituximab era, the cumulative incidence of any SPM increased over time and at 10 years after diagnosis was 12%, with about half of these due to non-melanoma skin cancers. While the cumulative incidence of AML/MDS at 10 years was low (0.7%), this represented a 5-fold excess risk over expected population rates, consistent with prior eras. In contrast, solid tumors were below expected population rates. Older age, male sex and systemic chemotherapy were associated with higher risk of SPM. Prevention and management of SPM continues to remain an important need for lymphoma survivors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Second Primary Malignancy Incidence in Patients Receiving Lenalidomide at Induction and Maintenance; Long-Term Follow up of 4358 Patients Enrolled to the Myeloma XI Trial

Background Early trials of long-term lenalidomide (len) use reported an increased incidence of second primary malignancies (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to len in combination with melphalan. Here we address the impact of len on SPM development when used at induction and maintenance, profiling SPM type and incidence in 4358 patients treated in the UK NCRI Myeloma XI trial, in which len was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len as maintenance treatment in newly diagnosed patients. TE patients received high dose melphalan supported by autologous stem cell transplantation. Patients in both pathways were randomised to maintenance with len (+/- vorinostat) or active observation. Within the TE pathway, 701 patients did not receive len at induction or maintenance, 1263 received len at induction or maintenance (single exposure) and 568 received len at induction and maintenance (double exposure). In TNE patients, 677 were not treated with len, 899 were single exposed and 260 double exposed. Median follow-up was 68 months (IQ range 49-83). Results 138 TE patients (IR 5.5%) developed an SPM, with 85 diagnosed following maintenance randomization (IR 5.9%). TE patients receiving len maintenance had an SPM incidence of 12.2% at 7 years, compared to 5.8% in those being observed (Pepe-Mori p=0.003). When profiling the SPM type, the incidence of most cancers was greater in the double exposed patients (non-exposed IR 1.6%, single exposed IR 2.9%, double exposed IR 8.3%). Despite this, the actual incidence was <1% for each SPM type in all groups, except for BCC (1.4%), SCC (1.2%) and MDS (1.1%) noted in >1% of double exposed patients. Haematological SPM were almost all confined to the len treated patients, with most in the double exposed group, Figure 1a. 180 TNE patients (IR 9.9%) developed an SPM, with 110 diagnosed following maintenance randomization (IR 13.2%). TNE patients receiving len maintenance had an SPM incidence of 17.1% at 5 years, compared to 10% in those being observed (p=0.09). There was a greater incidence of most SPM types in the double exposed patients (non-exposed IR 2.8%, single exposed IR 6.7%, double exposed IR 18.1%). Skin cancers were common, particularly in the double exposed patients, with an SCC incidence of 4.6% and BCC incidence of 3.1%. No SPM type was diagnosed in >1% of patients who did not receive len. In the double exposed patients, prostate cancer (1.2%) and melanoma (1.2%) were also noted in >1% of patients, Figure 1b. Haematological SPM were rare in TNE patients, with only 8 patients diagnosed, 7 of whom received len. We also determined the outcome in patients treated with len maintenance. In TE patients, 13 (IR 1.8%) deaths were secondary to an SPM, compared to 121 (IR 16.6%) myeloma related and 18 (IR 2.5%) non-myeloma related deaths. This compared to 2 (IR 0.4%) SPM deaths, 117 (IR 22.6%) myeloma related and 19 (IR 3.7%) non-myeloma related deaths in the observed patients. In TNE len maintenance patients, 25 (IR 6.1%) died due to a SPM, 133 (32.7%) due to progressive myeloma and 44 (IR 10.8%) due to other causes. In the observed TNE patients, 9 (IR 2.8%) died due to an SPM, 131 (IR 41.5%) due to progressive myeloma and 28 (IR 8.9%) secondary to non-myeloma related issues. Conclusions SPM incidence was higher in patients treated with len at both induction and maintenance compared to single exposure or no exposure. This was most marked in the TNE patients suggesting an innate risk of SPM development in older patients, particularly skin cancers, possibly impacted by len. Focusing on the maintenance therapy, there was a significant increase in SPM incidence in TE patients treated with len maintenance compared to observation. In TNE patients there was also a numerical increase in SPM incidence that did not reach statistical significance. Deaths due to SPM were rare but increased with lenalidomide maintenance. However, deaths due to myeloma were lower in patients treated with len. We suggest that clinic review of patients receiving maintenance len should include a history focused on identifying possible SPM, so intervention can be made early. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Second Primary Malignancies in Diffuse Large B-cell Lymphoma Survivors with 40 Years of Follow Up: Influence of Chemotherapy and Radiation Therapy

PurposePrevious studies have shown an increased risk of second primary malignancies (SPMs) in survivors of diffuse large B-cell lymphoma (DLBCL). Survivors live longer due to the intensification of and improvements in therapy; thus, we aimed to characterize SPM patterns in patients with DLBCL by treatment modality. Methods and MaterialsStandardized incidence ratio and absolute excess risk of SPMs were assessed in patients with primary DLBCL from 1975 to 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. A subgroup analyses based on, sex, race, age at the time of diagnosis, latency, and treatment modality were performed. Propensity score-adjusted cumulative incidence curves were generated, stratified by treatment and accounting for death as a competing risk. ResultsIn total, 45,946 patients with DLBCL were identified with a mean follow up of 70 months. Overall, 9.2% of patients developed an SPM with a standardized incidence ratio of 1.23 (95% confidence interval, 1.20-1.27). There was no difference in SPM risk between men and women or Black and White patients. Patients age <25 years were particularly susceptible to the development of SPMs, with a risk 2.5 times greater than patients aged 50 to 74 years. Temporal patterns showed increasing risk of solid malignancies and decreasing risk of hematologic malignancies over time, with bladder cancer posing the greatest absolute excess risk of any cancer type after 15 years. Patients treated with radiation therapy (RT), chemotherapy (CT), and chemoradiation therapy (CRT) all had an increased risk of SPM development compared with the general population. The cumulative incidence of SPMs was the lowest in patients treated with RT and the highest when treated with CRT. In the modern treatment era, the cumulative incidence of SPM for patients treated with CT versus CRT was not significantly different. ConclusionsIn this large population-based study, we demonstrate unique SPM risk patterns based on age, latency, and treatment modality that have important implications for the treatment and screening of patients diagnosed with DLBCL.