Subsequent malignant neoplasms after primary hematological malignancy in adult patients.

Patients with primary hematological malignancy (HM) are at an elevated risk of subsequent malignant neoplasms (SMNs), which is a common concern after treatment of primary cancer. We identified 45,533 patients aged ≥20 years and diagnosed with primary HM in Finland from 1992 to 2019 from the Finnish Cancer Registry and estimated standardized incidence ratios (SIR) and excess absolute risks per 1000 person-years (EAR) for SMNs. A total of 6076 SMNs were found (4604 solid and 1472 hematological SMNs). The SIRs were higher for hematological SMNs (SIR 4.9, 95% confidence interval [CI] 4.7-5.2) compared to solid SMNs (SIR 1.5, 95% CI 1.4-1.5). The SIRs for hematological SMNs were highest in the young HM patients aged 20-39 years (SIR 9.2, 95% CI 6.8-12.2 in males and SIR 10.5, 95% CI 7.2-14.7 in females) and decreased by age of first primary HM. However, EARs for hematological SMNs were highest in the older patients, aged 60-79 years at their first primary HM (EAR 5.7/1000 and 4.7/1000 in male and female patients, respectively). In conclusion, the incidence of both hematological and solid SMNs were increased in hematological cancer patients. The relative risk (SIR) was highest among younger HM patients with hematological SMNs. The absolute second cancer burden reflected by high EAR arises from solid malignancies in older patients. Our results accentuate the need for vigilance in the surveillance of HM patients.

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

OBJECTIVES: Thymic 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. METHODS: The 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. RESULTS: 1130 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. CONCLUSION: The 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.

Sub-lobar resections for peripheral non-small cell lung cancer measuring ≤ 2 cm: Insights from recent clinical trials.

The findings of two well conducted trials that randomised 1803 patients with a peripheral non-small cell lung cancer measuring ≤ 2 cm to a lobar to sub-lobar resection have established the latter as a new standard of care. It is important for non-surgical oncologists to appreciate the details of study design and outcomes of both studies, given the possible impact they have for considerations of stereotactic ablative radiotherapy (SABR) for operable patients with early-stage NSCLC. Differences in overall survival between the study populations highlight the impact of confounding factors like smoking history and comorbidities on reported outcomes. For example, despite low post-operative mortality rates in both trials, the 5-year disease-free survival rate in the CALGB 140503 trial was only approximately 60 % with either surgical procedure. Both phase III trials required guideline recommended nodal staging, which does not reflect real world surgical practice, and which may limit the generalisability of the reported findings to local institutional outcomes. Furthermore, the emergence of other malignancies was recorded in 15-18 % of study patients during follow-up, and patients who underwent sub-lobar resections had a better long-term survival associated with a higher likelihood of undergoing additional curative treatments. These findings from the JCOG0802 and the CALGB 140503 will encourage more interest in enrolling patients into ongoing trials comparing surgical resection with SABR.

Long-term outcomes of symptomatic optic pathway glioma: 32-year experience at a single Western Australian tertiary pediatric oncology center.

Introduction: Optic pathway gliomas (OPGs) are associated with significant risk of visual and endocrine morbidity, but data on long-term outcomes in symptomatic patients is sparse. This study reviews the clinical course, disease progression, survival outcomes and long-term sequelae in pediatric patients with symptomatic OPGs in our institution over three decades. Methods: Retrospective review of patients with symptomatic OPG treated in a single tertiary pediatric oncology center from 1984 to 2016. Results: A total of 37 patients were diagnosed with symptomatic OPG. Decreased visual acuity was the commonest presenting symptom (75.7%). Surgical intervention was performed in 62.2%; 56.5% underwent biopsy, 26.1% surgical debulking and 17.4% had orbital decompression with cystic fenestration and cosmetic optic nerve excision at different treatment intervals. CSF diversion was performed in 47.8% patients. Histopathologic examination confirmed 86% to be pilocytic astrocytoma and 1 ganglioglioma. 46% received chemotherapy and 48% had radiotherapy, at different intervals. Median follow-up was 13.74 years. In NF1 patients, overall survival (OS) was 100% at 5 years and 55.6 ± 24.8% at 25 years while progression-free-survival (PFS) was 50 ± 15.8% at 5 and 20 years. In non-NF1 patients, OS was 96.2 ± 3.8% at 5 years and 87.4 ± 9% at 25-years. 5-year PFS was 53.8 ± 9.8% and 25-year PFS was 49.0 ± 10%. Cumulative PFS was 53 ± 8.3% at 5 years and 49.7 ± 8.4% at 20 years while cumulative OS was 97.2 ± 2.7% at 5 years and 77.5 ± 10.8% at 25 years. 59.5% patients developed post-operative endocrinopathy. Long-term vision was normal in 8.1%, improved in 13.5%, stabilized in 40.5% but worsened in 37.8% patients. Three patients treated with radiotherapy developed second brain tumors. Conclusion: 25-year OS in this cohort was 77.5% but survivorship carried significant long-term morbidities including radiation-induced second malignant brain tumors.

Case Report: Avelumab and ruxolitinib to manage polycythemia vera and secondary metastatic Merkel cell carcinoma: a possible successful combination.

We describe a case of second primary malignancy in a 65-year-old patient affected by polycythemia vera treated with the JAK 1/2 inhibitor ruxolitinib. The latter is recognized as a risk factor for the onset of non-melanoma skin cancers in many retrospective and perspective studies, but the concomitant use of ruxolitinib with new immunotherapies is very rarely reported, and the safety of this association is still not clear. In our case, ruxolitinib combined with the anti-PD-L1 avelumab demonstrated both safety and efficacy for hematological disease control and underlying carcinoma remission.

Self-administered questionnaire assessing childhood cancer treatments and associated risks for adverse health outcomes - The KiKme study.

Background: Childhood cancer survivors (CCS) are at particularly high risk for therapy-related late sequelae, with secondary primary neoplasms (SPN) being the most detrimental. Since there is no standardized questionnaire for retrospective assessment of associations between prior cancer treatments and late health effects, we developed a self-administered questionnaire and validated it in a cohort of CCS. Methods: CCS of a first primary neoplasm (FPN, N=340) only or with a subsequent SPN (N=101) were asked whether they had received cancer therapies. Self-reports were compared to participants' medical records on cancer therapies from hospitals and clinical studies (N=242). Cohen's Kappa (κ) was used to measure their agreement and logistic regression was used to identify factors influencing the concordance. Associations between exposure to cancer therapies and late health effects (overweight/obesity, diseases of the lipid metabolism and the thyroid gland, cardiovascular diseases, occurrence of SPN) were analyzed in all participants by applying generalized linear mixed models to calculate odds ratios (OR) and 95% confidence intervals (95%CI). Results: For CCS of SPN, a perfect agreement was found between self-reports and medical records for chemotherapy (CT, κ=1.0) while the accordance for radiotherapy (RT) was lower but still substantial (κ=0.8). For the CCS of FPN the accordance was less precise (CT: κ=0.7, RT: κ=0.3). Cancer status, tumors of the central nervous system, sex, age at recruitment, vocational training, follow-up time, and comorbidities had no impact on agreement. CCS with exposure to CT were found to be less often overweight or obese compared to those without CT (OR=0.6 (95%CI 0.39; 0.91)). However, they were found to suffer more likely from thyroid diseases excluding thyroid cancers (OR=9.91 (95%CI 4.0; 24.57)) and hypercholesterolemia (OR=4.45 (95%CI 1.5; 13.23)). All other analyses did not show an association. Conclusion: Our new questionnaire proved reliable for retrospective assessment of exposure to CT and RT in CCS of SPN. For the CCS of FPN, self-reported RT was very imprecise and should not be used for further analyses. We revealed an association between late health outcomes occurring as hypercholesterolemia and thyroid diseases, excluding thyroid cancer, and the use of CT for the treatment of childhood cancer.

Long-term outcomes in Hodgkin lymphoma survivors. Temporary trends and comparison with general population.

The high cure rates of Hodgkin lymphoma (HL) make this oncological disease among those with the greatest number of long-term survivors. This single-institution study including 383 HL patients with up to 45 years of follow-up, analyses the morbidity and mortality of this population after treatments in comparison with the overall Spanish population, and investigates whether it has changed over time stratifying by periods of time, as a consequence of therapeutic optimization. The median age was 34.8 years (range 15-87) with median overall survival of 30 years, significantly higher in women (HR 0.58, 95% CI 0.42-0.79) (p = 0.0002). 185 late-stage diseases were noted (35% patients), cardiovascular disease (CVD) being the most frequent (23.2%). 30% of patients developed at least one second malignant neoplasm (SMN) to give a total of 174 SMNs. 20.9% of the patients died from HL and 67.0% died from non-HL causes (32.2% from SMN, 17% from CVD). The overall standardized mortality ratio (SMR) was 3.57 (95% CI: 3.0-4.2), with striking values of 7.73 (95% CI: 5.02-8.69) and of 14.75 (95% CI: 11.38-19.12) for women and patients <30 years at diagnosis, respectively. Excluding HL as the cause of death, the SMRs of those diagnosed before 2000 and from 2000 were proved to be similar (3.88 vs 2.73), maintaining in this last period an unacceptable excess of mortality due to secondary toxicity in patients cured of HL. Our study confirm that HL treatment substantially reduces the life expectancy of patients cured of HL. In recent periods, despite therapeutic optimization, deaths from toxicity continue to occur, mainly from CVD and SMN. Risk-factor monitoring should be intensified, prevention programs developed, and therapeutic optimization of LH investigated, especially in two vulnerable groups: those aged <30 years at diagnosis, and women.

Incidence of Bladder Cancer in Patients Undergoing Radiotherapy for Prostate Cancer.

INTRODUCTION: Radiotherapeutic treatment of prostate cancer has been validated in terms of efficacy, but its relationship with the occurrence of second pelvic primary malignancy and the relevance of radio-induced toxicity is still under debate. This study analyses the occurrence of second pelvic primary malignancy as well as morbidity secondary to radiotherapy treatment in patients treated for prostate cancer. MATERIAL AND METHODS: Retrospective consecutive descriptive study of 317 patients who received radiotherapy treatment for prostate cancer between 2007 and 2017. Predictor variables, side effects and the appearance of second pelvic primary malignancy during a maximum follow-up of 10 years were collected. We analyse whether there is a significant relationship in the appearance of second pelvic primary malignancy and describe the clinical toxicity presented by the patients. RESULTS: The median age was 62.27 years and the most commonly employed treatment modality was brachytherapy with IMRT (60%). 17 patients (5.4%) developed a second pelvic primary malignancy, with a median time to onset of 58 and 25 months for bladder and colon tumours, respectively. Local recurrence and mortality rates are 8% and 7%, respectively. Statistically significant association is demonstrated for the occurrence of second pelvic primary malignancy and for chronic radioinduced toxicity according to type of radiotherapy χ2 (4) = 16.34; p = 0.003 and χ2 (1) = 6.47; p = 0.011 respectively. CONCLUSIONS: In our series, the occurrence of a second pelvic primary malignancy is statistically associated with the modality of radiotherapy administered and occurrence of chronic adverse effects.

Incidence of Bladder Cancer in Patients Undergoing Radiotherapy for Prostate Cancer

Introduction: Radiotherapeutic treatment of prostate cancer has been validated in terms of efficacy, but its relationship with the occurrence of second pelvic primary malignancy and the relevance of radio-induced toxicity is still under debate. This study analyses the occurrence of second pelvic primary malignancy as well as morbidity secondary to radiotherapy treatment in patients treated for prostate cancer. Material and Methods: Retrospective consecutive descriptive study of 317 patients who received radiotherapy treatment for prostate cancer between 2007 and 2017. Predictor variables, side effects and the appearance of second pelvic primary malignancy during a maximum follow-up of 10 years were collected. We analyse whether there is a significant relationship in the appearance of second pelvic primary malignancy and describe the clinical toxicity presented by the patients. Results: The median age was 62.27 years and the most commonly employed treatment modality was brachytherapy with IMRT (60%). 17 patients (5.4%) developed a second pelvic primary malignancy, with a median time to onset of 58 and 25 months for bladder and colon tumours, respectively. Local recurrence and mortality rates are 8% and 7%, respectively. Statistically significant association is demonstrated for the occurrence of second pelvic primary malignancy and for chronic radioinduced toxicity according to type of radiotherapy χ2 (4) = 16.34; p = 0.003 and χ2 (1) = 6.47; p = 0.011 respectively. Conclusions: In our series, the occurrence of a second pelvic primary malignancy is statistically associated with the modality of radiotherapy administered and occurrence of chronic adverse effects (AU)

Second primary malignancies in chronic lymphocytic leukaemia: Skin, solid organ, haematological and Richter's syndrome.

Chronic lymphocytic leukaemia (CLL) is invariably accompanied by some degree of immune failure, and CLL patients have a high rate of second primary malignancy (SPM) compared to the general population. We comprehensively documented the incidence of all forms of SPM including skin cancer (SC), solid organ malignancy (SOM), second haematological malignancy (SHM) and separately Richter's syndrome (RS) across all therapy eras. Among the 517 CLL/small lymphocytic lymphoma (SLL) patients, the overall incidence of SPMs with competing risks was SC 31.07%, SOM 25.99%, SHM 5.19% and RS 7.55%. Of the 216 treated patients, 106 (49.1%) had at least one form of SPM, and 63 of 106 (29.2% of treated patients) developed an SPM 1.5 years (median) after treatment for their CLL. Melanoma accounted for 30.3% of SC. Squamous cell carcinoma (SCC), including eight metastatic SCCs, was 1.8 times more than basal cell carcinoma (BCC), a reversal of the typical BCC:SCC ratio. The most common SOMs were prostate (6.4%) and breast (4.5%). SHM included seven acute myeloid leukaemia (AML) and five myelodysplasia (MDS) of which eight (four AML, four MDS) were therapy-related. Any SPM occurred in 32.1% of 53 Monoclonal B-lymphocytosis (MBL) patients. Age-adjusted standardised rates of SPM (per 100,000) for CLL, MBL and the general Australian population were 2648, 1855 and 486.9, respectively. SPMs are a major health burden with 44.9% of CLL patients with having at least one SPM, and apart from SC, associated with significantly reduced overall survival. Dramatic improvements in CLL treatment and survival have occurred with immunochemotherapy and targeted therapies, but mitigating SPM burden will be important to sustain further progress.

Hyperfractionated-Accelerated Reirradiation with Proton Therapy for Radiation-Associated Breast Angiosarcoma.

Purpose: Radiation-associated angiosarcoma (RAAS) is a rare complication among patients treated with radiation therapy for breast cancer. Hyperfractionated-accelerated reirradiation (HART) improves local control after surgery. Proton therapy may further improve the therapeutic ratio by mitigating potential toxicity. Materials and Methods: Six patients enrolled in a prospective registry with localized RAAS received HART with proton therapy between 2015 and 2021. HART was delivered twice or thrice daily in fraction sizes of 1.5 or 1.0 Gy, respectively. All patients received 45 Gy to a large elective volume followed by boosts to a median dose of 65 (range, 60-75) Gy. Toxicity was recorded prospectively by using the Common Terminology Criteria for Adverse Events, version 4.0. Results: The median follow-up duration was 1.5 (range, 0.25-2.9) years. The median age at RAAS diagnosis was 73 (range, 60-83) years with a median latency of 8.9 (range, 5-14) years between radiation therapy completion and RAAS diagnosis. The median mean heart dose was 2.2 (range, 0.1-4.96) Gy. HART was delivered postoperatively (n = 1), preoperatively (n = 3), preoperatively for local recurrence after initial management with mastectomy (n = 1), and as definitive treatment (n = 1). All patients had local control of disease throughout follow-up. Three of 4 patients treated preoperatively had a pathologic complete response. The patient treated definitively had a complete metabolic response on her posttreatment PET/CT (positron emission tomography-computed tomography) scan. Two patients developed distant metastatic disease despite local control and died of their disease. Acute grade 3 toxicity occurred in 3 patients: 2 patients undergoing preoperative HART experienced wound dehiscence and 1 postoperatively developed grade 3 wound infection, which resolved. Conclusion: HART with proton therapy appears effective for local control of RAAS with a high rate of pathologic complete response and no local recurrences to date. However, vigilant surveillance for distant metastasis should occur. Toxicity is comparable to that in photon/electron series. Proton therapy for RAAS may maximize normal tissue sparing in this large-volume reirradiation setting.

Second primary malignancies in patients with clinical T1bN0 esophageal squamous cell carcinoma after definitive therapies: supplementary analysis of the JCOG trial: JCOG0502.

BACKGROUND: Previous studies have suggested that patients with esophageal squamous cell carcinoma (ESCC) are still at a high risk of developing second primary malignancies (SPMs) after definitive therapies. We evaluated the development of SPMs and explored its risk factors in patients with clinical T1bN0 ESCC. METHODS: JCOG0502 prospectively compared esophagectomy with definitive chemo-radiotherapy for clinical T1bN0 ESCC. Here, we reviewed all JCOG0502 patients' data for SPMs and investigated the risk factors for SPMs using uni-variable and multivariable analyses by Fine and Gray model. RESULTS: Among 379 enrolled patients, 213 underwent esophagectomy and 166 received chemo-radiotherapy. Patient characteristics were male (85%); median age [63 (range 41-75) years; location of the primary tumor (upper/middle/lower thoracic esophagus, 11%/63%/27%, respectively]; alcohol consumption history (79%); smoking history (66%); prevalence of no/several/many/unknown Lugol-voiding lesions (LVLs) (45%/36%/8%/11%, respectively). In a median follow-up of 7.1 years, 118 SPMs occurred in 99 (26%) patients. Cumulative incidences of SPMs after 3, 5, and 10 years were 9%, 15%, and 36%, respectively. The most common primary tumor sites were the head and neck (35%), stomach (20%) and lungs (14%). In multivariable analyses, compared to no LVLs, several LVLs [hazard ratio (HR) 2.24, 95% confidential interval (CI) 1.32-3.81] and many LVLs (HR 2.88, 95% CI 1.27-6.52) were significantly associated with the development of SPMs. Sixteen patients died due to the SPMs. CONCLUSION: The incidence of SPMs was high. The presence of LVLs, which was a predictive factor for SPMs, may be useful for surveillance planning.

Second cancer risk in childhood cancer survivors treated with intensity-modulated radiation therapy: An updated analysis of more than 10 years of follow-up.

BACKGROUND: It is unclear how intensity-modulated radiation therapy (IMRT) impacts long-term risk of second malignant neoplasms (SMNs) in childhood cancer patients. PROCEDURE: Patients aged ≤21 years treated with IMRT between 1998 and 2009 and who survived ≥5 years after IMRT were included. SMN site in relation to isodose level (IDL) of IMRT was evaluated. Standardized incidence ratios (SIR) and excess absolute risks (EAR) were calculated. Cumulative incidences were estimated with death as a competing risk. RESULTS: Three-hundred twenty-five patients were included with median follow-up of 11.2 years from IMRT (interquartile range: 9.4-14.0) among patients alive at the end of follow-up. Two hundred (62%) patients had ≥10 years of follow-up and 284 (87%) patients were alive at the time of analysis. Fifteen patients developed SMNs (11 solid, four hematologic). Median time from IMRT to solid SMN was 11.0 years (range: 6.8-19.2) with 10- and 15-year cumulative incidences 1.8% (95% CI: 0.7-3.9) and 3.5% (95% CI: 1.4-7.5), respectively; SIR was 13.7 (95% CI: 6.9-24.6) and EAR was 2.8 per 1000 person-years (95% CI: 1.0-4.6). Eight solid SMNs developed within the IMRT field (100% IDL [n = 5], 80% IDL [n = 1], 50% IDL [n = 1], 40% IDL [n = 1]), one within the 70%-80% IDL of a conventional field, one was out-of-field, and one could not be determined. CONCLUSIONS: With median follow-up of >10 years, many solid SMNs after IMRT in childhood cancer survivors develop in the high-dose region. These data serve as a foundation for comparison with other modalities of radiation treatment (e.g., proton therapy).

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

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.

Coexistence of Prefibrotic Myelofibrosis with Monoclonal Gammopathy of Undetermined Significance: A Case Report.

The coexistence of dual hematological neoplasms is an unusual and challenging presentation due to the different combination of etiopathology. The presentation of synchronous dual hematological malignancies can be one of the 3 types: myeloid + lymphoid or dual lymphoid or dual myeloid. Here, we are reporting a case of a 53-year-old male with simultaneous presence of JAK2 V617F-positive myeloproliferative neoplasm with features favoring prefibrotic phase of primary myelofibrosis (pre-PMF) in combination with monoclonal gammopathy of undetermined significance (MGUS). In such cases of simultaneous existence of dual hematological neoplasm management, it is recommended to treat the more aggressive one. Currently, our management plan is focusing on treating the pre-PMF and observation of MGUS with regular monitoring for transformation to MM.

The Pattern of Second Primary Tumours in Postmenopausal Women with Prior Breast Cancer in Western Romania: A Retrospective, Single-Institution Study.

With improved survival, more patients with prior breast cancer are at risk of having a second primary cancer diagnosed. The pattern and impact of second primary cancers following breast cancer is important for overall breast cancer therapeutic management. Our study is a first analysis of the trend of second primary tumours over time in terms of incidence, sites with significantly elevated risks and correlation with stage, molecular subtype and therapeutic strategies conducted in Eastern Europe in postmenopausal women with breast cancer. PATIENTS AND METHODS: Our study population included 28 patients with prior breast cancer (BC) and second primary tumours, which were diagnosed and treated in our Institution between 2004 and 2017. The criteria for selection were based on the completeness of the documentation of the first treatment for breast cancer, stage of disease, molecular subtype, the site of origin of the second tumours and the survival data. RESULTS: An increased risk of second primary cancer was associated with the 51-60 years age group (53.6%), with the greater prevalence in patients living in urban environments (82.1%). The use of chemotherapy increased the risk of the occurrence of gynecological second malignancies (75%). Our study is a first analysis of the trend of second primary tumours over time in terms of identifying sites with significantly elevated risks and correlation with therapeutic strategies conducted in Eastern Europe in postmenopausal women with breast cancer. CONCLUSIONS: Our study is a first analysis of the trend of second primary tumours over time in terms of correlation with luminal subtype and stage at diagnosis of primary cancer sites with significantly elevated risks and correlation with therapeutic strategies in postmenopausal women with breast cancer conducted in Eastern Europe. The reported time from primary to second primary malignancy onset, with a significantly higher rate for postmenopausal breast cancer patients, was less than one year (50%). With the advances and wider availability of genetic testing (e.g., gene panels), patients diagnosed with multiple primaries should be increasingly investigated for an underlying cancer predisposition. Postmenopausal women with breast cancer may benefit from increased surveillance and advice to avoid second malignancies.

Nasopharyngeal carcinoma in children: Multimodal treatment and long-term outcome of 92 patients in a single center over a 28-year period.

OBJECTIVES: The aim of the study was to evaluate the long-term outcome and late effects in pediatric patients with nasopharyngeal carcinoma (NPC) treated with neoadjuvant chemotherapy (NACT), followed by radiotherapy (RT). METHODS: Ninety-two children (65 male, 27 female) diagnosed with NPC between 1989 and 2017 in the Istanbul University, Institute of Oncology were evaluated retrospectively. NACT consisted of three cycles of cisplatin-containing regimen every 3 weeks, followed by RT. RESULTS: The median age was 13 years (5-18 years). Most had locoregionally advanced disease (stage III/IVA/IVB) and five had distant metastases at presentation. At a median follow-up of 108 months (3-332 months), 5- and 10-year overall survival rates and event-free survival rates were 87.5%, 79.7% and 82.1%, 78.9%, respectively. Three patients with distant metastasis are long-term survivors. Thirteen patients relapsed at a median of 8 months (2-23 months). Hypothyroidism (36%) and xerostomia (25%) were the most frequent long-term treatment-related toxicities. Nine second malignancies developed in eight patients, eight in the irradiated field at a median of 14 years (range 5-26 years), five of whom are long-term survivors after curative surgery. CONCLUSIONS: Three courses of cisplatin-containing NACT, followed by RT lead to high survival and locoregional control rate in advanced stage NPC in children. Patients with distant metastasis should also be treated with curative intent by systemic chemotherapy and locoregional radiotherapy. Patients should be followed closely for recurrences and long-term morbidities including second malignancies, which may be treated with curative surgeries if diagnosed early.

Risk for second bladder and rectal malignancies from cervical cancer irradiation.

The objective of this study was to estimate the risk of developing second malignancies to partially in-field organs from volumetric modulated arc therapy (VMAT) of cervical cancer and to compare the above risks with those from the conventional three-dimensional conformal radiotherapy (3D-CRT). Seventeen consecutive patients with uterine cervix carcinoma were selected. VMAT and 3D-CRT plans were generated with 6 and 10 MV photons, respectively. The prescribed tumor dose was 45 Gy given in 25 fractions. Differential dose-volume histogram data from the treatment plans were obtained for the partially in-field organs such as bladder and rectum. These data were used to estimate the patient-specific lifetime attributable risk (LAR) for bladder and rectal cancer induction with a non-linear model based on a mixture of plateau and bell-shaped dose-response relationships. The estimated risks per 10000 people were compared with the baseline risks for unexposed population. The patient-specific rectal cancer risk estimates from VMAT were significantly lower than those from 3D-CRT (P = 0.0144). The LARs for developing bladder malignancies from VMAT were significantly high compared to those from conventional irradiation (P = 0.0003). The mean difference between the patient-specific LARs for radiation-induced bladder and rectal malignancies as derived from 3D-CRT and VMAT plans was 6.6% and 2.0%, respectively. The average LAR for developing bladder and rectal malignant diseases due to VMAT was 9.2 × 10-4 and 43.7 × 10-4 , respectively. The corresponding risks following 3D-CRT were 8.6 × 10-4 and 44.6 × 10-4 . These average risks showed that pelvic irradiation increases the baseline probability for cancer induction by 12.6-19.1%. The differences in the second cancer risks associated with the VMAT and 3D-CRT for cervical cancer were found to be small. Both treatment techniques resulted in considerable increased probabilities for developing bladder and rectal malignancies relative to those of unirradiated population.

Cumulative exposure to melphalan chemotherapy and subsequent risk of developing acute myeloid leukemia and myelodysplastic syndromes in patients with multiple myeloma.

OBJECTIVES: The aim of this study was to determine risk factors for development of acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM). METHODS: We identified all patients diagnosed with MM in Sweden from January 1st, 1958 to December 31, 2011. A total of 26 627 patients were diagnosed with MM with during the study period. Of these, 124 patients (0.5%) developed subsequent AML/MDS. For each patient with MM and a subsequent AML/MDS diagnosis, we randomly selected a matched (age, sex, and date of MM diagnosis) MM patient without a subsequent second malignancy diagnosis. RESULTS: The cumulative melphalan exposure was significantly higher (OR = 2.8, 95% CI 1.7-5.2; P < .001) among cases (median 988 mg; IQR 644-1640) compared with controls (median 578 mg; IQR 360-967). Median time to AML/MDS development was 3.8 years (IQR 2.8-5.8). Risk of AML/MDS was not statistically altered by M protein isotype, anemia, renal failure, hypercalcemia, lytic bone lesions, or radiation therapy. CONCLUSION: In this nationwide population-based study, we show that increased cumulative doses of alkylating therapy with melphalan increases the subsequent risk of developing AML/MDS in patients with MM. Given improved survival in MM patients over the last decade future studies will be important to better define long-term risks.

Second tumor risk in children treated with proton therapy.

BACKGROUND: Out-of-field neutron dissemination during double-scattered proton therapy has raised concerns of increased second malignancies, disproportionally affecting pediatric patients due to the proportion of body exposed to scatter dose and inherent radiosensitivity of developing tissue. We sought to provide empiric data on the incidence of early second tumors. METHODS: Between 2006 and 2019, 1713 consecutive children underwent double-scattered proton therapy. Median age at treatment was 9.1 years; 371 were ≤3 years old. Thirty-seven patients (2.2%) had tumor predisposition syndromes. Median prescription dose was 54 Gy (range 15-75.6). Median follow-up was 3.3 years (range 0.1-12.8), including 6587 total person-years. Five hundred forty-nine patients had ≥5 years of follow-up. A second tumor was defined as any solid neoplasm throughout the body. RESULTS: Eleven patients developed second tumors; the 5- and 10-year cumulative incidences were 0.8% (95% CI, 0.4-1.9%) and 3.1% (95% CI, 1.5-6.2%), respectively. Using age- and gender-specific data from the Surveillance, Epidemiology, and End Results (SEER) program, the standardized incidence ratio was 13.5; the absolute excess risk was 1.5/1000 person-years. All but one patient who developed second tumors were irradiated at ≤5 years old (p < .0005). There was also a statistically significant correlation between patients with tumor predisposition syndromes and second tumors (p < .0001). Excluding patients with tumor predisposition syndromes, 5- and 10-year rates were 0.6% (95% CI, 0.2-1.7%) and 1.7% (95% CI, 0.7-4.0%), respectively, with all five malignant second tumors occurring in the high-dose region. CONCLUSION: Second tumors are rare within the decade following double-scattered proton therapy, particularly among children irradiated at >5 years old and those without tumor predisposition syndrome.