Higher Risk Of Second Malignancy Research Articles

A tale of multiple primaries: Primary neuroendocrine carcinoma, vaginal vault and renal cell carcinoma in a 52 years old female

Cancer patients have 15-25% higher risk of second malignancy compared to general population. We hereby describe an extremely unusual case of 52-years-old-female with Neuroendocrine Carcinoma (NEC) of vaginal vault developing 4

Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea.

Patients with classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary and secondary myelofibrosis (MF), are known to have an increased risk of second malignancies (SMs). Hydroxyurea (HU) is a guideline-recommended cytoreductive therapy for patients at high risk for MPNs. Controversy exists as to whether HU use is associated with a higher risk of SMs, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We conducted a retrospective cohort study of older patients diagnosed with MPN (age ≥66 years) between 2010 and 2017 and included the data in the Surveillance, Epidemiology, and End Results Medicare-linked database. Multivariable competing risk analyses adjusting for patient characteristics were used to assess the impact of HU on the development of SM. We identified 4023 patients (1688 with PV, 1976 with ET, and 359 with MF) with a median age of 77 (interquartile range [IQR], 71-83) years at the time of MPN diagnosis. After a median follow-up of 3.25 (IQR, 2.10-5.00) years, 489 patients developed an SM (346 solid, 73 lymphoid, and 70 myeloid malignancies). The cumulative incidence probability of SM was 19.88% (95% confidence interval [CI], 17.16%-22.75%) among 2683 HU users and 22.31% (95% CI, 17.51%-27.47%) among 1340 nonusers, respectively (Gray's test, P< .01). We did not identify significant differences in the incidence of solid or hematologic SMs, including AML/MDS (hazard ratio, 1.33; 95% CI, 0.77-2.29; P= .30), between HU users and nonusers. Our results suggest that the use of HU does not increase the risk of SM in older patients with MPN.

RARE-21. CANCER SPECTRUM IN GERMLINE SUFU MUTATION CARRIERS: A COLLABORATIVE PROJECT OF THE SIOPE HOST GENOME WORKING GROUP

BACKGROUNDLittle is known about cancer risk associated with pathogenic germline SUFU variants.METHODSData of all previously published and 25 still unpublished patients with a pathogenic germline SUFU mutation were compiled.RESULTS124 patients in 67 families were identified, most of them ascertained after the occurrence of a medulloblastoma (MB) or as part of Gorlin syndrome cohorts. Overall, 30 patients were healthy carriers and 94 patients developed a total of 129 tumors (up to 4 tumors/patient): 68 MBs, always as first tumor (median age at diagnosis: 1.5yr [0.1–5]), 22 patients with at least 1 basal cell carcinoma (BCC) (median 10/patient) (median age at first BCC: 43yr, [17–52]), 15 meningiomas (median age 43yr, [13–72]), 7 ovarian stromal/fibrous tumors (median age 12yr [5–34]), and 17 other tumors including 5 sarcomas (median age: 50yr [7–79]). Median age at last follow-up was 30yr. Nineteen patients died, including 11 from MB. Second malignancies were diagnosed in 21 patients including 13 in MB survivors. Mutations were inherited in 58/66 (88%) of cases in which inheritance could be tested and de novo in 8. In 6/67 families (9%), >2 children were diagnosed with a MB.CONCLUSIONIn this large cohort of germline SUFU mutation carriers, MB in infants is the most frequent tumor but the spectrum also includes typical Gorlin syndrome tumors (BCC, meningiomas, and ovarian stromal/fibrous tumors) either as first tumors or as second malignancies. This broad tumor spectrum and the high risk of second malignancies justify the implementation of specific cancer surveillance programs.

Risk of second primary malignancies after definitive treatment for esophageal cancer: A competing risk analysis.

BackgroundEsophageal cancer is associated with synchronous or metachronous cancer at other primary sites. However, few studies have evaluated the second malignancies after the treatment of esophageal cancer. The present study aimed to clarify the frequency of and risk factors for the second malignancies after definitive therapy for esophageal cancer.Patients and MethodsWe included patients with esophageal cancer who received definitive therapy between 2000 and 2010. Exclusion criteria were synchronous cancer or a past history of cancer. Standardized incidence rate (SIR) was calculated using age‐ and sex‐specific incidence rates from the cancer registry data. To conduct risk analyses, we used the competing risk regression model, which defined death and the development of second malignancies as competing risks.ResultsA total of 758 patients were included, with 131 second malignancies occurring in 106 patients (14%), over a median follow‐up of 3.7 years. Cumulative incidences of second malignancies after 3, 5, and 8 years were 4.0%, 7.6%, and 13.8%, respectively. The risk of second malignancy was significantly elevated [SIR = 1.83, 95% confidence interval (CI): 1.50‐2.22]. The most common sites of primary tumor were the head and neck (20%), followed by the lung (17%), stomach (16%), colon and rectum (11%), and urinary tract (9%). Risk analyses revealed that age ≥ 65 years [subdistribution hazard ratio (sHR): 1.51, 95% CI: 1.01‐2.24, vs age < 65] and clinical stages 0‐I (sHR: 2.48, 95% CI: 1.46‐4.22, vs stage III and IV) and II (sHR: 2.10, 95% CI: 1.23‐3.58, vs stage III and IV) were significantly associated with second malignancies.ConclusionsCompared with the general population, an increased incidence of second malignancies was observed in the patients with esophageal cancer in the present study even after definitive treatment. Careful follow‐up is required, especially in patients at a higher risk of second malignancies.

Impact of race and tumor subtype on second malignancy risk in women with breast cancer

PurposeWomen with breast cancer are at increased risk of second malignancy (SM). However, the impact of race and the hormone receptor (HR) status of the primary breast tumor on risk of SM are not known. The purpose of this study is to analyze the incidence of SM in women with a history of breast cancer according to race and HR status.MethodsIn the surveillance, epidemiology, and end results database, multiple primary standardized incidence ratio sessions were used to compare the incidence of SM in women with a history breast cancer to the cancer incidence in the general population. Analyses of SM by age, race, and hormone-receptor status were performed using the absolute excess risk (AER) and observed/expected (O/E) ratio.ResultsYounger black women (under the age of 50) were at greater risk of SM with an AER = 76.03 (O/E = 2.3, 95 % CI = 12.19–2.4) compared to younger white women who had an AER = 38.59 (O/E = 1.55, 95 % CI = 1.53–1.58). Older black women (50 years and older) had at an increased risk of SM with an AER = 42.26 (O/E = 1.3, 95 % CI = 1.26–1.34) compared to older white women who had an AER = 11.56 (O/E = 1.07, 95 % CI = 1.06–1.08). Second breast malignancy is the predominant SM in both black and white women. Women with hormone-receptor (HR)-negative breast cancer had higher risk of SMs with an AER = 43.53 (O/E = 1.41, 95 % CI = 1.38– 0.145–3.31) compared to women with HR-positive disease with an AER = 21.43 (O/E = 1.17, 95 % CI = 1.16–0.1.18). In HR-negative women, younger black women had an AER = 96.46 (O/E = 2.99, 95 % CI = 2.70–3.31), younger white women had an AER = 66 (O/E = 2.25, 95 % CI = 2.13–2.36), older black women had an AER = 58.58 (O/E = 1.45, 95 % CI = 1.34–1.57), and older white women had an AER = 20.88 (O/E = 1.14, 95 % CI = 1.11–1.18).ConclusionsBlack breast cancer survivors and women with HR-negative breast cancer are at increased risk of SM, which deserves further evaluation to understand the biological and clinical basis for this increased risk.

Risk of second malignancies in patients with early-stage classical Hodgkin's lymphoma treated in a modern era.

Second malignancies remain an issue affecting morbidity and mortality in long-term survivors of early stage Hodgkin's lymphoma (HL). We undertook this study to determine if treatment in the modern era resulted in decreased second malignancies. Patients diagnosed with stage I–II cHL between 1988 and 2009 who received radiation therapy (RT) were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Freedom from second malignancy (FFSM) was estimated using the Kaplan–Meier method. Univariate analysis (UVA) was performed using the Log-Rank test, and included age, gender, year of diagnosis, and stage. Multivariable analysis (MVA) was performed using Cox Proportional Hazards modeling. The study cohort included 8807 patients. The median age at diagnosis was 32 years (range: 2–85). The majority of patients had stage II disease (n = 6044, 69%), 597 (7%) had extranodal involvement (ENI), and 1925 (22%) had B symptoms. Median follow-up for the entire cohort was 7.2 years (range: 0–22). Five hundred twenty-three (6%) patients developed a second malignancy. Median latency to second malignancy was 5.8 years (range: 0.1–21.5). Of the 523 patients that developed a second malignancy, 228 (44%) occurred in the first 5 years, 139 (27%) were diagnosed between years 5–10, and 156 (30%) beyond 10 years. The 10 year FFSM for patients treated between 1988 and 1999 was 93.0% versus 95.1% for patients treated between 2000 and 2009 (P = 0.04), On MVA, treatment between 2000 and 2009 was associated with a HR for second malignancy of 0.77 (95% Confidence Interval: 0.62–0.96, P = 0.02) compared to the treatment between 1988 and 1999. Our analysis suggests that in patients treated with RT for stage I or II cHL, treatment prior to 2000 had a slightly higher risk of second malignancy compared to treatment in 2000 and later. Further studies, with longer follow-up of patients treated in the modern era are needed to confirm these findings.

Risk of second malignancies in patients with gastric marginal zone lymphomas of mucosa associate lymphoid tissue (MALT)

It is controversial whether patients with gastric marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) have higher risk of second malignancies. The aim of this study was to define the risk of second malignancies in these patients. We analyzed prospective follow-up data of 146 consecutive patients with gastric MALT lymphoma treated at Aichi Cancer Center Hospital and compared the incidence of second malignancies with that in the general population. We calculated the standardized incidence ratio (SIR), using age- and sex-specific incidence rates from the Aichi Cancer Registry. The median follow-up period was 74 months. A total of 27 tumors occurred in 22 patients (15.1%), including 19 solid tumors. Of these, nine tumors were detected concomitantly with, and 18 tumors following, the diagnosis of gastric MALT lymphoma. Four patients had two second malignancies each. For the entire group, the SIR of an additional malignancy was 3.39 (95% confidence interval [CI] 2.11-4.66). An increased incidence of solid tumors (SIR 2.91 [1.60-4.22]) and hematologic malignancies (SIR 5.54 [1.70-9.38]) were seen. In addition, there was increased risk for development of second malignancies during follow up (SIR 2.26 [1.21-3.30]). Chemotherapy for treatment of MALT was an independent risk factor for second malignancies (age-sex adjusted hazard ratio 3.98 [1.47-10.79]. Compared with the general population, patients with gastric MALT lymphoma are at increased risk for second malignancies, including gastric cancer.

Second Malignancy After Treatment for Non-Hodgkin Lymphoma: a Systematic Review and a Meta-Analysis of Population-Based and Cohort Studies.

Abstract 1918Poster Board I-941 Background:The risk of second malignancy in non-Hodgkin lymphoma (NHL) survivors have been described in several studies, but the available evidence have yielded conflicting results. Thus, we performed a systematic review and a meta-analysis on population-based and cohort studies to provide a quantitative assessment of the available evidence on the risk of secondary occurrence of cancer after treatment for NHL. Primary aims of our research were to evaluate the pooled Relative Risk (RR) of second cancer for overall malignancies and for every cancer. Methods:A Medline search from 1985 to 2008 was conducted for identification of relevant observational studies that provide estimates of RR, as measured by standardized incidence ratios (SIR) that is the observed-expected ratio of second malignancy appearing during follow up of NHL. The reference lists of identified articles were inspected to identify additional papers. Criteria for including studies in the meta-analysis were: a) studies on naïve patients with any stage of NHL, b) studies reporting measure of SIR or data allowing such outcome to be derived and c) English language. The article included, had to have been published in peer-reviewed literature. We did not exclude papers on the base of therapeutic regimens. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Pooled RR and 95% confidence interval (CI) were calculated using random effect models. Tests on heterogeneity and sensitivity analysis was conducted. Also, the publication bias was evaluated. Results:Eleven papers meet the inclusion criteria reporting RRs for all malignancies. These studies included 223,593 patients affected by NHL of which 14,952 presented a second cancer. RRs ranged from 0.93-1.90 and the meta-RR for second malignancy was 1.24 (95%CI: 1.11-1.39). The analysis on solid tumours, excluding haematological malignancies, based on seven studies did not show a significantly higher risk for secondary cancer: the meta-RR was 1.06 (95%CI: 0.84-1.34). However, some kind of cancer showed a statistically significant excess of risk, as lung cancer (meta-RR on nine studies: 1.46 95%CI: 1.33-1.59) and bladder cancer (meta-RR on eight studies: 1.42 95%CI: 1.33-1.51). Prostate (meta-RR on ten studies: 1.08 95%CI: 0.93-1.24) and breast cancer (meta-RR on eleven studies: 0.99 95%CI: 0.83-1.19) has demonstrated no evidence of association with NHL therapy. Moreover, we found a higher risk of developing Hodgkin lymphoma and myeloid leukemia (respectively meta-RR on seven studies: 6.44 95%CI: 5.59-11.55 and meta-RR on five studies: 7.81 95%CI: 2.59-24.46). Regarding leukemia, however we have to consider that they include either acute or chronic leukemia and sometime could also include higher risk myelodisplastic syndrome . No evidence of publication bias was observed. Conclusion:Although there exist a number of paper on this topic, until now there are not been attempts to perform a meta-analysis on RR of second malignancies after treatment for NHL. Indeed comparative analysis on the incidence of second cancer presents several issues, including the heterogeneity of NHL, the source of data, the time during which the study was performed, the different schedule of chemotherapy, the dosage of radiotherapy used in the different period of time and the length of follow-up. Although these problems could reduce the accuracy of the meta-analysis, our results indicate that NHL treatment is associated with a significantly higher risk of second malignancy, in particular for some specific cancer like lung and bladder and same haematological malignancies as Hodgkin lymphoma and myeloid leukemia.Finally, we think that it is important to determine by meta-analysis the incidence of each second cancer in survivor of NHL as for some malignancies screening test could be performed and early diagnosis could be made. Disclosures:No relevant conflicts of interest to declare.

The risk of developing second cancers among survivors of childhood soft tissue sarcoma

Previous studies have shown that children who are treated for soft tissue sarcoma (STS) are at increased risk for developing second cancers. However, the risk for specific cancer sites and variations in risk by treatment and STS histology remain unclear. The study evaluated 1499 children (age < 18 years) who survived for > or = 1 year after they were diagnosed with STS and who were reported to the Surveillance, Epidemiology, and End Results (SEER) population-based cancer registries from 1973 to 2000. Twenty-seven children developed 28 subsequent primary malignancies, compared with 4.5 expected malignancies based on general population rates (observed-to-expected [O/E] ratio = 6.3 (95% confidence interval [95% CI], 4.2-9.1). The risk of developing a subsequent malignancy was increased among children with rhabdomyosarcoma (observed = 11 malignancies; O/E ratio = 7.7), fibromatous neoplasms (observed = 9 malignancies; O/E ratio = 5.8), and other specified STS (observed = 7 malignancies; O/E ratio = 6.5). Initial therapy with radiation and chemotherapeutic agents was associated with a significantly higher risk of second malignancies compared with surgery alone (O/E ratio = 15.2 vs. 1.4; P < 0.0001). Elevated risks were observed for acute myeloid leukemia, cutaneous melanoma, female breast cancer, and sarcomas of the bone and soft tissue, with generally higher risks among patients who initially received combined modality therapy. Excess cancers of the oral cavity were prominent among long-term survivors. For several children, the pattern of multiple malignancies was consistent with a genetic syndrome, particularly neurofibromatosis type 1 and Li-Fraumeni syndrome. The risk of second malignancies was increased for all histologic types of childhood STS and was particularly high among patients who received combined modality therapy.

Stage IA–IIB Hodgkin's disease: Management and outcome of extensive thoracic involvement

To examine the presentation, management, and outcome of patients with extensive intrathoracic involvement in early-stage Hodgkin's disease. One hundred seventy-two patients with clinical Stage IA-IIB Hodgkin's disease and extensive intrathoracic involvement were studied. Extensive intrathoracic disease was defined as either large mediastinal adenopathy (LMA, defined as the width of the mass greater than one-third the maximum thoracic diameter, n = 154) or as extensive (> 10 cm) cephalocaudad intrathoracic disease that did not fulfill formal chest radiograph criteria for LMA (n = 18). Patients were divided into three groups based on staging and extent of treatment. Forty-seven patients were treated with radiation alone after a laparotomy (RT-lap), 47 patients received combined modality therapy after laparotomy (CMT-lap), and 78 patients were treated with combined modality therapy without staging laparotomy (CMT-no lap). MOPP was used in 82% of the CMT patients. Low-dose whole-cardiac RT was used in nearly 50% of patients treated either with RT or CMT. The 10-year actuarial freedom from relapse rates were 54% with RT alone and 88% with CMT (p = 0.001); overall survival rates were 84 and 89%, respectively (p = NS). The median time to relapse was only 17 months. Over 80% of relapses occurred within the first 3 years. The most common site of relapse in all patients was the mediastinum. Relapses below the diaphragm were rare, even in CMT patients who did not receive abdominal radiation treatment. The principal acute morbidity was symptomatic pneumonitis, which occurred in 29% of patients receiving any part of their chemotherapy after RT, compared to 13% if all the chemotherapy was given before RT and 11% if RT alone was administered. There was a low late risk of myocardial infarction (3%) in the two groups with the longest follow up (RT-lap, CMT-lap), but a higher risk of second malignancy in the CMT-lap group (21%) compared with the RT-lap group (2%). Extensive intrathoracic involvement is a distinctive presentation of early-stage HD that has a high relapse risk if treated with RT alone. The introduction of CMT has been associated with improvements in freedom from relapse. The low rate of peripheral relapse with CMT suggests that reductions in field size may be achievable. The use of low-dose whole-heart RT with modern techniques is not associated with a high risk of late cardiac complications and should be used in patients who present with extensive pericardial disease or cardiophrenic lymphadenopathy. The high rate of second malignancy in the CMT group with the longest follow-up suggests that careful long-term surveillance for such patients is warranted.

Hodgkin's disease: Study of treatment intensities and incidences of second malignancies

Advances in radiotherapy and chemotherapy have gradually increased cure rates for patients with Hodgkin's disease. With improved long-term survivals, increases in observed second malignancies over those of the general population have been reported as early as 1972. Recently, a number of investigators have suggested that the relative importance of recognized risk factors contributing to the development of acute myelogenous leukemia (AML), non-Hodgkin's lymphomas, and solid tumors may be different. Our study is concerned with the influence of various risk factors on patients who have been treated with modern radiotherapy and combination chemotherapy between 1966 and 1987. We reviewed the records of 1,022 patients with Hodgkin's disease of whom 1,013 had sufficient data for analysis. Kaplan-Meier methodology was used to calculate overall and determinate survivals and occurrences of acute myelogenous leukemia, non-Hodgkin's lymphoma, and solid tumors. The observed to expected incidences, calculated from the SEER incidence and population files for 1976, were compared. Using Cox's proportional hazards model, the following were analyzed singly for risk significance for the entire population: age, stage, splenectomy, treatment modality, treatment intensity, and number of treated relapses. Separate analyses were performed to determine the relative risks for subsets of the population. These included pelvic radiotherapy for those with stage III disease and specific alkylating agents for patients who were treated with chemotherapy only. Sixty-six instances of second malignancy were documented as follows: AML 14, non-Hodgkin's lymphoma 14, and solid tumors 38. The overall incidence of second malignancy was significantly greater than the expected incidence of 21.75 (p = 0.0001) and it was also significant for AML, non-Hodgkin's lymphoma and solid tumors. Analyses for risk of second malignancy demonstrated that age > or = 40 years, stage III or stage IV disease, and treatment with chemotherapy only were all associated with a significantly higher risk of second malignancy than any of the other factors. However, only treatment with regimens containing nitrogen mustard had a significantly higher risk for second malignancy. Treatment intensity and number of treated relapses had no specific effect on risk. Joint modeling of age, stage, and treatment showed that the combination of age and stage was the most significant risk factor for AML and non-Hodgkin's lymphoma (p = < 0.0003). However, only age was important for solid tumors. Our analysis suggests that the most critical host factor for developing a second malignancy was age. The fact that patients with stages III and IV disease had an increased risk of second malignancy regardless of age suggests that biologic factors related to the tumor also may have been significant. However, it is possible that the effect of treatment was hidden by stage.

Similar Histological Patterns in a Bilateral Malignant Teratoma of the Ovary and a Previous Retinoblastoma in a Girl

A 16-year old girl died from a bilateral teratoma of the ovary after she had been treated for a bilateral retinoblastoma at the age of 9 months. Remarkable are the similar morphological patterns of the malignant tissues in both tumors in the different organs. No genetic etiology could be proven by chromosomal analysis. Nevertheless, the reported case may also indicate a higher risk of second malignancies in children successfully treated for retinoblastoma.