Incidence Of Second Cancers Research Articles

A Longitudinal Definition of the Value of Cancer Drugs

Background Cancer drugs now account for a greater fraction of the national health care expenditure than ever before. A new movement has been formed that argues for meaningful definition of the value of drugs as a pre-requisite for their approval as well as for clinical decision-making. Numerous frameworks have been designed to allow comparison of different pharmacological agents based on patient-related factors (efficacy, safety, cost). However, these formulas largely ignore chronic, long-term toxicities which are particularly important in the case of highly-curable cancers like Hodgkin Lymphoma and testicular cancer. We propose a drug value scheme that incorporates debilitating and life-threatening long-term toxicities along with traditional factors (efficacy and acute safety) when defining a drug's merit. Methods A longitudinal framework for assessing drug value is suggested. Pertinent drug-related characteristics - efficacy, acute adverse events, and long-term toxicities - are included. For each drug characteristic, patient-centred surrogate markers are chosen: efficacy is defined by the 10-year overall survival, acute safety by the rate of neutropenia and life-threatening infections, and long-term toxicity by the cumulative incidence of secondary cancers and heart disease at 5 and 10 years, respectively. Advanced Hodgkin Lymphoma is chosen for simulation. The most commonly used regimens are compared. Data from high-value prospective clinical trials (see references) are used to grade each regimen. Points are given for each percentile range in each category (higher score for greater efficacy and lower toxicity; see Appendix 1). Percentile intervals are chosen according to the presumed clinical impact. The net value of each regimen is assessed by adding the score for each individual care component and comparing it to a similar model that does not include long-term toxicity. Results Risk score calculation yielded results as shown in Table 1. ABVD And Stanford V gained the highest score (26; of 30) while COPP-EBV-CAD and BEACOPP obtained lower scores (24 and 22, respectively). Stanford V reached a better value score than COPP-EBV-CAD, and was equivalent to ABVD, in contrast to a drug value scheme that neglected long-term toxicities, in which it was inferior to both. The superiority of ABVD to COPP-EBV-CAD and BEACOPP persisted in the model, as was the overall advantage of COPP-EBV-CAD over BEACOPP. Conclusions As the treatment of cancer continues to improve, value should no longer be derived only from a drug's overall survival and acute injury profiles. A more comprehensive appreciation of a drug's benefit-to-risk ratio entails an understanding of its more distant health implications. Our model shows that such an easily-constructible framework results in a different value estimation of drugs compared with the traditional one. Appendix 1: Value Score: - Efficacy * Overall Survival: 7 if <74.9%, 8 if 75.0-80.9%, 9 if 81.0-85.9%, 10 if 86.0-88.9%, 11 if >89.0% - Acute toxicity * Incidence of severe infections: 3 if >10.0%, 4 if 5.0-9.9%, 5 if <4.9% * Incidence of grade 3 neutropenia: 1 if > 50.0%, 2 if 28.0-49.9%, 3 if <27.9% - Late toxicity * Incidence of heart disease at 5 years: 1 if >5.6%, 3 if 4.0-5.5%, 4 if 2.0-3.9%, 5 if <1.9% * Incidence of secondary cancers at 10 years: 6 if <3.9%, 4 if 4.0-9.0%, 3 if 9.1-13.0%, 1 if >13.1% *** Example: ABVD value score = 9 (for OS of 85%) + 5 (for severe infection incidence of 2%) + 3 (for grade 3 neutropenia incidence of 25%) + 3 (for 5-year heart disease incidence of 5.5%) + 6 (for 10-year secondary cancer incidence of 0.9%) = 26

Risk of Developing Second Cancers in Plasmacytoma in United States

Background: There is a well-known risk of developing multiple myeloma in plasmacytoma, especially in solitary bone tumors. However, the risk of other cancers is not clear. The aim of this study was to estimate the risk of second cancers in patients with plasmacytoma, as compared to general population, and patients with multiple myeloma.Methods: Surveillance, Epidemiology and End results (SEER) 18 dataset was queried to identify patients (ageResults: With a follow-up of 13,392 person-years, 331-second cancers were diagnosed in 2046 plasmacytoma survivors (1155 SPB and 891 extraosseous plasmacytoma). The risk of subsequent solid tumors was not higher compared to age and sex matched background population with a SIR of 1.02 (95 % CI .88-1.17 AER 2.23/10,000). The risk was higher for developing multiple myeloma (SIR 30.8 25-38 AER 67/10,000), leukemia (SIR 3.4, 95% CI; 2-5.2 AER 10/10,000) and non-Hodgkin’s lymphoma (NHL) (SIR 3.2, 95 % CI 2.1-4.7 AER 13.4/10,000) in "two-month" survivors of plasmacytoma as compared to general population. The risk of developing solid tumors was similar in SPB (SIR 1.07, 95% CI; .87-1.30 AER 9/10,000) and extraosseous (SIR .98, 95% CI; .77-1.19 AER -5/10,000) plasmacytoma. However the risk of transformation to multiple myeloma was 3.7 fold (hazard ratio 3.7, 95% CI; 2.2-6.3) (p<.001) higher in survivors of SPB (SIR 47.3 95% CI; 37-59 AER 103/10,000) than extraosseous plasmacytoma (SIR 13.6 95% CI; 8.3-21 AER 29/10,000). The mean duration for progression to multiple myeloma was significantly shorter for SPB; 348 months (95% CI; 340-356) vs 404 months (95% CI; 395-415) (p=<.001). The cumulative incidence of subsequent malignancies in the study cohort at 15 years was 24.5% (95% CI; 20.1-29.8) for SPB and 25.9 % (95% CI; 21.8-30.2) for extraosseous plasmacytoma. The risk of second malignancies in survivors of plasmacytoma was similar to survivors of multiple myeloma, and the cumulative incidence of second cancers did not differ according to the type of tumor (extraosseous, SPB, or multiple myeloma) (P=0.48). On a subgroup analysis risk did not change after excluding plasmacytoma survivors who developed multiple myeloma. The risk of NHL was significantly higher for patients with extraosseous plasmacytoma, with 42.3% (24.5-75.6%) of these patients developing NHL after 15 years. This stands in contrast to the 16.2% (11.6-20.1) of multiple myeloma survivors who subsequently developed NHL. The patients with SPB were at intermediate risk.Conclusion: The risk of second cancers in plasmacytoma survivors is not significantly different from the risks for second cancers in survivors of multiple myeloma. The extraosseous plasmacytoma survivors are at higher risk of developing NHL, which suggests further study. The risk of transformation into multiple myeloma, despite lower than solitary plasmacytoma of bone, is still very high (13.6 times than general population), and thus active surveillance by treating physicians is mandatory. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Incidence of cutaneous squamous cell carcinoma in a New Zealand population of chronic lymphocytic leukaemia patients.

Chronic lymphocytic leukaemia (CLL) is associated with an increased incidence and aggressiveness of skin cancers, particularly cutaneous squamous cell carcinoma (cSCC), but little is known about cSCC incidence in Australasian CLL patients. In this retrospective study, we analysed the incidence of cSCC in patients seen at a tertiary hospital in New Zealand (NZ). We retrospectively assessed the clinical history and histology data of CLL patients (n = 371) who presented to the Haematology Department, Christchurch Hospital, NZ during the period 1996-2015. Baseline characteristics, incidence of second cancers, treatment details and overall survival were analysed. During follow-up (median = 11.8 years), 221 second cancers were recorded in 88 patients. Of these cancers, 185 were cSCC, removed from 61 patients. In 56% of these patients, >1 cSCC was removed, and the majority of cSCC occurred following the treatment for CLL. The cumulative incidence of a first cSCC was 11% at 5 years, whereas the cumulative incidence of a subsequent cSCC was 88% at 5 years. The incidence of cSCC in male patients was threefold higher than that reported for the general NZ population. NZ CLL patients have a high incidence of cSCC relative to the levels observed in the general population, which are themselves among the highest in the world. The careful monitoring of CLL patients is warranted, particularly those who have a progressive disease or have had a first cSCC removed.

Risk of secondary cancers in women with breast cancer and the influence of radiotherapy: A national cohort study in Taiwan.

Breast cancer is the most common cancer in women worldwide; thus, the prolongation of survival, and the incidence and risk factors, including radiotherapy, for developing secondary malignancies are important. We compared the incidence of secondary and new primary cancers in women with breast cancer (CAPos) and well-matched for age, geographic region, and monthly income cancer-free controls (CANeg). The risk for secondary cancers with and without radiotherapy was also compared in CAPos women. We enrolled 2422 CAPos patients and CANeg 12,110 controls. In a 4-year follow-up, the secondary cancers risk was significant in the CAPos group (adjusted hazard ratio [AHR]: 1.59; 95% confidence interval [CI]: 1.17–2.18). Only the risk of uterine cancer was significant compared with the controls (AHR: 6.30; 95% CI: 2.28–17.38). CAPos patients and <50 years old had a higher risk for secondary cancers. Developing secondary cancers was significant in the first follow-up year (AHR: 1.51; 95% CI: 1.11–2.06). Radiotherapy had no significant effect on the CAPos group, but it was significant (P = 0.0298) in women ≥60 years old (elderly). We recommend monitoring secondary cancers in CAPos women, especially those <50 years old, and during the first year of follow-up. Radiotherapy should be used more carefully in elderly CAPos women.

Factors Associated With Metachronous Gastric Cancer Development After Endoscopic Submucosal Dissection for Early Gastric Cancer.

To clarify the factors associated with metachronous gastric cancer development after endoscopic submucosal dissection (ESD) for early gastric cancer. Patients who undergo ESD for early gastric cancer have an appreciable risk of developing metachronous gastric cancer. However, there have been few reports on the association between life style and the development of such cancer. Patients with early gastric cancer who underwent ESD at our institution between 2003 and 2012 were enrolled. Metachronous gastric cancer was defined as secondary gastric cancer detected >1 year after initial ESD. Factors, including age, gender, body mass index, eradication of Helicobacter pylori, cigarette smoking, drinking, and continuous use of a proton pump inhibitor, associated with metachronous gastric cancer development were evaluated by Cox proportional hazard regression analysis. A total of 539 patients with a mean 53.6-month follow-up period were analyzed. The 5-year cumulative incidence of secondary gastric cancer was 13.0%. Multivariate analysis exhibited that age of 60 years and above [hazard ratio (95% confidence interval)=4.05 (1.23-13.4)] and cigarette smoking [2.12 (1.19-3.78)] were independent risk factors for metachronous gastric cancer development. Furthermore, ≥20 pack-years of smoking [1.51 (1.03-2.24)] was a significant risk factor with a dose-response relationship (P for trend=0.042). There was no significant association between Helicobacter pylori eradication and metachronous gastric cancer development. This is the first study to demonstrate the detailed association between cigarette smoking and metachronous gastric cancer development.

Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center.

Survivors of heritable retinoblastoma carry a high risk to develop second cancers. Eye-preserving radiotherapy raises this risk, while the impact of chemotherapy remains less defined. This population-based study characterizes the impact of all treatment modalities on second cancers incidence and type after retinoblastoma treatment in Germany. Data on second cancer incidence in 648 patients with heritable retinoblastoma treated between 1940 and 2008 at the German national reference center for retinoblastoma were analyzed to identify associations with treatment. The cumulative incidence ratio (per 1,000 person years) of second cancers was 8.6 (95% confidence interval 7.0-10.4). Second cancer incidence was influenced by type of retinoblastoma treatment but not by the year of diagnosis or by sex. Radiotherapy and systemic chemotherapy increased the incidence of second cancers (by 3.0- and 1.8-fold, respectively). While radiotherapy was specifically associated with second cancers arising within the periorbital region in the previously irradiated field, chemotherapy was the strongest risk factor for second cancers in other localizations. Soft tissue sarcomas and osteosarcomas were the most prevalent second cancers (standardized incidence ratio 179.35 compared to the German population). Second cancers remain a major concern in heritable retinoblastoma survivors. Consistent with previous reports, radiotherapy increased second cancer incidence and influenced type and localization. However, chemotherapy was the strongest risk factor for second malignancies outside the periorbital region. Our results provide screening priorities during life-long oncological follow-up based on the curative therapy the patient has received and emphasize the need for less-detrimental therapies for children with heritable retinoblastoma.

Abstract B37: Chemi-genomic analysis of patient-derived xenografts to identify personalized therapies for medulloblastoma

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. Even with an intensive regimen of surgery, radiation and chemotherapy, one-third of patients still die from their disease. Moreover, survivors suffer devastating side effects including cognitive deficits, endocrine disorders and an increased incidence of secondary cancers later in life. Thus, more effective and less toxic therapies are desperately needed. Recent genomic analyses have identified 4 major subgroups of MB—WNT, SHH, Group 3 and Group 4—that differ in terms of mutations, gene expression profiles and patient outcomes. Despite this heterogeneity, all MB patients currently receive the same therapy. To identify novel therapies for each subgroup of MB, we have assembled a diverse panel of patient-derived xenograft (PDX) lines. These lines, established by orthotopic transplantation of tumor cells obtained from surgery, recapitulate the properties of patients' tumors more accurately than cultured cell lines. We are using these PDX lines to screen small molecule libraries and identify compounds that can inhibit tumor growth and survival. To date we have completed screening of 18 lines, including 10 representing Group 3 MB, the most aggressive and lethal form of the disease. Among the ~7800 compounds tested, we have found 20 that are effective against the majority of Group 3 PDX lines. Ongoing studies are focused on validating the activity of these compounds against additional Group 3 lines and moving the most promising ones forward into in vivo efficacy studies. Similar approaches will be pursued for each of the other subgroups of MB. Drug response data will also be compared with genomic and epigenomic data (whole exome and low coverage whole genome DNA sequencing, DNA methylation analysis, and gene expression profiling) to identify biomarkers of drug responsiveness and key pathways that may be exploited for therapy. Based on these studies, we hope to move away from a one-size-fits-all approach, and begin to treat each patient with therapies that are likely to be effective against their tumor. Citation Format: Jessica M. Rusert, Alexandra Garancher, Yoko T. Udaka, Sebastian Brabetz, Lourdes A. Esparza, Huriye Seker-Cin, Lin Qi, Mari Kogiso, Simone Schubert, Till Milde, Yoon-Jae Cho, Xiao-Nan Li, James M. Olson, John R. Crawford, Michael L. Levy, Marcel Kool, Stefan M. Pfister, Robert J. Wechsler-Reya. Chemi-genomic analysis of patient-derived xenografts to identify personalized therapies for medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B37.

Incidence of Second Cancers in Thyroid Cancer Patients Treated with Radioactive Iodine Ablation: How High Is Really the Risk?

Incidence of Second Cancers in Thyroid Cancer Patients Treated with Radioactive Iodine Ablation: How High Is Really the Risk?

Treatment outcomes and secondary cancer incidence in young patients with hairy cell leukaemia.

Repeated therapy of hairy cell leukaemia (HCL) with treatments that have potential long-term toxicities has raised concerns regarding increased risk for younger patients. We compared clinical outcomes and disease complications in 63 patients with HCL aged ≤40years at diagnosis with 268 patients >40years treated at Memorial Sloan Kettering Cancer Center. The rate of complete remission following initial therapy was 87% and 83% (P=0·71) and estimated 10-year overall survival was 100% and 82% (P=0·25) in younger and older patients, respectively. Younger patients required therapy earlier and had a significantly shorter time between first and second therapy (median: 63months vs. 145months) (P=0·008). Younger patients required significantly more lines of therapy during follow-up. The 10-year cumulative incidence of secondary malignancies in young and old patients was 0·205 and 0·287, respectively (P=0·22). The incidence of secondary cancers in patients aged >40years at diagnosis increased with the number of treatments for HCL (P=0·018). These results highlight that young patients with HCL have shorter responses to treatment and require more lines of therapy to maintain disease control, while attaining similar long-term survival. This has implications in the design of future clinical trials given our findings that secondary malignancies increase with more chemotherapy exposure.

High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer.

Overall survival rates are disappointing for women with early poor prognosis breast cancer. Autologous transplantation of bone marrow or peripheral stem cells (in which the woman is both donor and recipient) has been considered a promising technique because it permits use of much higher doses of chemotherapy. To compare the effectiveness and safety of high-dose chemotherapy and autograft (either autologous bone marrow or stem cell transplantation) with conventional chemotherapy for women with early poor prognosis breast cancer. We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE (1966 to October 2015), EMBASE (1980 to October 2015), the World Health Organization's International Clinical Trials Registry Search Platform, and ClinicalTrials.gov on the 21 October 2015. Randomised controlled trials (RCTs) comparing high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. Two review authors selected RCTs, independently extracted data and assessed risks of bias. We combined data using a Mantel-Haenszel fixed-effect model to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed the quality of the evidence using GRADE methods. Outcomes were survival rates, toxicity and quality of life. We included 14 RCTs of 5600 women randomised to receive high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. The studies were at low risk of bias in most areas.There is high-quality evidence that high-dose chemotherapy does not increase the likelihood of overall survival at any stage of follow-up (at three years: RR 1.02, 95% CI 0.95 to 1.10, 3 RCTs, 795 women, I² = 56%; at five years: RR 1.00, 95% CI 0.96 to 1.04, 9 RCTs, 3948 women, I² = 0%; at six years: RR 0.94, 95% CI 0.81 to 1.08, 1 RCT, 511 women; at eight years: RR1.17, 95% CI 0.95 to 1.43, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.99 to 1.42, 1 RCT, 382 women).There is high-quality evidence that high-dose chemotherapy improves the likelihood of event-free survival at three years (RR 1.19, 95% CI 1.06 to 1.34, 3 RCTs, 795 women, I² = 56%) but this effect was no longer apparent at longer duration of follow-up (at five years: RR 1.04, 95% CI 0.99 to 1.09, 9 RCTs, 3948 women, I² = 14%; at six years RR 1.04, 95% CI 0.87 to 1.24, 1 RCT, 511 women; at eight years: RR 1.27, 95% CI 0.99 to 1.64, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.95 to 1.45, 1 RCT, 382 women).Treatment-related deaths were much more frequent in the high-dose arm (RR 7.97, 95% CI 3.99 to 15.92, 14 RCTs, 5600 women, I² = 12%, high-quality evidence) and non-fatal morbidity was also more common and more severe in the high-dose group. There was little or no difference between the groups in the incidence of second cancers at four to nine years' median follow-up (RR 1.25, 95% CI 0.90 to 1.73, 7 RCTs, 3423 women, I² = 0%, high-quality evidence). Women in the high-dose group reported significantly worse quality-of-life scores immediately after treatment, but there were few statistically significant differences between the groups by one year.The primary studies were at low risk of bias in most areas, and the evidence was assessed using GRADE methods and rated as high quality for all comparisons. There is high-quality evidence of increased treatment-related mortality and little or no increase in survival by using high-dose chemotherapy with autograft for women with early poor prognosis breast cancer.

Risk of second cancers in the era of modern radiation therapy: does the risk/benefit analysis overcome theoretical models?

In the era of modern radiation therapy, the compromise between the reductions in deterministic radiation-induced toxicities through highly conformal devices may be impacting the stochastic risk of second malignancies. We reviewed the clinical literature and evolving theoretical models evaluating the impact of intensity-modulated radiation therapy (IMRT) on the risk of second cancers, as a consequence of the increase in volumes of normal tissues receiving low doses. The risk increase (if any) is not as high as theoretical models have predicted in adults. Moreover, the increase in out-of-field radiation doses with IMRT could be counterbalanced by the decrease in volumes receiving high doses. Clinical studies with short follow-up have not corroborated the hypothesis that IMRT would drastically increase the incidence of second cancers. In children, the risk of radiation-induced carcinogenesis increases from low doses and consequently the relative risk of second cancers after IMRT could be higher than in adults, justifying current developments of proton therapy with priority given to this population. Although only longer follow-up will allow a true assessment of the real impact of these modern techniques on radiation-induced carcinogenesis, a comprehensive risk-adapted strategy will help minimize the probability of second cancers.

Abstract P1-09-02: Higher incidence of second cancers in African American (AA) patients compared to Caucasian patients with a primary breast cancer

Abstract Background: AA women with breast cancer have lower survival rates compared to Caucasian women. Since this lower survival rate may be related to genetic mutations, and environmental/socioeconomically factors, we hypothesize that the same factors may lead to a higher risk of secondary cancers after an initial diagnosis of breast cancer. Method: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Program data using Multiple Primary - Standardized Incidence Ratio parameters. The incidence of second cancer diagnoses in AA and Caucasian women previously diagnosed with breast was compared to the incidence of cancer in the general population matched by age, race, and year of diagnosis. Results are reported as the observed risk divided by the expected risk (O/E). Results: For the 43,688 AA pts, the overall O/E and excess risks were 1.48 and 51.2 compared to 1.11 and 14.7 for the 428,103 Caucasian patients. The mean ages of diagnoses of initial breast cancer diagnosis and second cancer were 57.2 and 65 years for AA patients compared to 61.8 and 70.2 years for Caucasian patients. The following is a summary of statically significant (p &amp;lt;0.05) selected O/E by the site of second cancer : O/E for AA and white by site of second cancerSiteAAWhiteOral Cavity and Pharynx1.651.41Digestive System1.181Respiratory System1.271.13Skin excluding Basal and Squamous1.931.33Breast1.671.18Female Genital System1.110.95Urinary System1.561.18Endocrine System1.521.38All Lymphatic and Hematopoietic Diseases1.261.05 This higher risk of second cancers occurred despite the lower relative survival rate for AA compared to Caucasian patients with a 5-year relative survival rate of 68.6% for AA and 78.3% for Caucasian patients. Conclusions: To our knowledge, this is the first report of the incidence of second cancers in AA patients with breast cancer compared to caucasian. More research to understand the biological, genetic, therapeutic, and environmental factors leading to this higher risk of second cancers is warranted. Citation Format: Diab N, Clark G, Hamlington B, Brzeskiewicz L, Langer L, Diab S. Higher incidence of second cancers in African American (AA) patients compared to Caucasian patients with a primary breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-02.

Second Cancer Risk and Late Mortality in Adult Australians Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Population-Based Cohort Study

We quantified the risk of second cancer and late mortality in a population-based Australian cohort of 3273 adult (≥15 years) allogeneic hematopoietic stem cell transplant recipients (1992 to 2007). Most recipients received nonradiation-based conditioning and a peripheral blood graft from a matched related donor. Using record linkage with death and cancer registries, 79 second cancers were identified a median of 3.5 years after transplantation. The competing-risk adjusted cumulative incidence of second cancers was 3.35% (95% CI, 2.59 to 4.24) at 10 years, and the cancer risk relative to the matched general population was 2.10 (95% CI, 1.65 to 2.56). We observed an excess risk of melanoma and lip, tongue, esophagus, and soft tissue cancers. Cancer risk relative to the general population was elevated for those transplanted for lymphoma, some leukemia subtypes, and severe aplastic anemia, recipients who developed chronic graft-versus-host disease (cGVHD) and irrespective of radiation-based conditioning or stem cell source. In those alive 2 years after transplantation (n = 1463), the cumulative incidence of late mortality was 22.2% (95% CI, 19.7 to 24.9) at 10 years, and the risk of death relative to the matched general population was 13.8 (95% CI, 12.2 to 15.6). In multivariable modeling, risk of late death was reduced for females compared with males and those transplanted for chronic myeloid leukemia compared with acute myeloid leukemia; risk was increased for recipients with discordant sex donors, cGVHD, those undergoing second transplants, and disease relapse. Adults undergoing allogeneic transplantation have unique cancer and mortality risk profiles that continue to warrant prevention and surveillance activities targeted at high-risk subgroups.

Risk of secondary cancers after breast conserving therapy in Japan.

256 Background: There is a growing body of evidence that vast majority of patients with early breast cancer who underwent breast conserving therapy (BCT) live their longer ‘cancer survivor’ lives through modern sophisticated treatment. Accordingly, second malignancies after BCT are on the rise, which are sticky dilemmas accompanied by additional anxiety and need for further medical care. Investigation of secondary malignancies should be made the first priority in Japan as the world's top country for longevity. Methods: In order to investigate the second malignancies after BCT, a cohort study was conducted based on our database from 1982 to mid-2015. Actuarial rates of second malignancies, overall (OS) and cause-specific survival (CSS), were calculated by using the Kaplan-Meier method. We calculated standardized incidence ratios (SIR) for each cancer type corresponding to the national registry. Results: 1,557 patients (49.5%) were followed-up for more than 10 years. At a median follow-up of 113 months, 180 patients had developed a second malignancy. The increases in risk were for leukemia (SIR: 3.89 (1.76–6.84)) and ovarian cancer (SIR: 3.65 (2.26–5.38)). Trends toward increased risk was seen in reno-ureteral cancer (SIR: 2.25 (0.96–4.08)) and endometrial cancer (SIR: 1.59 (0.92–2.43)) though it was not statistically significant. No increased risk was observed for other gastrointestinal and genitourinary cancer, malignant melanoma, lymphoma, thyroid or head and neck cancer. Overall 10-year cumulative incidence of OS was 93.3%, and overall 10-year cumulative incidence of CSS was 95.0%. Overall 10-year incidence of secondary cancer was 5.9%. A total number of secondary malignancies within 10 years was 157 and this number explained 84.4% of all cases observed during follow-up. Secondary cancers continued to occur afterward, and cumulative incidence at 15- and 20-years were 8.4% , and 9.6%, respectively. Conclusions: Secondary cancers after BCT continue to arise as long as patients survive. Given its nature of life-threatening to cancer survivors, attending care team must pay persistent attention to secondary malignancies especially in Japan with the longest life-span.

Second Cancer Risk Up to 40 Years after Treatment for Hodgkin’s Lymphoma

BackgroundSurvivors of Hodgkin’s lymphoma are at increased risk for treatment-related subsequent malignant neoplasms. The effect of less toxic treatments, introduced in the late 1980s, on the long-term risk of a second cancer remains unknown.MethodsWe enrolled 3905 persons in the Netherlands who had survived for at least 5 years after the initiation of treatment for Hodgkin’s lymphoma. Patients had received treatment between 1965 and 2000, when they were 15 to 50 years of age. We compared the risk of a second cancer among these patients with the risk that was expected on the basis of cancer incidence in the general population. Treatment-specific risks were compared within the cohort.ResultsWith a median follow-up of 19.1 years, 1055 second cancers were diagnosed in 908 patients, resulting in a standardized incidence ratio (SIR) of 4.6 (95% confidence interval [CI], 4.3 to 4.9) in the study cohort as compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8 to 5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4 to 51.5). The cumulative incidence of second solid cancers did not differ according to study period (1965–1976, 1977–1988, or 1989–2000) (P=0.71 for heterogeneity). Although the risk of breast cancer was lower among patients who were treated with supradiaphragmatic-field radiotherapy not including the axilla than among those who were exposed to mantle-field irradiation (hazard ratio, 0.37; 95% CI, 0.19 to 0.72), the risk of breast cancer was not lower among patients treated in the 1989–2000 study period than among those treated in the two earlier periods. A cumulative procarbazine dose of 4.3 g or more per square meter of body-surface area (which has been associated with premature menopause) was associated with a significantly lower risk of breast cancer (hazard ratio for the comparison with no chemotherapy, 0.57; 95% CI, 0.39 to 0.84) but a higher risk of gastrointestinal cancer (hazard ratio, 2.70; 95% CI, 1.69 to 4.30).ConclusionsThe risk of second solid cancers did not appear to be lower among patients treated in the most recent calendar period studied (1989–2000) than among those treated in earlier periods. The awareness of an increased risk of second cancer remains crucial for survivors of Hodgkin’s lymphoma. (Funded by the Dutch Cancer Society.)

Secondary Cancer after Allogeneic Hematopoietic Stem Cell Transplantation

▪IntroductionSecondary cancer is one of the life-threatening late complications among long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies have reported that survivors of allo-HSCT had a 2-3-fold increased risk of developing new malignancies compared to the general population, although results were inconsistent among the studies in types, incidence, and risk factors of secondary cancers. We conducted a retrospective single-center study, in order to assess the incidence, risks, and risk factors of developing secondary cancers.MethodsWe retrospectively evaluated data on patients who received a first allo-HSCT for hematological disorders between 1982 and 2012. Cumulative incidences of secondary cancers were estimated, with death without developing secondary cancers treated as a competing risk. Standardized incidence ratios (SIRs) of secondary cancers were calculated using the incident rate in the general population. Multivariate analyses were used to identify risk factors of developing secondary cancers. Variables considered in multivariate analyses were patient age at HSCT (<50, 50 or older), patient gender (male, female), donor type (related, unrelated bone marrow, or unrelated cord blood), disease type (acute leukemia, malignant lymphoma/adult T-cell leukemia, chronic myelogenous leukemia [CML]/myeloproliferative disease [MPD], or others), conditioning regimens (myeloablative with total body irradiation [TBI], myeloablative without TBI, or reduced intensity), graft-versus-host disease (GVHD) prophylaxis (cyclosporine-based or tacrolimus-based), and the presence or absence of chronic GVHD. Kaplan-Meier method was used to calculate survival probability among patients who developed secondary cancers.ResultsA total of 1060 patients were included in the analysis, with the median age of 46 years (1-69) and the median follow-up of 4.2 years. 60% of patients were males. 43% of patients had peripheral blood transplantation from a related donor, 22% had bone marrow transplantation from a related donor, 31% had bone marrow transplantation from an unrelated donor, and the remaining 4% had others including cord blood transplantation or haplo-identical transplantation. Approximately half (49%) of the patients received reduced-intensity conditioning, and in those who received myeloablative regimens, two-thirds had total body irradiation (>10Gy). Overall, 42 secondary cancers were identified: the sites of cancers with >2 patients were esophagus (8), stomach (5), colon (4), oral (4), lung (4) and breast (3). The cumulative incidence rate of developing any secondary cancers at 5, 10, and 15 years after allo-HSCT were 2.5% (95% CI 1.6-3.8%), 5.9% (95% CI 4.1-8.3%), and 8.5% (95% CI 5.6-12.1%), respectively. Allo-HSCT recipients had a 3.4-fold higher risk of developing cancers compared with the general population. SIR was particularly higher for the oral (SIR = 15.3) and esophagus (SIR = 23.4). The development of oral or esophageal cancer was detected at ≥3 years after allo-HSCT. Multivariate analysis showed that patient age ≥50 years, CML/MPD, and chronic GVHD were associated with onset of secondary cancers. As for the site of chronic GVHD, patients who developed oral or intestinal GVHD had a higher incidence of secondary cancers compared with those who did not. The overall survival rate was 62% at 3 years after the diagnosis of a secondary cancer. In 18 of the 42 patients who developed secondary cancers, cancers were diagnosed by routine medical checkups or follow-up screenings at outpatient clinic.ConclusionsRecipients of allo-HSCT have a significantly higher risk of developing secondary cancers than the general population. SIRs were especially higher in oral and esophageal cancers. Lifelong screening is important for patients who have risk factors such as older age and oral or intestinal chronic GVHD. DisclosuresNo relevant conflicts of interest to declare.

Impact of Anti-CD20 Antibodies on the Incidence of Secondary Cancers in Patients Treated for Chronic Lymphocytic Leukemia

Background:An increased incidence of second primary malignancies (SPM) is described in chronic lymphocytic leukemia (CLL). Current hypothesis to explain this phenomenon mainly relies on immunosuppression conferred by both CLL itself and CLL treatment. The imputability of fludarabine has been long recognized but the risk associated with monoclonal antibodies, especially rituximab recently shown to improve overall survival in CLL when combined with fludarabine and cyclophosphamide (FC), remains unknown.Materials and methods:We conducted a retrospective study of the incidence of secondary cancers in 1255 CLL patients diagnosed since 1980 in the University Hospital of Lille to better characterize the possible risk of SPM associated with rituximabResults:Of 1255 patients, 651 (52%) received therapy including rituximab (38%), FC (26.7%), F alone (22.4%), chlorambucil (27.5%), alemtuzumab (15.5%) and bendamustine (9.3%). Rituximab was given either in combination with FC (27.5%), other chemotherapy (2.6%) or as a single-agent (3.5%). There was no significant difference in terms of age (58 versus 62 years), gender, Binet stage, cytogenetic abnormalities and number of regimen received between patients treated with or without rituximab. Median follow-up was 6 years for all patients (range 2-23), 4.8 years (range, 2-8) since initiation of therapy for patients treated without rituximab and 3.6 years (range, 0.2-11) for patients who received rituximab. Median overall survival (OS) was 18 years for patients treated with R-chemotherapy versus 11 years for patients treated with chemotherapy alone (p<0,001). Of 1255 patients, 21.5% were diagnosed with SPM. The incidence of SPM was 17.1% in patients who did not receive treatment compared to 10% in those treated. Among treated patients, the incidence of SPM was significantly higher (19% v 2%) in patients who received rituximab (p <0.001). SPM incidence was increased after R-FC (24.4%), FC (10.5%) compared to other regimen (p<0,001) (table1). Most frequent SPM were skin (25%)-and urologic cancers (23%). Median onset of SPM was 5 years (range, 2-20) without rituximab and 2 years (range, 1-7) with rituximab.Table 1Incidence of SPMpTreatment, %- Purine analogs- FC- RFC- Chlorambucil- Bendamustine- Alemtuzumab- CorticothŽrapie- 1,9 10,5* 24,4* 4,9 0 3,5 0<0,001Conclusion:In this large single center retrospective study, we found an earlier and significantly increased incidence of SPM, mainly skin cancers, in CLL patients treated with R-chemotherapy compared to those given chemotherapy alone. It remains to be determined whether this increased SPM incidence is a due to a direct toxicity of rituximab or merely a collateral consequence of improved OS observed after rituximab. DisclosuresFacon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Cazin:ROCHE: Consultancy; MUNDIPHARMA: Honoraria, Research Funding; NOVARTIS: Honoraria; GILEAD,: Honoraria. Morschhauser:Genentech Inc./Roche: Other: Advisory boards.

Secondary Malignancies in Chronic Lymphocytic Leukemia: A Single Centre Retrospective Analysis of 514 Cases

Background: chronic lymphocytic leukemia (CLL) is characterized by progressive immunodeficiency with high prevalence of infections, autoimmune phenomena and secondary malignancies. The immune deregulation may be due to the disease itself or it may be a consequence of the treatment performed. Despite the use of highly effective chemo-immunotherapy, CLL remains incurable nowadays, even if the availability of new drugs is improving life expectancy.Aims: to evaluate the incidence of second cancers in CLL patients, and to investigate their relationship with disease features and therapy lines.Methods: 514 CLL patients diagnosed and followed from 1983 until 2014 at our Institution were retrospectively evaluated. Secondary cancers were categorized according to the originating organ or tissue; skin cancers were divided into melanoma and non-melanoma. History of neoplasia preceding CLL diagnosis was also registered.Results: clinical, hematological and biological characteristics at CLL diagnosis are listed in Table 1. During the follow up 88 patients (17%) developed secondary cancers, with a mean time from diagnosis to secondary neoplasia of 9 years.Considering tumor site, we observed 9 hematological malignancies, 9 lung, 5 breast, 19 uro-genital tract (5 kidney, 10 prostate, 4 bladder, 2 uterus, and 2 ovarian), 15 gastro-enteric tract (12 colon, 2 gastric and 1 tongue), 4 pancreas, 3 melanoma and 15 skin cancers other than melanoma.No significant differences were observed according to age, gender, Rai/Binet stage and hematologic parameters in patients with or without secondary tumors (Table 1).Considering prognostic features, no association was found with 13q deletion, chromosome 12 trisomy, VHIG mutational status, or with ZAP-70 and CD-38 positivity. On the contrary, the development of second cancers was associated with the presence of chromosome 17p (8% with secondary neoplasia versus 6% without, p=0.05) and 11q deletions (13% versus 9%, p=0.08).Medical history was positive for malignancies in 70 patients (13%): 2 hematological malignancies, 3 airways (2 lower and 1 upper), 3 breast, 6 uro-genital tract (3 bladder, 3 prostate, 2 uterus and 1 ovarian), 3 gastro-enteric tract, 3 skin cancers other than melanoma, and 3 melanoma.As regards treatment, 46/88 (52.3%) and 219/426 (51.4%) patients with or without secondary cancers, underwent at least one therapy line.Eighty-six patients were treated with fludarabine containing regimens, of whom 11 developed a secondary cancer; 180 patients received chlorambucil and 34 developed a secondary tumor. Among 65 patients who underwent alemtuzumab treatment, 10 were later diagnosed with a second cancer.During the follow up, 121 patients died, 18 with secondary malignancy.Of note, 41 patients died from CLL progression, 2 from thrombotic events, 11 from infections and 8 from secondary malignancy.Conclusions: secondary malignancies are not infrequent in patients with CLL and their occurrence is not clearly related to biologic markers or to the treatment performed. A careful clinical follow up, encompassing sex and age adjusted tumors screening, is advisable for an early diagnosis and appropriate treatment of secondary malignancies in CLL.Table 1clinical and laboratory features of 514 CLL patients with or without secondary malignancies. Data are expressed as median (range) or absolute number (%).Secondary malignanciesYes (N=88)No (N=426)Age years64 (39-80)63 (31-90)Gender M/F57/31250/176Follow-up years12 (0-30)12 (1-25)Rai/Binet<C/III> C/III85 (97) 3 (3)401 (94) 25 (6)WBC x10e3/mmc18.74 (3.6-138)17.3 (3-384)ALC x10e3/mmc12.63 (1.8-91.8)11.9 (1.4-381)Hb g/dL14 (9-17)14 (8-18)PLT x10e3/mmc198 (77-608)184 (58-472)LDH U/L325 (144-838)334 (142-795)Beta2microglobulin mg/L2 (1-23)2 (0-10)FISH*Del11qDel13qDel17p+126 (13) 19 (40) 4 (8) 6 (13)23 (9) 101 (40) 15 (6) 38 (15)VHIG unmutated**15 (42)80 (39)ZAP-70 positive***14 (39)73 (36)CD-38 positive****15 (42)76 (37)*Tested in 48 and 252 patients respectively. **Tested in 36 and 205 patients respectively. ***Tested in 33 and 182 patients respectively. ****Tested in 56 and 291 patients respectively. DisclosuresNo relevant conflicts of interest to declare.

Secondary cancers after a childhood cancer diagnosis: a nationwide hospital-based retrospective cohort study in Japan

The epidemiology of secondary cancers in childhood cancer survivors has been unknown in Asian countries. Our aim is to assess the incidence and risk factors for secondary cancers through a nationwide survey in Japan. A retrospective cohort study comprising 10,069 children who were diagnosed with cancer between 1980 and 2009 was conducted in 15 Japanese hospitals. The cumulative incidence rate was calculated using death as the competing risk and compared by the Gray method. The standardized incidence ratio (SIR) was defined as the ratio of the number of observed cancers divided by the number of expected cancers. The risk factors were analyzed using Cox regression analysis. One hundred and twenty-eight patients (1.3%) developed secondary cancers within a median follow-up of 8.4years. The cumulative incidence rate was 1.1% (95% confidence interval [CI] 0.9-1.4) at 10years and 2.6% (95% CI 2.1-3.3) at 20years after primary cancer diagnosis. Sensitivity analysis, limited to 5-year survivors (n=5,387), confirmed these low incidence rates. The SIR of secondary cancers was 12.1 (95% CI 10.1-14.4). In the Cox analysis, the hazard ratios for secondary cancers were 3.81 (95% CI 1.53-9.47) for retinoblastoma, 2.78 (95% CI 1.44-5.38) for bone/soft tissue sarcomas, and 1.81 (95% CI 1.16-2.83) for allogeneic stem cell transplantation. The cumulative incidence of secondary cancers in children in Japan was not high; however, the SIR was relatively high. Retinoblastoma or sarcoma in addition to allogeneic stem cell transplantation were significant risk factors for secondary cancers.

Radiotherapy Compared to Other Strategies in the Treatment of Stage I/II Follicular Lymphoma: A Study of 404 Patients with a Median Follow-Up of 15 Years.

PurposeTo investigate outcome for patients with follicular lymphoma (FL) stage I-II treated at a population-based referral institution with a median follow-up of 15 years. Overall and cause-specific survival was compared to that of a sex, age and residency matched individuals from normal population.Material and Methods404 patients with early stage FL treated between 1980 and 2005 were retrospectively analyzed. Two of three patients had stage I disease. Based on clinical characteristics, first line treatments were radiotherapy (RT) (48% of patients), chemotherapy (CT) (16%), combined chemo-and radiotherapy (CRT) (16%) or observation (OBS) (15%). Survival was modeled with Kaplan-Meier methodology. Multivariate analyses were performed with the Cox model.ResultsFifteen years overall survival (OS), progression free survival (PFS) and time to next treatment (TNT) were 50% (95% confidence interval [CI]: 45–55), 42% (95% CI: 36–47) and 48% (95% CI, 42–54), respectively. For patients treated with RT 97% achieved a complete remission, and 15 year OS, PFS and TNT were 57% (95% CI, 50–64), 46% (95% CI, 39–54) and 49% (95% CI, 42–57), respectively. Relapse rate after RT and CRT was 49% and 36%, respectively. Only 2% of patients who received RT or CRT relapsed inside the radiation field and 5% had isolated near-field relapse. No statistical differences were found between treatment groups regarding death from cardiovascular disease or incidence of second cancer. Compared to a matched normal population, non-lymphoma cancer mortality was higher among patients given RT, hazard ratio 1.66 (95% CI: 1.14–2.42; P<0.01). Compared to other treatment modalities, patients selected for observation without treatment did not have inferior outcome.ConclusionsA differentiated treatment strategy in early stage FL results in long term survival for the majority of patients. OBS is a valid initial choice for selected patients without lymphoma-related symptoms.