Enfermedad tromboembólica venosa en hemopatías malignas: un enfoque desde la prevención / Venous thromboembolic disease in hematologic malignancies: a preventive approach

Introducción: La enfermedad tromboembólica venosa es una complicación frecuente en las hemopatías malignas, con incidencia similar a la observada en tumores sólidos de alto riesgo trombótico. Objetivo: Describir la influencia de factores de riesgo y biomarcadores de la enfermedad tromboembólica venosa asociada a hemopatías malignas y su aplicación en el diseño de modelos de evaluación de riesgo para la prevención de esta enfermedad. Métodos: Se realizó una revisión exhaustiva en la literatura especializada de artículos publicados sobre la temática a través de las bases de datos: PubMed, SciELO, ScienceDirect, Medline y el motor de búsqueda Google académico. Análisis y síntesis de la información: En pacientes con hemopatías malignas han sido descritos múltiples factores de riesgo para la ocurrencia de eventos tromboembólicos venosos: moleculares, relacionados con el paciente, la enfermedad y el tratamiento, así como biomarcadores de riesgo. Basados en ellos, varias investigaciones han sido desarrolladas para elaborar y validar modelos predictivos de enfermedad tromboembólica venosa que guíen la estratificación del riesgo y el tratamiento profiláctico de esta enfermedad en hemopatías malignas, aunque aún son insuficientes. Enfermedades como los linfomas y el mieloma múltiple tienen más investigaciones en esta área que el resto de las hemopatías malignas. Conclusión: Se necesita diseñar nuevos modelos de riesgo y validar los existentes en un mayor número de casos; así como desarrollar estudios prospectivos en pacientes con riesgo de eventos tromboembólicos y hemopatías malignas, para realizar una estrategia de prevención primaria personalizada con estratificación de la tromboprofilaxis(AU)

Introduction: Venous thromboembolic disease is a frequent complication in hematologic malignancies with incidence similar to that observed in solid tumors with high thrombotic risk. Objective: To describe the influence of risk factors and biomarkers of venous thromboembolic disease associated with hematologic malignancies and their application in the design of risk assessment models for the prevention of this disease. Methods: An exhaustive review was carried out in the specialized literature of articles published on the subject using the following databases: PubMed, SciELO, ScienceDirect, Medline and the academic Google search engine. Analysis and synthesis of the information: Multiple risk factors for the occurrence of venous thromboembolism have been described in patients with hematologic malignancies: patient-related, disease-related, treatment-related and molecular, as well as biomarkers of risk. Based on these, several investigations have been developed to elaborate and validate predictive venous thromboembolism models to guide risk stratification and prophylactic treatment of venous thromboembolic disease in hematologic malignancies, although they are still insufficient. Lymphomas and multiple myeloma have more research in this area than other hematologic malignancies. Conclusion: There is a need to design new risk models and validate existing ones in a larger number of cases, as well as to develop prospective studies in patients at risk of thromboembolic events and hematologic malignancies, to carry out a personalized primary prevention strategy with thromboprophylaxis stratification(AU)

Prophylactic donor lymphocyte infusion for relapse prevention: a meta-analysis.

OBJECTIVE: Primary disease relapse (PDR) of malignant hematologic conditions after standard hematopoietic stem cell transplant (HSCT) is one of the most challenging diseases; therefore ongoing researches are aiming at relapse prevention and minimizing the transplant-related side effects. Prophylactic donor lymphocytes (pDLI) had been proposed as a valuable strategy for PDR prevention, but early studies had been discouraging due to the limited benefit and possible association with acute graft-versus-host disease (aGVHD). Therefore, we conducted a meta-analysis to evaluate the association between pDLI use, PDR, aGVHD and OS. METHOD: We performed a comprehensive literature search in MEDLINE, Cochrane library and Embase database from inception to May 2019 for studies that evaluated the association between pDLI and PDR. We conducted a random effect meta-analysis of 9 studies involving a total of 748 participants (pDLI = 398, non-pDLI = 350) and reported the pooled odd ratio (OR) for association of pDLI use, PDR, aGVHD and OS. RESULT: We found a significant decreased odd of PDR in the pDLI group (pooled OR = 0.42, 95% CI 0.30-0.58, I2 = 0%), but there was no significant increased odd of aGVHD (pooled OR of 0.98, 95% CI 0.56-1.72, I2 = 0.8%). We also found that there was an increased odd of overall survival (OS) (pooled OR 3.17, 95% CI 1.85-5.45, I2 = 50.2%). CONCLUSION: There are significantly decreased odd of PDR and increased odd of OS in the pDLI group compared to the control group, but there is no statistically significant increased odd of aGVHD as suggested by previous studies. We concluded that pDLI is a potentially valuable method for post-transplant PDR prevention.

Increased risk of second primary hematologic and solid malignancies in patients with mycosis fungoides: A Surveillance, Epidemiology, and End Results analysis.

BACKGROUND: Mycosis fungoides (MF) is associated with increased risk of second primary hematologic malignancies, but its association with second primary solid tumors is less well characterized. OBJECTIVE: This retrospective analysis seeks to assess the risk of being diagnosed with a second primary hematologic or solid malignancy in patients with MF. DESIGN: We performed an analysis of patients diagnosed with MF from 2000 through 2015 in the United States cancer registries of SEER-18 (N = 6742). RESULTS: Relative risks were estimated by using standardized incidence ratios (SIRs). Among 6742 patients, there were 511 (7.5%) second cancer events (SIR, 10.15; 95% confidence interval [CI], 9.29-11.07). These included 184 (36.0%) hematologic malignancies (SIR, 39.71; 95% CI, 34.05-46.05) and 327 (64.0%) solid tumor malignancies (SIR, 7.33; 95% CI, 6.56-8.17). Patients with MF were at increased risk for non-Hodgkin lymphoma; Hodgkin lymphoma; melanoma; and lung, female breast, prostate, colon, and renal cancers. Females were at higher risk than males (P < .05). All ethnic groups showed a statistically significant elevation in SIRs. Elevation of SIRs was observed across all stages of MF. CONCLUSIONS AND RELEVANCE: Patients with MF are at increased risk for diagnosis of second primary malignancies and should be carefully screened for discernable signs and symptoms of second malignancies.

[Therapeutic cancer vaccination for treatment of haematological cancers].

Few trials testing the clinical efficacy of therapeutic cancer vaccination have been successful, and therapeutic cancer vaccines are yet to enter the clinic for treatment of haematological cancers. The review summarises the present knowledge of the interplay between cancer and the immune system. These novel insights have uncovered knowledge, which can be used to enhance the effect of therapeutic cancer vaccines in haematology. Immune checkpoint inhibitors, immunomodulating agents, radiotherapy and vaccination against regulatory mechanisms can potentially increase the clinical effect of cancer vaccines for haematological cancer.

Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders.

A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.

Prevention and treatment of relapse after stem cell transplantation in lymphoid malignancies.

Relapse is now the major cause of treatment failure after allogeneic HSCT (alloHSCT). Many novel strategies to address this critical issue are now being developed and tested. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg, Germany in November 2016, international experts presented and discussed recent developments in the field. Some approaches may be applicable to a wide range of patients after transplant, whereas some may be very disease-specific. We present a report from the session dedicated to issues related to prevention and treatment of relapse of lymphoid malignancies after alloHSCT. This session included detailed reviews as well as forward-looking commentaries that focused on Hodgkin lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma, diffuse large cell and follicular lymphoma, and multiple myeloma.

[Donor Lymphocyte Infusions (DLI): Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Injections de lymphocytes du donneur (DLI) : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Donor lymphocyte infusion (DLI) can be proposed to treat or prevent the relapse of malignant hemopathies following allogeneic stem cell transplantation. The efficiency has been mainly reported in the treatment of CML and low-grade lymphomas while the anti-tumoral activity is less in forms of acute leukemia and myelodysplastic syndromes. The GVL benefit should always be compared to the possible toxic effects of GVHD. This article updates the initial SFGM-TC recommendations, proposed in 2013, that were focused on the use of DLI. Doses of DLI in the context of haplo-identical stem cell transplantation are now indicated. We confirm that remaining mobilized stem cells may be used as classical DLI. The definition and the place of preemptive and prophylactic DLI are precisely given. Recommendations regarding the quality of thawed DLI as well as necessary clinical and biological follow-up are also described in detail.

Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia.

Ataxia telangiectasia (A-T) is a primary immunodeficiency with mutations in the gene encoding the A-T mutated (ATM) protein that interacts with immune, hematopoietic, and endocrine targets resulting in broad multi-systemic clinical manifestations with a devastating outcome. Apart from a progressive neurodegenerative disorder, A-T leads to significantly increased susceptibility to malignancies. It is a matter of discussion whether pre-emptive allogeneic hematopoietic stem cell transplantation (alloHSCT) using a reduced intensity conditioning regimen would be an option to restore immune-competence and prevent malignancy, as shown in animal models, because conventional treatment protocols of malignant diseases using radio- and/or chemotherapy have a high rate of therapy-related morbidity and mortality in these patients. We present the course of the disease, including immune reconstitution and neurological outcome following pre-emptive alloHSCT in a 4-year-old boy with A-T on a 6 year follow-up. Our manuscript provides a proof-of-concept of alloHSCT as an individual pre-emptive treatment strategy from which some A-T patients might benefit.

Micronutrient Intake and Risk of Hematological Malignancies in Adults: A Systematic Review and Meta-analysis of Cohort Studies.

There has been accumulating evidence that several micronutrients may play a protective role in the risk of solid cancers. However, their role in hematological malignancies remains to be elucidated; this meta-analysis aims to evaluate the associations between micronutrient intake as well as supplementation and risk of hematological cancer in adults. Eligible cohort studies (examining intake of vitamin A, vitamin C, vitamin D, vitamin E, lycopene, folate, iron, carotenoids, beta-carotene, selenium, pyridoxine) were sought in PubMed up to July 31, 2016. Random-effects models were used for the calculation of pooled relative risks (RR) with their 95% confidence intervals (CI). Twelve cohort studies were deemed eligible. Null associations were noted regarding supplemented vitamin A (pooled relative risk [RR] = 0.92, 95% confidence interval [CI]: 0.80-1.07), supplemented vitamin C (pooled RR = 1.00, 95%CI: 0.90-1.12), total vitamin D (pooled RR = 1.05, 95%CI: 0.91-1.20), supplemented vitamin E (pooled RR = 0.98, 95%CI: 0.88-1.10), and dietary lycopene intake (pooled RR = 1.00, 95%CI: 0.86-1.16) and the risk of non-Hodgkin lymphoma. No summary estimates are provided for other hematological malignancies due to the limited number of studies. Future prospective trials should be conducted for a better understanding of this field; especially regarding Hodgkin lymphoma, leukemia and plasma cell neoplasms, on which data are scarce.

Building a Cardio-Onco-Hematology Program.

PURPOSE OF REVIEW: This review aims to outline the general principles of how to build a cardio-onco-hematology clinic, acknowledging that there are diverse practices ranging from private community settings to academic hospitals and each practice environment has to build its own program. RECENT FINDINGS: The refinement of regimens and introduction of molecularly directed therapies have substantially increased survival rates for patients with cancer. In fact, a number of previous imminently fatal malignant disease processes have been turned into chronic diseases, such that patients now live with certain incurable cancers as they do, for instance, with rheumatoid arthritis. Improved cure rates and longer survivals have raised side effects of cancer treatments to a completely new level of significance. Cardiovascular toxicities are of particular concern given their impact on morbidity and mortality. In most extreme cases, patients might be cured from cancer but remain debilitated or die prematurely because of cardiovascular disease. Furthermore, not an insignificant proportion of cancer patients start cancer therapy with cardiovascular risk factors and diseases at baseline. With the aging of the population, this "joint venture" is only expected to increase with important implications for the management of cancer patients. Given the need for familiarity with both, cancer and cardiovascular diseases and their ever-evolving start-of-the-art therapy and interaction potential, specialized efforts have been invoked, which may collectively be termed "onco-cardiology," "cardio-oncology," or "cardio-onco-hematology." Herein, we provide recommendations for the creation and optimization of any such programmatic efforts.

Enfermedad Mínima Residual en leucemia: rompiendo el paradigma de remisión completa / Residual minimal disease: breaking the paradigm of complete remission

Las malignidades hematológicas constituyen un grupo heterogéneo de condiciones. La enfermedad mínima residual (EMR) hace referencia a la presencia de enfermedad maligna hematológica, en pacientes que se encuentran en remisión según análisis convencionales. La EMR ha mostrado tener importancia pronóstica en condiciones como: leucemia mieloide aguda, leucemia mieloide crónica, mieloma múltiple, y en leucemia linfoide aguda y crónica. La detección ultrasensible de este estado podría permitir una mejor estratificación del riesgo y de igual forma abrir oportunidades para intervenciones terapéuticas tempranas. En el siguiente artículo se realiza una breve revisión acerca de la importancia pronóstica de la EMR en diferentes malignidades hematológicas(AU)

Hematological malignancies constitute a heterogeneous group of conditions. Residual minimal disease (RMS) refers to the presence of haematological malignancy in patients who are in remission if conventional pathological analyzes are used. RMS has been shown to have prognostic significance in conditions such as: acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, and acute and chronic lymphoblastic leukemia. Ultrasensitive detection of this condition could allow a better risk stratification and open opportunities for early therapeutic interventions. In the following article there will be a brief review about the prognostic importance of RMS in different hematologic malignancies(AU)

Comprehensive review of post-organ transplant hematologic cancers.

A higher risk for a variety of cancers is among the major complications of posttransplantation immunosuppression. In this part of a continuing series on cancers posttransplantation, this review focuses on the hematologic cancers after solid organ transplantation. Posttransplantation lymphoproliferative disorders (PTLDs), which comprise the great majority of hematologic cancers, represent a spectrum of conditions that include, but are not limited to, the Hodgkin and non-Hodgkin lymphomas. The oncogenic Epstein-Barr virus is a key pathogenic driver in many PTLD cases, through known and unknown mechanisms. The other hematologic cancers include leukemias and plasma cell neoplasms (multiple myeloma and plasmacytoma). Clinical features vary across malignancies and location. Preventive screening strategies have been attempted mainly for PTLDs. Treatments include the chemotherapy regimens for the specific cancers, but also include reduction of immunosuppression, rituximab, and other therapies.

[Preventative and therapeutic relapse strategies after allogeneic hematopoietic stem cell transplantation: Guidelines from the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Stratégies préventives et thérapeutiques de la rechute après allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Disease relapse remains the first cause of mortality of hematological malignancies after allogeneic hematopoietic stem cell transplantation (allo-HCT). The risk of recurrence is elevated in patients with high-risk cytogenetic or molecular abnormalities, as well as when allo-HCT is performed in patients with refractory disease or with persistent molecular or radiological (PET-CT scan) residual disease. Within the frame of the 7th annual workshops of the francophone society for bone marrow transplantation and cellular therapy, the working group reviewed the literature in order to elaborate unified guidelines for the prevention and treatment of relapse after allo-HCT. For high risk AML and MDS, a post transplant maintenance strategy is possible, using hypomethylating agents or TKI anti-FLT3 when the target is present. For Philadelphia positive ALL, there was a consensus for the use of post-transplant TKI maintenance. For lymphomas, there are no strong data on the use of post-transplant maintenance, and hence a preemptive strategy is recommended based on modulation of immunosuppression, close follow-up of donor chimerism, and donor lymphocytes infusion. For multiple myeloma, even though the indication of allo-HCT is controversial, our recommendation is post transplant maintenance using bortezomib, due to its a good toxicity profile without increasing the risk of GVHD.

Hematologic neoplasms: Dendritic cells vaccines in motion.

Dendritic cells (DCs) are bone-marrow-derived immune cells accounted for a key role in cancer vaccination as potent antigen-presenting cells within the immune system. Cancer microenvironment can modulate DCs maturation resulting in their accumulation into functional states associated with a reduced antitumor immune response. In this regard, a successful cancer vaccine needs to mount a potent antitumor immune response able to overcome the immunosuppressive tumor milieu. As a consequence, DCs-based approaches are a safe and promising strategy for improving the therapeutic efficacy in hematological malignancies, particularly in combinations with additional treatments. This review summarizes the most significant evidence about the immunotherapeutic strategies performed to target hematologic neoplasms including the tumoral associated antigens (TAA) pulsed on DCs, whole tumor cell vaccines or leukemia-derived DCs.

Coste-efectividad de una estrategia de cribado del virus de la hepatitis B para prevenir la reactivación en pacientes con neoplasia hematológica / Cost-effectiveness of a hepatitis B virus screening strategy to prevent reactivation in patients with hematologic neoplasms

Introducción: se analizó la efectividad de una estrategia de cribado de la infección por el virus de la hepatitis B (VHB) con consiguiente profilaxis en pacientes con neoplasia hematológica para evitar la reactivación del VHB. Material y métodos: se utilizó un árbol de decisión para comparar costes y eficacia (reactivaciones evitadas), en 18 meses, de una estrategia con cribado previo a quimioterapia con R-CHOP (rituximab, ciclofosfamida, doxorrubicina, vincristina y prednisona) versus una estrategia sin cribado. Los pacientes HBsAg+ (antígeno de superficie de la hepatitis B) y/o antiHBc+ (anticuerpos del núcleo de la hepatitis B) y ADN-VHB+ recibieron profilaxis antiviral con tenofovir disoproxil desde el inicio de la quimioterapia hasta un año después de su finalización. Los pacientes sin cribado recibieron tenofovir en caso de reactivación. Las probabilidades del modelo se obtuvieron de la literatura. El coste total (Euros, 2015) incluyó: profilaxis antiviral, R-CHOP, pruebas de cribado (HBsAg, antiHBc y ADN-VHB) y función hepática. El coste farmacológico se calculó con el precio de venta al laboratorio aplicando la deducción obligatoria. Resultados: en una cohorte hipotética de 1.000 pacientes, el cribado evitó 7,36 reactivaciones frente a la estrategia sin cribado (14,9 versus 22,3). El coste total/paciente (incluyendo 8.282 Euros de coste de R-CHOP) fue de 8.584 Euros para la estrategia con cribado y 8.449 Euros para la estrategia sin cribado. La relación coste-efectividad incremental del cribado versus la estrategia sin cribado fue de 18.376 Euros/reactivación evitada. Conclusión: el cribado de la infección por el VHB permite implementar una profilaxis antiviral en pacientes con alto riesgo de reactivación, disminuyendo la frecuencia de dichas reactivaciones en pacientes con neoplasias hematológicas en tratamiento quimioterapia, con un coste incremental aceptable (AU)

Introduction: The effectiveness of a screening strategy for the detection of a hepatitis B virus (HBV) infection followed by prophylaxis in order to prevent HBV reactivation was assessed in patients with hematologic neoplasms. Material and methods: A decision tree was developed to compare the cost and effectiveness (prevented reactivations) over an 18 month period of a screening strategy prior to chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) with a non-screening approach. HBsAg+ (hepatitis B surface antigen) and/or anti-HBc+ (antibodies to hepatitis B core antigen) and HBV-DNA+ patients received oral antiviral prophylaxis with tenofovir disoproxil (245 mg once daily) from chemotherapy baseline until one year after chemotherapy completion. Non-screened patients received tenofovir in case of a reactivation. Model probabilities were obtained from the literature. The total cost (Euros, 2015) included: antiviral prophylaxis, R-CHOP, screening tests (HBsAg, anti-HBc, HBV-DNA) and liver function tests. Drug therapy costs were estimated using ex-factory prices with mandatory deductions. The incremental cost-effectiveness ratio (ICER) was calculated in order to assess the cost-effectiveness of this intervention in terms of cost per reactivation averted versus no screening. Results: In a hypothetical cohort of 1,000 patients, screening prevented 7.36 reactivations when compared to the non-screening approach (14.9 versus 22.3). Total cost/patient (including Euros 8,282 for R-CHOP) was Euros 8,584 for the screening strategy and Euros 8,449 for the non-screening approach. The ICER for screening versus non-screening was Euros18,376/prevented reactivation. Conclusion: HBV screening followed by oral antiviral prophylaxis yielded more health benefits than non-screening, reducing HBV reactivation in patients with hematologic neoplasms on chemotherapy (AU)

Posicionamiento y actitudes de manejo sobre la profilaxis antifúngica en el paciente hematológico (proyecto PROMIC) / Consensus opinion on antifungal prophylaxis in haematologic patients: Results of the PROMIC project

Introducción. La enfermedad fúngica invasora (EFI) es una importante causa de morbimortalidad en pacientes hematológicos. La profilaxis antifúngica (PAF) está indicada en muchos episodios de este grupo de pacientes. El objetivo de este trabajo fue alcanzar un consenso sobre el abordaje profiláctico de las EFI en el paciente hematológico con el fin de optimizar su manejo. Métodos. Un comité de expertos en hematología y enfermedades infecciosas planteó un cuestionario de 79 ítems con aspectos controvertidos sobre la profilaxis antifúngica en el paciente hematológico. El cuestionario fue evaluado en dos rondas por un panel de expertos siguiendo una metodología Delphi modificada. Resultados. El cuestionario fue respondido por 44 expertos en hematología y enfermedades infecciosas. Tras dos rondas de evaluación se consensuaron 48 ítems en el acuerdo (60,7%) y 19 en el desacuerdo (24%) por lo que hubo consenso en 67 de los 79 ítems planteados (84,8%). Se consensuaron los perfiles de pacientes candidatos a profilaxis y se dilucidaron cuestiones relacionadas con indicaciones, mecanismos de acción, espectro de actividad, toxicidad e interacciones de los antifúngicos. Se analizó particularmente la utilidad de micafungina como profilaxis de EFI. Se consensuó que micafungina es un antifúngico a considerar en este contexto. Puede presentar ventajas sobre otros antifúngicos por su seguridad y menor potencial de interacciones. Conclusiones. Se encontró un alto nivel de consenso en el manejo de la profilaxis de la EFI en el paciente hematológico. Este consenso ofrece indicaciones prácticas sobre su manejo óptimo y puede ayudar a determinar el perfil de los pacientes idóneos a recibir este tipo de intervención (AU)

Introduction. Invasive fungal disease (IFD) is an important cause of morbidity and mortality in haematological patients. Antifungal prophylaxis (AFP) is indicated for a number of clinical scenarios in this group of patients. The aim of this study was to reach a consensus on IFD prophylaxis in haematological patients in order to optimize their management. Methods. A committee of experts in haematology and infectious diseases compiled a survey of 79 items with controversial aspects about antifungal prophylaxis in haematological patients. The survey was evaluated in two rounds by a panel of experts following a modified Delphi methodology. Results. Forty-four experts in haematology and infectious diseases answered the survey. After two evaluation rounds, consensus was reached in 67 of the 79 items (84.8%), specifically 48 items were consensually agreed on (60.7%) and 19 were disagreed on (24.0%). Consensus was reached on prophylaxis candidates profiles and questions related to indications, mechanisms of action, spectrum of activity, toxicity and interactions of antifungal were elucidated. The usefulness of micafungin in IFD prophylaxis was particularly analysed. The consensus reached was that micafungin is an antifungal to be considered in this context as its safety profile and lower interaction potential may be advantageous. Conclusions. A broad consensus was found in the management of IFD prophylaxis in the haematological patient. This consensus provides practical indications about its optimal management and can help determine the profile of patients eligible for this type of intervention (AU)

Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners' Oral Contraception Study.

BACKGROUND: Oral contraceptives have been used by hundreds of millions of women around the world. Important questions remain regarding the very long-term cancer risks that are associated with oral contraception. Despite previous research, important questions remain about the safety of these contraceptives: (1) How long do endometrial, ovarian, and colorectal cancer benefits persist? (2) Does combined oral contraceptive use during the reproductive years produce new cancer risks later in life? (3) What is the overall balance of cancer among past users as they enter the later stages of their lives? OBJECTIVES: The purpose of this study was to examine the very long-term cancer risks or benefits associated with the use of combined oral contraceptives, including the estimated overall life-time balance. STUDY DESIGN: The 46,022 women who were recruited to the UK Royal College of General Practitioners' Oral Contraception Study in 1968 and 1969 were observed for up to 44 years. Directly standardized rates of specific and any cancer were calculated for "ever" and "never" users of combined oral contraceptives; data were standardized for age, parity, social class, and smoking. Attributable risk and preventive fraction percentages were calculated. Poisson regression that adjusted for the same variables was used to estimate incidence rate ratios between ever and never users and to examine effects by time since last oral contraceptive use. RESULTS: There were 4661 ever users with at least 1 cancer during 884,895 woman-years of observation and 2341 never users with at least 1 cancer during 388,505 woman-years of observation. Ever use of oral contraceptives was associated with reduced colorectal (incidence rate ratio, 0.81; 99% confidence interval, 0.66-0.99), endometrial (incidence rate ratio, 0.66; 99% confidence interval, 0.48-0.89), ovarian (incidence rate ratio, 0.67; 99% confidence interval, 0.50-0.89), and lymphatic and hematopoietic cancer (incidence rate ratio, 0.74; 99% confidence interval, 0.58-0.94). An increased risk of lung cancer was seen only among ever users who smoked at recruitment. An increased risk of breast and cervical cancer that was seen in current and recent users appeared to be lost within approximately 5 years of stopping oral contraception, with no evidence of either cancer recurring at increased risk in ever users with time. There was no evidence of new cancer risks appearing later in life among women who had used oral contraceptives. Thus, the overall balance of cancer risk among past users of oral contraceptives was neutral with the increased risks counterbalanced by the endometrial, ovarian, and colorectal cancer benefits that persist at least 30 years. CONCLUSION: Most women who choose to use oral contraceptives do not expose themselves to long-term cancer harms; instead, with some cancers, many women benefit from important reductions of risk that persist for many years after stopping.