You are here

Article Text

Article menu
Review
Implications of cancer prior to and after heart transplantation
  1. Parvathi Mudigonda1,
  2. Cecilia Berardi1,
  3. Vishaka Chetram2,
  4. Ana Barac3,
  5. Richard Cheng1
  1. 1 Department of Medicine, Division of Cardiology, University of Washington, Seattle, Washington, USA
  2. 2 Department of Medicine, MedStar Washington Hospital Center, Georgetown University, Washington, DC, USA
  3. 3 Department of Cardiology, MedStar Heart and Vascular Institute, Georgetown University, Washington, DC, USA
  1. Correspondence to Dr Richard Cheng, Department of Medicine, Division of Cardiology, University of Washington Medical Center, Seattle, WA 98195, USA; rkcheng{at}uw.edu

Abstract

Cancer and cardiovascular disease share many risk factors. Due to improved survival of patients with cancer, the cohort of cancer survivors with heart failure referred for heart transplantation (HT) is growing. Specific considerations include time interval between cancer treatment and HT, risk for recurrence and risk for de novo malignancy (dnM). dnM is an important cause of post-HT morbidity and mortality, with nearly a third diagnosed with malignancy by 10 years post-HT. Compared with the age-matched general population, HT recipients have an approximately 2.5-fold to 4-fold increased risk of developing cancer. HT recipients with prior malignancy show variable cancer recurrence rates, depending on years in remission before HT: 5% recurrence if >5 years in remission, 26% recurrence if 1–5 years in remission and 63% recurrence if <1 year in remission. A myriad of mechanisms influence oncogenesis following HT, including reduced host immunosurveillance from chronic immunosuppression, influence of oncogenic viruses, and the cumulative intensity and duration of immunosuppression. Conversely, protective factors include acyclovir prophylaxis, use of proliferation signal inhibitors (PSI) and female gender. Management involves reducing immunosuppression, incorporating a PSI for immunosuppression and heightened surveillance for allograft rejection. Cancer treatment, including immunotherapy, may be cardiotoxic and lead to graft failure or rejection. Additionally, there exists a competing risk to reduce immunosuppression to improve cancer outcomes, which may increase risk for rejection. A multidisciplinary cardio-oncology team approach is recommended to optimise care and should include an oncologist, transplant cardiologist, transplant pharmacist, palliative care, transplant coordinator and cardio-oncologist.

  • heart transplantation
  • heart failure

https://doi.org/10.1136/heartjnl-2020-318139

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Malignancy prior to heart transplantation

    Due to improved survival of patients with cancer and the use of cardiotoxic chemotherapeutic agents, an increasingly encountered scenario involves patients undergoing evaluation for cardiac transplantation with a history of pretransplant malignancy (PTM). Registry data from the International Society for Heart and Lung Transplantation (ISHLT) showed that from 1992 to 2000, 3.7% of heart transplant recipients (HTr) had prior malignancy, which more than doubled to 8.6% in 2010–2018.1

    The rationale for cancer screening as part of the heart transplant (HT) evaluation is supported by the concern for progression of previously indolent subclinical cancers with post-HT immunosuppression and the well-recognised risk of adverse outcomes in immunosuppressed patients with solid organ cancers.2 3 Accordingly, patients with active or recent cancer (non-skin) have been traditionally excluded from transplant candidacy until they can be considered cured and/or the risk for long-term recurrence is estimated as low. With recent advances in cancer treatment, the prognosis of many cancers continues to rapidly improve, thus bringing into question the validity of historical survivorship definitions and existing screening recommendations, and highlighting the potential need for new methods of risk stratification.

    In patients with a history of malignancy, different durations of lapsed time may be optimal between completing cancer treatment and eligibility for HT. Among other factors, the interval depends on tumour type, response to cancer therapy, risk for recurrence and negative metastatic evaluation.3 While there are site-specific recommendations for time from cancer treatment before listing for kidney transplant, similar criteria have not been developed or consistently adopted for HT. In the kidney transplant recommendations, time intervals are variable depending on the specific cancer type and stage, ranging from 0 to 5 years.4 Conversely, for HT, guidelines have suggested that cancer be in remission for 5 years unless they are low grade.3

    A review by Mistiaen5 compiled 13 retrospective studies of 2017 paediatric and adult patients undergoing HT, finding that cancer recurrence inversely correlated with longer cancer-free periods before transplant: 63% in those cancer-free <1 year, 26% in those cancer-free for 1–5 years and 5% with >5 years cancer-free interval.5

    Table 1 (and online supplemental file 1) summarise the published studies that included >20 HTr with history of PTM. Although outcomes were different across studies, most evaluated cancer-free survival, including the risk of recurrence, risk of new malignancy and overall mortality. In a large analysis of 23 171 HTr through the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) database, history of malignancy was associated with increased risk of cancer post-HT. However, this risk was largely driven by post-transplant skin cancer.6 Another large study that used the UNOS database did not find a significant increase in 1-year or 5-year mortality in patients with PTM.7 In the subgroup matched cohort analysis, based on the PTM diagnosis, only haematological malignancies were associated with higher 1-year post-HT mortality, underscoring the importance of a cancer site-specific approach.7

    Supplemental material

    View this table:
    Table 1

    Selected studies investigating outcomes in patients with pretransplant malignancy

    Recommendations for cancer screening pre-HT

    Most clinical documents addressing cancer screening strategies have included age-appropriate and history-appropriate screening (figure 1), with addition of focused imaging (table 2). The ISHLT listing criteria acknowledges diversity of pre-existing malignancies and outcomes in the setting of contemporary oncology treatments,3 8 but specific recommendations by cancer type are not provided. They recommend collaboration between HT and oncology teams to assure individualised patient risk stratification.

    Figure 1
    Figure 1

    Monitoring for cancer pre-HT and post-HT. BRCA, breast cancer gene; EBV, Epstein-Barr virus; HPV, human papilloma virus; HT, heart transplantation; PTLD, post-transplant lymphoproliferative disease.

    View this table:
    Table 2

    Screening for cancer pre-heart transplant

    Malignancy after HT

    Given the increased risk and high morbidity of cancer post-HT, routine surveillance is recommended. The ISHLT guidelines recommend routine screening for breast, colon and prostate cancer in alignment with standard intervals used for the general population. Additionally, HTr require close skin surveillance with annual dermatological evaluations due to high risk for skin cancers associated with chronic immunosuppression.9

    De novo malignancy

    Over the last three decades, the characteristics of HTr have evolved, with a rise in higher risk individuals receiving HT. From 1992 to 2000, 13.3% of HTr had diabetes mellitus; this more than doubled to 26.9% in 2010–2018, and HTr with a history of dialysis increased from 3% to 4.8%.1 Due to steadily improving survival post-HT, there are now HTr who are older, with chronic comorbidities, who will be exposed to prolonged immunosuppression, all well-established risk factors for malignancy.10 11

    De novo malignancy (dnM) is defined as incident cancer occurring after transplantation not directly related to the transplanted organ. Since 1995, a rising incidence of non-lymphoma cancer has been observed in HTr, largely attributable to an increase in skin cancer.1 12 ISHLT registry data showed that between 1995 and 2018, 16% of HTr developed cancer within 5 years, 28% at 10 years and more than 40% at 15 years after HT.1 HTr with malignancy have significantly lower survival compared with HTr without malignancy or the general population.12 dnM was the most common cause of death in the late-transplant period, overtaking graft failure at 5 years after HT.1

    The most common malignancies in HTr are non-melanoma skin cancers (NMSC), solid malignancies, and rarely lymphomas (table 3 and online supplemental file 1). The ISHLT registry showed the incidence of skin cancer at 5 and 10 years after transplant was 9.6% and 18.5%, respectively. HTr with skin cancer generally had a favourable prognosis and comparable survival with HTr without malignancy. The rates of developing a non-cutaneous solid malignancy at 5 and 10 years after transplant were 6.3% and 10.2%, respectively. Post-transplant lymphoproliferative disease (PTLD) tended to be the most aggressive form of malignancy, with the worst survival; however, the overall incidence was low, with 5-year and 10-year rates of 1% and 1.7%, respectively.1

    View this table:
    Table 3

    Selected studies investigating de novo malignancy in heart transplant recipients

    In summary, dnM is not only common in HTr but potentially life-limiting and a competing risk for death with allograft failure in the intermediate-term to long-term setting. Future research is needed on whether systematic efforts on pretransplant selection and post-HT surveillance would reduce the risk associated with dnM.

    Mechanisms of carcinogenesis

    Drivers of oncogenesis after transplantation are multidomain, with oncogenic viral infections, environmental exposures and a genetic predisposition all aggravated in the milieu of high-intensity and chronic immunosuppression. Long-term immunosuppression, necessary to prevent rejection, is the single most important risk factor for carcinogenesis in HTr. Parallels have been drawn between solid organ transplant recipients (SOTRs) and immunocompromised individuals in that they share an unusually high incidence of cancers uncommon in the general population, including lymphomas, anogenital tumours and tumours related to oncogenic viruses.13 14 On the contrary, common malignancies in the general population such as breast and colorectal cancer are less commonly seen in HTr.12 15 16

    Oncogenic viruses and malignancy associations in HTr include Epstein-Barr virus (EBV) with lymphoma, human herpes virus 8 with Kaposi’s sarcoma, and human papilloma virus (HPV) with urogenital and anogenital cancers, cutaneous squamous cell carcinoma (SCC), and lip and oral cavity cancers.17–19

    dnM development is closely related to the deliberate modulation of the innate immune system, with several proposed mechanisms: (1) reduced immunosurveillance of neoplastic cells and oncogenic viruses, allowing unchecked proliferation; (2) action of oncogenic viruses from latent reactivation in the recipient, acquired from the donor at the time of transplantation or after transplantation; and (3) direct carcinogenic effects of immunosuppressive medications.

    Risk factors for dnM

    Various risk factors for dnM were identified from several large cohort analyses of HTr and other SOTRs. Older age at the time of transplant and male gender were consistently observed. Other strong risk factors were chronic immunosuppression, influence of oncogenic viruses, retransplantation and malignancy prior to HT. Less robust risk factors include recipient smoking history, use of induction immunosuppression, radiation exposure prior to transplantation and genetic variance (figure 2).11–13 15 18 19

    Figure 2
    Figure 2

    Risk factors for malignancy in the general population and specific to heart transplant (figure made with Biorender.com). ATG, antithymocyte globulin; EBV, Epstein-Barr virus; HPV, human papilloma virus; UV, ultraviolet.

    A study using the ISHLT registry between 2000 and 2011 identified several risk factors for developing cutaneous malignancy, non-cutaneous malignancy and PTLD within 5 years of HT.12 In cutaneous malignancies, the strongest association was with older age, later calendar year of transplant, congenital heart disease and retransplant/graft failure. Other risk factors included azathioprine (AZA) use compared with mycophenolate mofetil (MMF), cytomegalovirus mismatch, taller stature, use of interleukin-2 receptor (IL-2R) antagonist or muromonab-CD3 induction, and readmission within 1 year of HT.12

    Risk factors for non-cutaneous solid cancer were older age, recipient former tobacco use, later calendar year of transplant and readmission within 1 year of HT. Risk factors for developing PTLD were cell cycle inhibitor non-use or AZA as compared with MMF use, antithymocyte globulin induction, recipient EBV seronegativity, readmission within 1 year of HT and obesity.12

    Immunosuppression

    Whether induction therapy is directly associated with dnM after HT remains unclear. While the above studies suggested an association,12 13 other studies found similar risk for malignancy with induction and non-induction regimens.20 21

    Direct carcinogenic effects of chronic immunosuppressive medications are well recognised, particularly with AZA and calcineurin inhibitors (CNI). For example, in a cohort that included any SOTR, AZA was associated with a 56% greater risk of developing cutaneous SCC compared with other immunosuppressants.22 23 MMF is a non-competitive inhibitor involved in purine synthesis. A 2005 multicentre randomised trial comparing MMF with AZA over 3 years showed improved survival in patients on MMF. dnM occurred in 15.6% of the AZA group and 12.5% of the MMF group; however, this did not reach statistical significance.24 These findings were supported in a 2006 ISHLT registry analysis of HTr between 1995 and 1997 that showed a lower incidence of dnM in immunosuppressive regimens with MMF as compared with AZA.25

    Sirolimus (SRL) and everolimus are proliferation signal inhibitors (PSI) belonging to the mammalian target of rapamycin (mTOR) inhibitor family. The mTOR pathway regulates cell growth and survival and is frequently dysregulated in various malignancies.26 Hence, it would be anticipated that SRL might reduce the risk of cancer. Supporting this, studies have demonstrated a reduction in risk of malignancy and NMSC in post-transplant patients treated with SRL.27 The lower incidence of malignancy following conversion from CNI to mTOR inhibitors has been attributed to antiproliferative effects, particularly from suppressing tumour growth and angiogenesis.27

    A recent study of 523 patients who underwent HT between 1994 and 2016 examined whether conversion from a CNI-based to SRL-based regimen was associated with decreased risk of malignancy. Over a median follow-up of 10 years post-HT, the risk for malignancies (excluding NMSC) was 13% in those on SRL and 31% in those on CNI-based regimens. Findings were consistent for all dnMs and for PTLD.28 In this study, late survival was better in those on SRL-based regimens who were free from malignancy.

    While prospective trials of PSI use in HT specifically to reduce cancer risk are lacking, these data suggest that individuals at high risk for malignancy after HT (such as those with prior cancer) should be considered for a PSI-based regimen.

    Post-transplant lymphoproliferative disease

    PTLD describes a heterogeneous group of lymphoid disorders that result from abnormal lymphocyte proliferation in the setting of chronic immunosuppression. Disease severity is highly variable and ranges from reactive lymphoid hyperplasia to aggressive malignant lymphomas, most commonly diffuse large B cell lymphoma.17 Serological EBV mismatch at the time of transplant (EBV-positive donor to an EBV-negative recipient) results in a 12-fold increase in the risk for PTLD.29 Nearly 50%–80% of PTLD cases are associated with EBV, especially in the first few years after transplantation. T cell immunity is weakened by cytolytic immunosuppressive agents in transplant recipients, leading to impaired surveillance against EBV and other oncoviruses.29

    The incidence of PTLD in HTr is between 1.2% and 6.5%,30 with a median time to diagnosis of 3.3 years.31 Increased risk of developing PTLD is driven by age extremes (<18 years and >50 years), use of tacrolimus, use of AZA, and most significantly with lymphocyte-depleting antibody agents used for either induction or rejection treatment. The risk was reduced when antiviral prophylaxis was administered with lymphocyte-depleting antibodies, particularly with acyclovir.13 29 Overall, the cumulative degree and duration of immunosuppression drives the risk for PTLD, rather than exposure to any single specific medication.

    Survival was profoundly worse after developing PTLD, with only a third of HTr alive at 5 years.31 32 However, survival improved significantly if complete remission was achieved within 3 months and subsequent rate of relapse was low at 13%. Use of a rituximab-based treatment regimen compared with other chemotherapy for treating PTLD was associated with improved survival in multiple cohorts.31 33 In all cases, the basis for PTLD treatment begins with dose reduction of immunosuppression to restore host immunity.

    Skin cancer

    Skin cancers are the most common post-transplant malignancy and account for 40%–50% of total cancers.34 By 15 years post-HT, nearly a third of HTr will have skin cancer of any type.1 SCC and basal cell carcinoma (BCC) comprise >90% of all skin cancers.35

    Risk factors for skin cancer include ultraviolet radiation exposure, older age at transplant, male gender, white race, smoking, high-intensity immunosuppression, HPV infection, human leucocyte antigen DR (HLA-DR) mismatches and a history of NMSC.12 34 36 Immunosuppression regimens with AZA and/or cyclosporine had a higher incidence of SCC development.27 34 MMF use was associated with a lower risk of SCC and a greater risk of BCC, compared with AZA.34 PSI reduced the risk of NMSC.27

    Despite the high incidence of skin cancer and risk for metastasis, survival is generally favourable and only slightly worse than HTr without malignancy.1 12 36 This may be related to the heightened dermatological surveillance in HTr, leading to early detection of skin cancers.

    Cancer management

    Data are sparse on specific cancer treatment regimens in HTr. Prevailing considerations include (1) the need for clinical pharmacists to review medications for potential drug–drug interactions particularly with CNIs and mTOR inhibitors; (2) the desire to minimise immunosuppression during cancer treatment; (3) potential antioncogenic effects of mTOR inhibitors; and (4) heightened concern for cardiotoxicity risk in a vulnerable cohort. Discussion on treatment for each cancer type is beyond the scope of this review. The primary focus will be on immunotherapy as there are unique considerations for the HTr.

    Immunotherapy

    In recent years, modulation of the immune system, specifically T cell activity, has become a new and important aspect of targeted cancer therapy. Immune checkpoint inhibitors (ICIs) were the first class to be used in clinical practice; chimeric antigen receptor T cells (CAR-T) therapy and bispecific T cell engagers (BiTEs) followed in recent years.

    ICIs are monoclonal antibodies that enhance T cell proliferation and activation by removing inhibitory feedback through different pathways. ICI-associated cardiovascular toxicity can present with myocarditis, non-inflammatory cardiomyopathy, arrhythmia, pericardial disease or vasculitis. In the general population, the incidence of cardiovascular adverse effects in patients treated with ICIs has been reported to be as low as 0% and as high as 5.5%, likely reflecting differences in methods and population characteristics and the lack of standardised diagnostic criteria.37 38

    Little is known regarding ICI use in HTr as they have been generally excluded from clinical trials. In a retrospective case series, three of four HTr treated with ICI had biopsy-proven allograft rejection with cardiac dysfunction, including one death.39 The fourth patient, who received pembrolizumab for metastatic melanoma and remained on tacrolimus monotherapy, was alive at 15 months of follow-up; no specific demographic, malignancy-related or graft-related differences were observed that explained this favourable outcome. A systematic review of 83 patients with kidney, liver or heart transplants treated with ICI showed a 39.8% incidence of allograft rejection, with the vast majority within the first 2 weeks of treatment.40 Overall, 48 (57.8%) patients died. Of six HT patients, only one had rejection, but four out of six died, suggesting that factors beyond rejection may have a prognostic role. Recently, a pharmacovigilance analysis identified 96 reports of any organ transplant rejection after ICI exposure, including five HTr. The median time to rejection in HTr was 5 days with 20% short-term mortality. Across all SOTRs, anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) were more frequently implicated than cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) .41 Unfortunately, the sample sizes in these studies are too small to inform optimal use of ICI in HTr. Due to the rare nature of ICI use in HTr, multicentre registries were developed, including a thoracic-focused registry at the University of Utah39 and a SOTR registry at the University of Washington.

    CAR-T and BiTEs use single-chain variable fragments to direct the activity of cytotoxic T lymphocytes against antigens expressed by tumour cells. The most severe adverse effect is cytokine release syndrome. Generally observed early in the treatment course, this severe inflammatory state can lead to haemodynamic instability, arrhythmia, tachycardia and fluid overload. Data for these newer therapies in HT are lacking.

    While immunotherapy is increasingly used for cancer treatment, its mechanism of action poses specific risks to the HT population (figure 3). A paucity of data is available to estimate the risk of rejection or how best to modulate immunosuppression regimens during immunotherapy. Both rejection and the malignancies treated with immunotherapy carry high mortality, making the risk–benefit balance challenging.

    Figure 3
    Figure 3

    Specific considerations for immunotherapy in heart transplantation recipients. BiTEs, bispecific T cell engagers; CAR-T, chimeric antigen receptor T cells; ICIs, immune checkpoint inhibitors.

    Multidisciplinary approach for individualised cardio-oncology care

    Given the complex decision-making, a multidisciplinary cardio-oncology approach is recommended. This should ideally include the HT cardiology team, an oncologist, pharmacy, palliative care and a cardio-oncologist. These models are increasingly common in other cohorts and should be adopted for the HTr that develops cancer (figure 4). Additionally, given the large mental and psychosocial challenges placed on the patient, early involvement of palliative care can assist with decision-making and care planning in the setting of an uncertain prognostic trajectory.42

    Figure 4
    Figure 4

    Multidisciplinary approach to cancer treatment in heart transplantation recipients.

    Future areas of research

    An international standardised collaboration for studying this unique population is currently lacking but is necessary to achieve a sufficiently sized cohort through a common protocol. Given the rapid improvements in cancer treatment, this field will continue to evolve and there remain many gaps in knowledge and future directions for research. Key considerations are summarised in table 4.

    View this table:
    Table 4

    Gaps in knowledge and future areas of research

    Conclusion

    With progressive improvements in cancer treatment, there is a growing cohort of long-term cancer survivors that develop significant cardiovascular toxicities including severe HF. Multidisciplinary consideration is necessary for decision-making to proceed with HT based on risk for recurrence, mitigating risk for dnM by tailoring immunosuppression and the need to balance immunosuppression with cancer treatment in those with dnM. Given the rapid incorporation of immunotherapy into many cancer treatment regimens, specific implications for HTr need to be recognised. These gaps in knowledge require further exploration to develop an optimal holistic treatment framework for a cohort that will be increasingly encountered.

    Ethics statements

    Patient consent for publication

    References

    1. ↵
      2. Khush KK ,
      3. Cherikh WS ,
      4. Chambers DC , et al
      . The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report - 2019; focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1056–66.doi:10.1016/j.healun.2019.08.004 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31548031
      OpenUrlPubMed
    2. ↵
      2. Conraads VM ,
      3. Denollet J ,
      4. Vorlat A , et al
      . Screening for solid organ malignancies prior to heart transplantation. Transplantation 2001;71:1481–3.doi:10.1097/00007890-200105270-00021 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11391239
      OpenUrlPubMed
    3. ↵
      2. Mehra MR ,
      3. Kobashigawa J ,
      4. Starling R , et al
      . Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates--2006. J Heart Lung Transplant 2006;25:1024–42.doi:10.1016/j.healun.2006.06.008 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16962464
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      2. Batabyal P ,
      3. Chapman JR ,
      4. Wong G , et al
      . Clinical practice guidelines on wait-listing for kidney transplantation: consistent and equitable? Transplantation 2012;94:703–13.doi:10.1097/TP.0b013e3182637078 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22948443
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      2. Mistiaen WP
      . Heart transplantation in patients with previous malignancy. An overview. Acta Cardiol 2015;70:123–30.doi:10.1080/AC.70.2.3073502 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26148371
      OpenUrlPubMed
    6. ↵
      2. Yoosabai A ,
      3. Mehta A ,
      4. Kang W , et al
      . Pretransplant malignancy as a risk factor for posttransplant malignancy after heart transplantation. Transplantation 2015;99:345–50.doi:10.1097/TP.0000000000000563 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25606783
      OpenUrlCrossRefPubMed
    7. ↵
      2. Beaty CA ,
      3. George TJ ,
      4. Kilic A , et al
      . Pre-transplant malignancy: an analysis of outcomes after thoracic organ transplantation. J Heart Lung Transplant 2013;32:202–11.doi:10.1016/j.healun.2012.11.003 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23265911
      OpenUrlPubMed
    8. ↵
      2. Mehra MR ,
      3. Canter CE ,
      4. Hannan MM , et al
      . The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant 2016;35:1–23.doi:10.1016/j.healun.2015.10.023 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26776864
      OpenUrlCrossRefPubMed
    9. ↵
      2. Costanzo MR ,
      3. Dipchand A ,
      4. Starling R , et al
      . The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29:914–56.doi:10.1016/j.healun.2010.05.034 pmid:http://www.ncbi.nlm.nih.gov/pubmed/20643330
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      2. Miao Y ,
      3. Everly JJ ,
      4. Gross TG , et al
      . De novo cancers arising in organ transplant recipients are associated with adverse outcomes compared with the general population. Transplantation 2009;87:1347–59.doi:10.1097/TP.0b013e3181a238f6 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19424035
      OpenUrlCrossRefPubMed
    11. ↵
      2. Sampaio MS ,
      3. Cho YW ,
      4. Qazi Y , et al
      . Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. national transplant database. Transplantation 2012;94:990–8.doi:10.1097/TP.0b013e318270bc7b pmid:http://www.ncbi.nlm.nih.gov/pubmed/23085553
      OpenUrlPubMedWeb of Science
    12. ↵
      2. Youn J-C ,
      3. Stehlik J ,
      4. Wilk AR , et al
      . Temporal trends of de novo malignancy development after heart transplantation. J Am Coll Cardiol 2018;71:40–9.doi:10.1016/j.jacc.2017.10.077 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29301626
      OpenUrlFREE Full Text
    13. ↵
      2. Crespo-Leiro MG ,
      3. Alonso-Pulpón L ,
      4. Vázquez de Prada JA , et al
      . Malignancy after heart transplantation: incidence, prognosis and risk factors. Am J Transplant 2008;8:1031–9.doi:10.1111/j.1600-6143.2008.02196.x pmid:http://www.ncbi.nlm.nih.gov/pubmed/18416739
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      2. Engels EA ,
      3. Pfeiffer RM ,
      4. Fraumeni JF , et al
      . Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011;306:1891–901.doi:10.1001/jama.2011.1592 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22045767
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      2. Higgins RS ,
      3. Brown RN ,
      4. Chang PP , et al
      . A multi-institutional study of malignancies after heart transplantation and a comparison with the general United States population. J Heart Lung Transplant 2014;33:478–85.doi:10.1016/j.healun.2014.01.862 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24630406
      OpenUrlPubMed
    16. ↵
      2. Wong G ,
      3. Au E ,
      4. Badve SV , et al
      . Breast cancer and transplantation. Am J Transplant 2017;17:2243–53.doi:10.1111/ajt.14368 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28544474
      OpenUrlCrossRefPubMed
    17. ↵
      2. Dharnidharka VR ,
      3. Webster AC ,
      4. Martinez OM , et al
      . Post-transplant lymphoproliferative disorders. Nat Rev Dis Primers 2016;2:15088.doi:10.1038/nrdp.2015.88 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27189056
      OpenUrlPubMed
    18. ↵
      2. Geissler EK
      . Post-transplantation malignancies: here today, gone tomorrow? Nat Rev Clin Oncol 2015;12:705–17.doi:10.1038/nrclinonc.2015.186 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26483298
      OpenUrlCrossRefPubMed
    19. ↵
      2. Buell JF ,
      3. Gross TG ,
      4. Woodle ES
      . Malignancy after transplantation. Transplantation 2005;80:S254–64.doi:10.1097/01.tp.0000186382.81130.ba pmid:http://www.ncbi.nlm.nih.gov/pubmed/16251858
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      2. Briasoulis A ,
      3. Inampudi C ,
      4. Pala M , et al
      . Induction immunosuppressive therapy in cardiac transplantation: a systematic review and meta-analysis. Heart Fail Rev 2018;23:641–9.doi:10.1007/s10741-018-9691-2 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29532201
      OpenUrlPubMed
    21. ↵
      2. Hertig A ,
      3. Zuckermann A
      . Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: an update. Transpl Immunol 2015;32:179–87.doi:10.1016/j.trim.2015.04.003 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25936966
      OpenUrlCrossRefPubMed
    22. ↵
      2. Jiyad Z ,
      3. Olsen CM ,
      4. Burke MT , et al
      . Azathioprine and risk of skin cancer in organ transplant recipients: systematic review and meta-analysis. Am J Transplant 2016;16:3490–503.doi:10.1111/ajt.13863 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27163483
      OpenUrlPubMed
    23. ↵
      2. Cho HG ,
      3. Kuo KY ,
      4. Xiao K , et al
      . Azathioprine and risk of multiple keratinocyte cancers. J Am Acad Dermatol 2018;78:27–8.doi:10.1016/j.jaad.2017.09.063 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28989107
      OpenUrlPubMed
    24. ↵
      2. Eisen HJ ,
      3. Kobashigawa J ,
      4. Keogh A , et al
      . Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant 2005;24:517–25.doi:10.1016/j.healun.2005.02.002 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15896747
      OpenUrlCrossRefPubMedWeb of Science
    25. ↵
      2. O'Neill JO ,
      3. Edwards LB ,
      4. Taylor DO
      . Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:1186–91.doi:10.1016/j.healun.2006.06.010 pmid:http://www.ncbi.nlm.nih.gov/pubmed/17045930
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      2. Guba M ,
      3. von Breitenbuch P ,
      4. Steinbauer M , et al
      . Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002;8:128–35.doi:10.1038/nm0202-128 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11821896
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      2. Cangemi M ,
      3. Montico B ,
      4. Faè DA , et al
      . Dissecting the Multiplicity of Immune Effects of Immunosuppressive Drugs to Better Predict the Risk of de novo Malignancies in Solid Organ Transplant Patients. Front Oncol 2019;9:160. doi:10.3389/fonc.2019.00160 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30972289
      OpenUrlPubMed
    28. ↵
      2. Asleh R ,
      3. Clavell AL ,
      4. Pereira NL , et al
      . Incidence of Malignancies in Patients Treated With Sirolimus Following Heart Transplantation. J Am Coll Cardiol 2019;73:2676–88.doi:10.1016/j.jacc.2019.03.499 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31146812
      OpenUrlFREE Full Text
    29. ↵
      2. Dierickx D ,
      3. Habermann TM
      . Post-Transplantation lymphoproliferative disorders in adults. N Engl J Med 2018;378:549–62.doi:10.1056/NEJMra1702693 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29414277
      OpenUrlCrossRefPubMed
    30. ↵
      2. Nagle SJ ,
      3. Reshef R ,
      4. Tsai DE
      . Posttransplant lymphoproliferative disorder in solid organ and hematopoietic stem cell transplantation. Clin Chest Med 2017;38:771–83.doi:10.1016/j.ccm.2017.08.001 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29128025
      OpenUrlCrossRefPubMed
    31. ↵
      2. Kumarasinghe G ,
      3. Lavee O ,
      4. Parker A , et al
      . Post-Transplant lymphoproliferative disease in heart and lung transplantation: defining risk and prognostic factors. J Heart Lung Transplant 2015;34:1406–14.doi:10.1016/j.healun.2015.05.021 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26279197
      OpenUrlCrossRefPubMed
    32. ↵
      2. Opelz G ,
      3. Döhler B
      . Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4:222–30.doi:10.1046/j.1600-6143.2003.00325.x pmid:http://www.ncbi.nlm.nih.gov/pubmed/14974943
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      2. Evens AM ,
      3. David KA ,
      4. Helenowski I , et al
      . Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol 2010;28:1038–46.doi:10.1200/JCO.2009.25.4961 pmid:http://www.ncbi.nlm.nih.gov/pubmed/20085936
      OpenUrlAbstract/FREE Full Text
    34. ↵
      2. Mittal A ,
      3. Colegio OR
      . Skin cancers in organ transplant recipients. Am J Transplant 2017;17:2509–30.doi:10.1111/ajt.14382 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28556451
      OpenUrlCrossRefPubMed
    35. ↵
      2. Fortina AB ,
      3. Caforio AL ,
      4. Piaserico S , et al
      . Skin cancer in heart transplant recipients: frequency and risk factor analysis. J Heart Lung Transplant 2000;19:249–55.doi:10.1016/S1053-2498(99)00137-0 pmid:http://www.ncbi.nlm.nih.gov/pubmed/10713249
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      2. Brewer JD ,
      3. Colegio OR ,
      4. Phillips PK , et al
      . Incidence of and risk factors for skin cancer after heart transplant. Arch Dermatol 2009;145:1391–6.doi:10.1001/archdermatol.2009.276 pmid:http://www.ncbi.nlm.nih.gov/pubmed/20026847
      OpenUrlCrossRefPubMedWeb of Science
    37. ↵
      2. Ball S ,
      3. Ghosh RK ,
      4. Wongsaengsak S , et al
      . Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week. J Am Coll Cardiol 2019;74:1714–27.doi:10.1016/j.jacc.2019.07.079 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31558256
      OpenUrlFREE Full Text
    38. ↵
      2. Lyon AR ,
      3. Yousaf N ,
      4. Battisti NML , et al
      . Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol 2018;19:e447–58.doi:10.1016/S1470-2045(18)30457-1 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30191849
      OpenUrlCrossRefPubMed
    39. ↵
      2. Daud A ,
      3. Mehra MR ,
      4. Siu A , et al
      . Immune checkpoint inhibitors in heart or lung transplantation: early results from a registry initiative. J Heart Lung Transplant 2020;39:604–6.doi:10.1016/j.healun.2020.02.015 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32265077
      OpenUrlPubMed
    40. ↵
      2. d'Izarny-Gargas T ,
      3. Durrbach A ,
      4. Zaidan M
      . Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: a systematic review. Am J Transplant 2020;20:2457–65.doi:10.1111/ajt.15811 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32027461
      OpenUrlCrossRefPubMed
    41. ↵
      2. Nguyen LS ,
      3. Ortuno S ,
      4. Lebrun-Vignes B , et al
      . Transplant rejections associated with immune checkpoint inhibitors: a pharmacovigilance study and systematic literature review. Eur J Cancer 2021;148:36–47.doi:10.1016/j.ejca.2021.01.038 pmid:http://www.ncbi.nlm.nih.gov/pubmed/33721705
      OpenUrlPubMed
    42. ↵
      2. Cheng R ,
      3. Kirkpatrick J ,
      4. MSorror M
      . Cardio-Oncology and the intersection of cancer and cardiotoxicity: the role of palliative care. J Am Coll Cardiol CardioOnc 2019;2:314–7.
      OpenUrl
      2. Ladowski SD ,
      3. Abel M ,
      4. Beatty L , et al
      . Long-term follow-up of hearttransplant recipients with pre-transplant malignancies. Tex Heart Inst J 2006;33:27–30.pmid:http://www.ncbi.nlm.nih.gov/pubmed/16572865
      OpenUrlPubMed
      2. Fernández-Vivancos C ,
      3. Paniagua-Martín MJ ,
      4. Marzoa-Rivas R , et al
      . Long-term outcome in heart transplant patients with pretransplant malignancies. Transplant Proc 2010;42:3006–10.doi:10.1016/j.transproceed.2010.08.012 pmid:http://www.ncbi.nlm.nih.gov/pubmed/20970594
      OpenUrlCrossRefPubMed
      2. Sigurdardottir V ,
      3. Bjortuft O ,
      4. Eiskjær H , et al
      . Long-term follow-up of lung and heart transplant recipients with pre-transplant malignancies. J Heart Lung Transplant 2012;31:1276–80.doi:10.1016/j.healun.2012.09.007 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23089300
      OpenUrlCrossRefPubMedWeb of Science
      2. Delgado JF ,
      3. Alonso-Pulpón L ,
      4. Mirabet S , et al
      . Cancer incidence in heart transplant recipients with previous neoplasia history. Am J Transplant 2016;16:1569–78.doi:10.1111/ajt.13637 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26613555
      OpenUrlPubMed
      2. Kellerman L ,
      3. Neugut A ,
      4. Burke B , et al
      . Comparison of the incidence of de novo solid malignancies after heart transplantation to that in the general population. Am J Cardiol 2009;103:562–6.doi:10.1016/j.amjcard.2008.10.026 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19195521
      OpenUrlPubMed
      2. Collett D ,
      3. Mumford L ,
      4. Banner NR , et al
      . Comparison of the incidence of malignancy in recipients of different types of organ: a UK registry audit. Am J Transplant 2010;10:1889–96.doi:10.1111/j.1600-6143.2010.03181.x pmid:http://www.ncbi.nlm.nih.gov/pubmed/20659094
      OpenUrlCrossRefPubMedWeb of Science
      2. Jiang Y ,
      3. Villeneuve PJ ,
      4. Wielgosz A , et al
      . The incidence of cancer in a population-based cohort of Canadian heart transplant recipients. Am J Transplant 2010;10:637–45.doi:10.1111/j.1600-6143.2009.02973.x pmid:http://www.ncbi.nlm.nih.gov/pubmed/20121725
      OpenUrlCrossRefPubMed
      2. Jäämaa-Holmberg S ,
      3. Salmela B ,
      4. Lemström K , et al
      . Cancer incidence and mortality after heart transplantation - A population-based national cohort study. Acta Oncol 2019;58:859–63.doi:10.1080/0284186X.2019.1580385 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30821595
      OpenUrlPubMed

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Twitter @RichardKCheng2

    • Contributors All authors have read and approved the manuscript. All authors contributed significantly to the final manuscript with design of the review, drafting of the sections, revisions and critical review prior to submission.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.