Review
Heart: first published as 10.1136/heartjnl-2020-318139 on 1 July 2021. Downloaded from http://heart.bmj.com/ on December 12, 2023 at Universidad Nacional Autonoma de Mexico.
► Additional supplemental
material is published online
only. To view, please visit the
journal online (http://d​ x.​doi.​
org/1​ 0.​1136/​heartjnl-­​2020-­​
318139).
1
Department of Medicine,
Division of Cardiology,
University of Washington,
Seattle, Washington, USA
2
Department of Medicine,
MedStar Washington Hospital
Center, Georgetown University,
Washington, DC, USA
3
Department of Cardiology,
MedStar Heart and Vascular
Institute, Georgetown
University, Washington, DC, USA
Correspondence to
Dr Richard Cheng, Department
of Medicine, Division of
Cardiology, University of
Washington Medical Center,
Seattle, WA 98195, USA;
​rkcheng@​uw.​edu
Received 27 March 2021
Accepted 2 June 2021
Published Online First
1 July 2021
© Author(s) (or their
employer(s)) 2022. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Mudigonda P,
Berardi C, Chetram V, et al.
Heart 2022;108:414–421.
414   Mudigonda P, et al. Heart 2022;108:414–421. doi:10.1136/heartjnl-2020-318139
Implications of cancer prior to and after
heart transplantation
Parvathi Mudigonda,1 Cecilia Berardi,1 Vishaka Chetram,2 Ana Barac,3
Richard Cheng ‍ ‍1
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.
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 indo-
lent subclinical cancers with post-­HT immunosup-
pression 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 recommenda-
tions, 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
Protected by copyright.
time from cancer treatment before listing for kidney
transplant, similar criteria have not been developed
or consistently adopted for HT. In the kidney trans-
plant 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 remis-
sion for 5 years unless they are low grade.3
A review by Mistiaen5 compiled 13 retrospective
studies of 2017 paediatric and adult patients under-
going 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 Trans-
plantation 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 anal-
ysis, based on the PTM diagnosis, only haemato-
logical malignancies were associated with higher
1-­year post-­HT mortality, underscoring the impor-
tance of a cancer site-­specific approach.7
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Heart: first published as 10.1136/heartjnl-2020-318139 on 1 July 2021. Downloaded from http://heart.bmj.com/ on December 12, 2023 at Universidad Nacional Autonoma de Mexico.
Table 1 Selected studies investigating outcomes in patients with pretransplant malignancy
Study Study design, population Outcome Comments
Ladowski et al43 Retrospective, HTr 10-­year survival was 63% for PTM and 62% for no PTM Younger, leaner patients with a cured PTM show similar
(p=NS). long-­term survival to patients without PTM.
­ ivancos et al44
Fernández-V Retrospective, SOTR SOTR with PTM: pooled HR. PTM associated with increased risk of all-­cause
► All-­cause mortality: HR 1.51. mortality, cancer-­specific mortality and dnM
► Cancer-­related mortality: HR 3.13. development.
► dnM development: HR 1.92.
Sigurdardottir et al45 Retrospective, heart and lung Remission <1 year had worse survival than >1 year Cancer-­free survival of 5 years before heart or lung
recipients (p=0.044). transplant is associated with the lowest recurrence.
Beaty et al7 Retrospective, heart and lung PTM hazard of mortality in HTr, all cancer: PTM largely not associated with reduced survival
recipients ► 30-­day: HR 1.19, p=0.40. post-­HT, with notable exception for haematological
► 1 year: HR 0.87, p=0.35. malignancies.
► 5 years: HR 0.99, p=0.98.
PTM hazard of mortality in HTr, haematological:
► 30-­day: HR 1.82, p=0.04.
► 1 year: HR 1.93, p<0.001.
► 5 years: HR 1.54, p=0.01.
Mistiaen5 Systematic review, HTr Short-­term and long-­term post-­HT survival similar in PTM HT safe in PTM, especially with remission interval >5
vs no PTM. years.
Remission <1 year had markedly lower 5-­year survival Haematological malignancies pretransplant had worst
compared with a longer remission. post-t­ ransplant survival.
Yoosabai et al6 Retrospective, HTr PTM increased risk of post-­HT cancer. PTM increased the risk of post-­transplant malignancy,
► Any cancer: SHR 1.51. especially skin cancer.
► Skin: SHR 2.79. Older, white, men were risk factors for post-­transplant
► Solid organ malignancy: SHR 1.54. malignancy.
Delgado et al46 Retrospective, HTr ► 1-­year survival: PTM 95%, non-­PTM 93%. No significant differences of mortality incidence rates
► 5-­year survival: PTM 74%, non-­PTM 79%. or HR in HTr with PTM and without PTM. Mortality
► 10-­year survival: PTM 65%, no PTM 51% (p=0.048). declined in the recent time periods. Women had
►

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Cancer-­related mortality: leading cause of death in significantly better survival than men.
PTM (32.1%) and penultimate cause of death in no Overall PTM associated with higher post-­transplant
PTM (21.3%), after cardiovascular causes (22.8%). tumour incidence and haematological malignancies had
lower 10-­year survival compared with no PTM.
Please see online supplemental file 1 for the expanded version of this table.
dnM, de novo malignancy; HT, heart transplant; HTr, heart transplant recipients; PTM, pretransplant malignancy; SHR, subhazard ratio; SOTR, solid organ transplant recipient.

Recommendations for cancer screening pre-HT
Most clinical documents addressing cancer screening strate-
gies 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.
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 immunosup-
pression, all well-­established risk factors for malignancy.10 11
Mudigonda P, et al. Heart 2022;108:414–421. doi:10.1136/heartjnl-2020-318139
De novo malignancy (dnM) is defined as incident cancer occur-
ring 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, over-
taking 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 trans-
plant 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
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.
415
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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.
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 immuno-
suppression, 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,
Table 2 Screening for cancer pre-­heart transplant
Author Year Cancer screening recommendations
Mehra et al3
2006 ► Stool for occult gastrointestinal bleeding ×3.
► Colonoscopy if indicated or >50 years of age.
► Mammography if indicated or women >40 years of age.
► Gynaecological examination/Pap test in sexually active
women >18 years of age.
► PSA and digital rectal examination in men >50 years
of age.
► Serum protein electrophoresis/urine protein
electrophoresis if multiple myeloma suspected.
Mehra et al8 2016 In addition to the above, consider the following:
► Chest X-­ray and chest CT.
► Oesophagogastroduodenoscopy.
► Colonoscopy.
Pap, Papanicolaou smear test; PSA, prostate-­specific antigen.
416
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Protected by copyright.
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 modula-
tion of the innate immune system, with several proposed mech-
anisms: (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 immuno-
suppressive 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
A study using the ISHLT registry between 2000 and 2011
identified several risk factors for developing cutaneous malig-
nancy, non-­cutaneous malignancy and PTLD within 5 years of
HT.12 In cutaneous malignancies, the strongest association was
Mudigonda P, et al. Heart 2022;108:414–421. doi:10.1136/heartjnl-2020-318139
 Review

Table 3 Selected studies investigating de novo malignancy in heart transplant recipients
Study
Crespo-­Leiro et al,13 retrospective
Kellerman et al,47 prospective
Collett et al,48 retrospective
Jiang et al,49 retrospective
Engels et al,14 retrospective
Sampaio et al,11 retrospective
Higgins et al,15 retrospective
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Conclusions
► Most dnMs were skin cancers (50%) and NHL (10%).
► ATG use was a strong risk factor for lymphomas and non-­skin cancers in the absence of acyclovir prophylaxis.
► Male gender and age ≥45 years were risk factors for all cancers, except lymphoma.
► Smoking before HT was a risk factor for all cancers, except skin cancer and lymphoma.
► Oncogenic viruses had a strong association with dnM: EBV with lymphoma and HPV with cervical cancer.
► Older age and retransplantation were significant risk factors for dnM.
► Cancer incidence in HTr greater than twofold compared with general population.
► NMSC was the most common.
► Low incidence of breast and cervical cancer in SOTRs, overall.
► Male gender and older age were common in dnM after HT.
► NMSC was excluded (lower SIR in this study).
► Most common cancers in HTr were lymphomas, oral cancers and lung cancer.
► Lymphomas most common in the first year after HT and the most common cancer in young HTr.
► Risk factors for malignancy development in HTr were smoking, sun exposure and prior malignancy.
► HTr at an increased risk of developing dnM compared with the general population.
► Cancer incidence higher in thoracic organ recipients compared with abdominal organ recipients.
► In all SOTRs, older age and male gender were risk factors for malignancy.
► Most common dnM in HTr were lung cancer, PTLD and colorectal cancer.
► NMSC was excluded (declining malignancy risk over 15 years and lower malignancy rates).
► No significant gender differences were observed.
► Lung cancer, lymphomas and melanomas were the most common cancers.
► Risk factors for dnM were older age and earlier era of transplant.
► 5-­year survival: lung cancer 21%, lymphoma 32%, prostate cancer and melanoma >50%.

Youn et al,12 retrospective ► Between 1 and 5 years after HT, >10% of HTr developed dnM.
► HTr with dnM had worse survival than HTr without dnM.
► Overall cancer incidence rising during the studied periods, largely due to skin cancer incidence.

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Jäämaa-­Holmberg et al, 50 prospective ► Compared with general population, HTr had higher cancer incidence, with greater morbidity and three times the mortality
rate.
► Most common cancers were NMSC (BCC 31% and SCC 21%), followed by NHL (13.5%).
► DnM risk increased temporally over the study duration.
► Male gender was a powerful risk factor, with over 95% of all observed cancers in men.
Please see online supplemental file 1 for the expanded version of this table.
ATG, antithymocyte globulin; BCC, basal cell carcinoma; dnM, de novo malignancy; EBV, Epstein-­Barr virus; HPV, human papilloma virus; HT, heart transplant; HTr, heart
transplant recipient; NHL, non-­Hodgkin's lymphoma; NMSC, non-­melanoma skin cancer; PTLD, post-­transplant lymphoproliferative disorder; SCC, squamous cell carcinoma; SIR,
standardised incidence ratio; SOTR, solid organ transplant recipient.

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.
Mudigonda P, et al. Heart 2022;108:414–421. doi:10.1136/heartjnl-2020-318139 417
 Review
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 inter-
leukin-2 receptor (IL-­2R) antagonist or muromonab-­CD3 induc-
tion, 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 asso-
ciation,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 immu-
nosuppressants.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 inhib-
itors (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 demon-
strated 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 vari-
able and ranges from reactive lymphoid hyperplasia to aggres-
sive malignant lymphomas, most commonly diffuse large B cell
418
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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 cyto-
lytic 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 anti-
bodies, 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
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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 expo-
sure, 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 metas-
tasis, 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 phar-
macists to review medications for potential drug–drug inter-
actions 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 immuno-
therapy 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
Mudigonda P, et al. Heart 2022;108:414–421. doi:10.1136/heartjnl-2020-318139

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.
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 prolifer-
ation 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
Figure 4 Multidisciplinary approach to cancer treatment in heart transplantation recipients.
Mudigonda P, et al. Heart 2022;108:414–421. doi:10.1136/heartjnl-2020-318139
Review
Heart: first published as 10.1136/heartjnl-2020-318139 on 1 July 2021. Downloaded from http://heart.bmj.com/ on December 12, 2023 at Universidad Nacional Autonoma de Mexico.
population characteristics and the lack of standardised diag-
nostic 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 rejec-
tion, but four out of six died, suggesting that factors beyond
rejection may have a prognostic role. Recently, a pharmacovigi-
lance analysis identified 96 reports of any organ transplant rejec-
tion 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.
Protected by copyright.
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 treat-
ment course, this severe inflammatory state can lead to haemo-
dynamic instability, arrhythmia, tachycardia and fluid overload.
Data for these newer therapies in HT are lacking.
While immunotherapy is increasingly used for cancer treat-
ment, its mechanism of action poses specific risks to the HT
419
 Review

Table 4 Gaps in knowledge and future areas of research
Scenario
Malignancy prior to HT:
► What screening should be required prior to HT?
► What is the optimal time interval after cancer
treatment prior to HT?
► How do you estimate risk for recurrence or secondary
malignancy in those with prior cancer prior to HT? ► Current risk estimates use standard oncological
Risk for cancer after HT:
► What is the optimal screening after HT?
► Should immunosuppression regimens be tailored
based on risk for cancer?
► Should immunosuppression be minimised as much
as possible?
Management of post-­HT cancer:
► How much can immunosuppression be reduced in
those with active cancer?
Heart: first published as 10.1136/heartjnl-2020-318139 on 1 July 2021. Downloaded from http://heart.bmj.com/ on December 12, 2023 at Universidad Nacional Autonoma de Mexico.
Current practice Gaps in knowledge and implications
► Standard population screening and incorporation of ► For patients in shock, can some aspects of this
imaging such as CT chest and abdomen. be skipped? In particular, colonoscopy may be
► Current recommendations and most programmes wait challenging in an unstable patient.
5 years after cancer prior to HT. ► Survival and risk for recurrence varies by cancer type,
stage and treatment. With improving treatment for
risk tools and do not account for chronic cancer, can HT be considered sooner in those with
immunosuppression after HT. good prognosis?
► The impact of immunosuppression on risk for
recurrence likely varies by cancer type. Additional
studies are needed on this topic.
► Despite increased risk for cancer, standard population ► It remains unclear whether intensified screening for
screening with addition of skin examinations are cancer post-­HT would lead to earlier detection or
performed. better long-­term outcomes. There is a need to balance
► Most HT programmes use standard protocols and do additional testing and risk for incidental findings with
not tailor regimens based on risk. benefit.
► Most HT programmes have set dosing for ► Rather than a reactive approach, data are needed on
immunosuppression that is reduced over time and whether a pre-­emptive approach may improve long-­
then reduced further when there is a complication. term outcomes in high-­risk patients. Considerations
include avoiding induction immunosuppression or an
early transition to sirolimus.
► The optimal immunosuppression regimen prevents
rejection, and coronary vasculopathy while minimising
risk for malignancy needs further study.
► Most programmes reduce immunosuppression in ► Can HT patients be reduced to monotherapy or even
those with active cancer. temporarily hold immunosuppression during cancer

► Is there increased risk for cardiotoxicity in HT
patients?
► Is immunotherapy an option in HT patients?
HT, heart transplantation; HTr, heart transplant recipients; ICI, immune checkpoint inhibitor.
► Risk estimates for cardiotoxicity from the general
population are used in HT.
► There are limited data on immunotherapy in HT
patients.
Protected by copyright.
treatment?
► Are HT patients more susceptible to cardiotoxicity
from cancer treatments such as anthracyclines,
tyrosine kinase inhibitors or radiation therapy?
► The use of ICI will continue to increase, creating a
difficult decision-­making scenario for HT transplants
with cancer. Research is paramount to understanding
whether ICI therapy is a viable option in HTr,
which patients are at increased risk, what type of
surveillance is necessary and how to manage HTr who
experience ICI-­associated rejection.

population (figure 3). A paucity of data is available to estimate
the risk of rejection or how best to modulate immunosuppres-
sion regimens during immunotherapy. Both rejection and the
malignancies treated with immunotherapy carry high mortality,
making the risk–benefit balance challenging.
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 involve-
ment of palliative care can assist with decision-­making and care
planning in the setting of an uncertain prognostic trajectory.42
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.
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. Multi-
disciplinary 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.
Twitter Richard Cheng @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.

420 Mudigonda P, et al. Heart 2022;108:414–421. doi:10.1136/heartjnl-2020-318139


Patient consent for publication Not required.
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.
ORCID iD
Richard Cheng http://orcid.org/0000-0001-5994-5998
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