Second Primary Malignancies in

Cancer Survivors
Danielle M. Fournier, MSN, AGPCNP-BC, and Angela F. Bazzell, DNP, FNP-BC

ABSTRACT
Advances in early detection and treatment of cancer have resulted in a growing
population of cancer survivors across the United States. Cancer survivors may be at
increased risk for the development of a second primary malignancy as a result of
environmental factors, genetic predisposition, or as a late effect of the cancer treatment
they received. This review examines the risk for second primary malignancy and
necessary screening in the six cancers with the highest 5-year survival rates, including:
breast cancer, Hodgkin’s lymphoma, melanoma, prostate, testicular, and thyroid
cancer.

Keywords: cancer screening, cancer survivor, second primary malignancy, surveillance

Ó 2017 Elsevier Inc. All rights reserved.

INTRODUCTION cancer, including chemotherapy, radiotherapy, and

A
dvances in the early detection and treatment
of cancer have contributed to a growing
population of cancer survivors. As of 2016,
there were 15.5 million cancer survivors in the
United States, and it is estimated this number will rise
to 20.3 million by 2026.1,2 An individual is
recognized as a cancer survivor from the time of their
diagnosis throughout the remainder of their life.3
Survivorship can be divided into three distinct stages:
diagnosis to the end of treatment, transition from
active treatment to extended survival, and long-term
survival.3 The average 5-year survival rate for any
cancer diagnosed between 2005 and 2011 was 69%;
however, in select cancer diagnoses, this figure is
much higher.4
Cancer survivors have an increased likelihood of
developing a second primary malignancy (SPM),
which is defined as a neoplasm that arises indepen-
dently in a new site or tissue at least 2 months after
the primary cancer is diagnosed.5 In cancer survivors,
the lifetime risk of developing a SPM may be as high
as 33%.1 The risk of SPM in survivors may be because
of environmental exposures, genetic predisposition,
or the cancer treatment they received. Tobacco and
alcohol consumption, obesity, sun exposure, and
infections are some of the contributing factors in the
development of SPMs.5 Therapies used to treat
hormone therapy, may increase a patient’s risk to
develop a subsequent malignancy. With an
expanding population of cancer survivors, the
incidence and mortality caused by a SPM will
likely increase.1
According to the National Cancer Institute’s
Surveillance, Epidemiology and End Results (SEER)
program, the cancers with the highest survival rates
include: breast, Hodgkin’s lymphoma, melanoma,
prostate, testicular, and thyroid cancer, all of which
have an overall 5-year survival rate of greater than
85%.4 Because of the high chance of cure with these
diagnoses, the vast majority of these patients will
become cancer survivors. This review provides
information for nurse practitioners (NPs) on the risk
of SPMs in adult cancer survivors after a diagnosis of
breast, Hodgkin’s lymphoma, melanoma, prostate,
testicular, and thyroid cancer (Table), and examines
screening guidelines for these populations.
BREAST CANCER
Breast cancer is the most frequently diagnosed ma-
lignancy in the US, with approximately 246,660 new
cases of invasive breast cancer and 61,000 new cases
of in situ breast cancer diagnosed in women in 2016.4
Over the last 3 decades, the 5-year relative survival
rate of breast cancer in women has increased to 89%.2

238 The Journal for Nurse Practitioners - JNP Volume 14, Issue 4, April 2018
 When diagnosed while the cancer is localized

Central nervous system

Hodgkin’s lymphoma
(without lymph node involvement or distant spread
outside of the breast), the 5-year survival rate is 99%.4
Thyroid Cancer

Non-Hodgkin’s

 Salivary gland
Hereditary cancer syndromes (BRCA1/2) and

lymphoma
Melanoma
Leukemia
exposure to cancer therapies (chemotherapy,

Myeloma

 Stomach
Kidney
Breast

radiation therapy, and hormonal therapy) place breast

Colon

cancer survivors at risk for SPMs. The most common










SPMs seen in breast cancer survivors include
malignancies of the contralateral breast, lung, pleura,
Connective tissue

esophagus, thyroid, bone, uterus, and ovary, as well

Testicular Cancer

as sarcoma and leukemia.6-11

Esophagus

Melanoma

Testicular
Leukemia

In the last 20 years, the incorporation of post-

Pancreas

Stomach
Bladder

Thyroid
Rectum
Kidney

Pleura
Colon

operative radiation therapy in breast cancer treatment

Lung

has become commonplace because studies have
















shown that it decreases locoregional breast cancer

recurrence and improves overall survival.7 While
Soft tissue

tissue-sparing radiation techniques have improved,

Bladder

Thyroid
Kidney
Prostate
Cancer

breast cancer patients who receive radiation therapy

are at higher risk for SPM in tissue and organs that are





adjacent to the breast because radiation has the

potential to cause genetic mutations that lead to
Articular cartilage

carcinogenesis.6-8 The risk for a SPM is 23% for

Non-Hodgkin’s

Salivary gland
Colon/rectum

irradiated breast cancer survivors, compared with 8%

Melanoma

lymphoma
Melanoma

Soft tissue

for survivors who did not receive radiation. Survivors

Prostate
Table. Risks for second primary malignancies (SPM) by Primary Cancer Site

Thyroid
Kidney
Breast
Brain

remain at risk for a SPM for more than a decade after

Bone

Skin

completion of treatment.6















The highest risk for a SPM in breast cancer

survivors is cancer in the contralateral breast, which
 Urothelial tract
Non-Hodgkin’s

may be a consequence of radiation exposure during

 Oropharynx
lymphoma
Melanoma
Lymphoma

treatment.10 The relative risk for a contralateral breast

Hodgkin’s

 Thyroid
GI tract
Breast
Cervix

cancer after radiation therapy is lower for patients

Lung

treated after 1993, likely because of the introduction








of computed tomography (CT) radiation simulation

and planning, improving accuracy of radiation
Fallopian tubes

administration, and reducing the volume of

Breast Cancer

Esophagus

needlessly irradiated tissue.8 Patients receiving

Leukemia

Sarcoma
Thyroid
Uterus

radiation therapy for breast cancer at a younger age

Breast

Pleura
Ovary
Bone

Lung

(< 45 years) are at a higher risk for a contralateral

breast cancer than older patients.8












Radiation exposure is also associated with risk for

Primary Malignancies

SPM of the esophagus, lung and pleura, thyroid, and

Associated Second

soft tissue sarcomas.6 The risk for cancer of the lung

or pleura is correlated with the total delivered dose of
radiation to the lung and increases if the patient has a
personal history of smoking.7 The risk for soft tissue
sarcoma is elevated in both breast cancer patients who
were treated with radiation, as well in those who

www.npjournal.org The Journal for Nurse Practitioners - JNP 239

were not.6 Soft tissue sarcomas after radiation occur
most commonly in the thorax, shoulder, and pelvis.9
With the exception of tamoxifen therapy,
systemic therapy for breast cancer has not been
correlated with an elevated risk for solid secondary
malignancies; however, administration of chemo-
therapy has been linked with an elevated risk for
secondary leukemia.10 Acute myeloid leukemia is
associated with the use of alkylating chemotherapy
agents and tends to present roughly 5 years after
exposure.11 Patients receiving radiation therapy are
also more likely to develop secondary leukemia than
those patients who did not.10
Tamoxifen therapy is one of the most common
endocrine therapies prescribed to pre-menopausal
women with hormone receptor-positive breast
cancer. While tamoxifen is used to prevent breast
cancer recurrence, its use is linked to an elevated risk
for the development of endometrial carcinoma and
uterine sarcomas. Women taking tamoxifen have a
two to three times higher relative risk of developing
endometrial cancer that increases with longer dura-
tion of treatment.12
Approximately 5% to 10% of breast cancers are
caused by a genetic predisposition.13 Breast cancer
survivors who carry germline mutations in the
BRCA1 or BRCA2 genes, which are associated with
the development of hereditary breast and ovarian
cancer, have a higher chance of developing a SPM of
the contralateral breast, ovaries, fallopian tubes,
peritoneum, and pancreas, as well as melanoma.13,14
In breast cancer survivors with a BRCA mutation,
the risk for developing a contralateral breast cancer
within 20 years of their primary diagnosis is
approximately 40%.14 Furthermore, 44% of
individuals with a BRCA1 mutation and 17% of
individuals with a BRCA2 mutation will develop
ovarian cancer by the age of 80.14
HODGKIN’S LYMPHOMA
Chemotherapy and radiation therapy have drastically
improved survival for patients with Hodgkin’s lym-
phoma, which now has an overall 5-year survival rate
of 88%.4,15 Hodgkin’s lymphoma survivors have a
significantly increased risk for a SPM.15-17 In one
cohort study of Hodgkin’s lymphoma survivors, the
cumulative incidence of a SPM was 48.5% at 40 years
240 The Journal for Nurse Practitioners - JNP
after diagnosis.18 Cancers of the breast and lung are
the most common SPMs in Hodgkin’s lymphoma
survivors; however, these patients are also at risk for
secondary non-Hodgkin’s lymphoma, melanoma,
cervical, thyroid, oropharyngeal, gastrointestinal, and
urothelial tract cancers.15,16,19 The excess risk does
not present until 10 to 15 years after the completion
of treatment, and may remain elevated for
decades.17,18
Patients who receive radiation therapy as part of
their first-line treatment are at highest risk for
developing a SPM.19 Patients have typically received
more limited doses of radiation to treat their disease
since the late 1980s because of significant
advancements in radiotherapy techniques.15 Risk for
SPM is correlated with the size of the radiation field
and total dose of radiation received.
Chemotherapy remains an integral part of treat-
ment for Hodgkin’s lymphoma patients. As previ-
ously discussed, the use of alkylating chemotherapy
agents for Hodgkin’s lymphoma increases a patient’s
risk for secondary acute myeloid leukemia.16,17 The
risk for a SPM is highest 5 to 9 years after completion
of chemotherapy.17
MELANOMA
The incidence of melanoma has increased over the
past 30 years. In 2016, approximately 76,380 new
patients were diagnosed with melanoma in the
US.4,20 The incidence rates for patients over the age
of 50 has increased by 2.6% annually since 1996.4
The 5-year survival rate for cutaneous melanoma at
all stages is 92%, and is as high as 98% with localized
disease.4 Ultraviolet radiation exposure is one of the
biggest risk factors for melanoma, although other
factors, such as fair skin, personal history of
melanoma, and multiple atypical nevi, also put
individuals at risk.
Cutaneous melanoma survivors carry an increased
risk for a SPM of the articular cartilage, bone, skin,
salivary gland, thyroid, brain, soft tissue, colon/
rectum, female breast, prostate, and kidney, as well as
non-Hodgkin’s lymphoma.21,22 Patients are also at
risk for a second primary melanoma, often occurring
in the same region of the body as the primary
lesion.20 It is estimated that 2% to 10% of patients
cured of their primary melanoma will develop a
Volume 14, Issue 4, April 2018
second primary melanoma, although this risk
decreases over time.20
Emerging research has correlated a small
percentage of melanoma cases with hereditary cancer
syndromes that can predispose patients to melanoma
and other primary internal malignancies.20-23
However, more research is needed to understand the
genetic mutations that put patients at risk for
melanoma and other malignancies and to identify the
role that environmental factors play in gene
expression, disease risk, and prognosis in these
patients.23
PROSTATE CANCER
Prostate cancer is the most frequently diagnosed
cancer in men, with 180,890 new cases diagnosed in
the US in 2016.4 Prostate cancer mortality has
decreased steadily since the 1990s across all ethnic
backgrounds, with a current 5-year survival rate of
99%.4 Patients with disease that is confined to the
prostate gland have several treatment options,
including active surveillance, prostatectomy, and
radiation therapy. Prostate cancer survivors have been
shown to have a higher risk of a SPM of the bladder,
kidney, soft tissue, and thyroid.24
Exposure to ionizing radiation during prostate
cancer treatment is an established risk factor for the
development of a SPM. Men who receive radiation
therapy are at an elevated risk for a secondary
malignancy of adjacent tissues, including the bladder
and colon/rectum, compared with prostate cancer
patients who do not receive radiation therapy.24 Several
studies suggest that individuals treated with radiation
therapy for prostate cancer are also at increased risk for
lung and hematologic malignancies; however, the
evidence to support this correlation is inconsistent.24
TESTICULAR CANCER
Testicular cancer is the most common cancer diag-
nosed in men between the ages of 18 and 39.25
Because of the development of effective
chemotherapy in the 1970s, testicular cancer became
a highly curable disease.26 The 5-year survival rate for
testicular cancer is 95%, and increases to 99% for
patients with localized disease.4 Given the early
average age at diagnosis and high rate of cure,
testicular cancer survivors often have a long projected
www.npjournal.org
life expectancy after their diagnosis, which comes
with a 1.7- to 3.5-fold increased risk for a SPM.25
Cisplatin-based chemotherapy regimens remain
an integral part of the treatment for this diagnosis and
may contribute to an individual’s risk for SPM.
Testicular cancer survivors have an elevated risk of a
secondary solid primary malignancy after completing
chemotherapy, with a 3- to 7-fold increased risk for
cancer of the kidney, thyroid, or soft tissue.25,27
Additionally, administration of chemotherapy agents
such as cisplatin and etoposide are associated with the
development of secondary leukemia, with the risk
increasing with a higher cumulative dose.25
Radiation therapy for testicular cancer is associ-
ated with increased risk for leukemia and solid
tumors.25 Patients who received radiation therapy are
at elevated risk for melanoma and cancer of the lung,
pleura, thyroid, esophagus, stomach, pancreas, colon/
rectum, kidney, bladder, and connective tissue.28
Individuals treated with a combination of
chemotherapy and radiation therapy have a higher
risk of a SPM than those who received only one of
these modalities, with a relative risk of 2.9 for patients
who received both radiation and chemotherapy.28
THYROID CANCER
The American Cancer Society (ACS) estimates there
were 64,300 new cases of thyroid cancer diagnosed in
2016.4 The incidence in the US has continued to
increase, likely because of improved detection; from
2003 to 2012, the incidence rate increased by 5.1%
annually.4 Differentiated thyroid cancer (papillary
and follicular subtypes) accounts for 90% of thyroid
cancer diagnoses and is highly curable. More
aggressive subtypes of thyroid cancer, such as
medullary and anaplastic, are less common, but are
more likely to metastasize. For all subtypes, the
overall 5-year survival rate is 97%.4 Surgery is
first-line treatment and can be curative. Radioactive
iodine (RAI) treatment is indicated in the presence of
residual thyroid tissue after surgery or metastatic
disease. In certain situations, external beam radiation
therapy is used, especially if there is evidence of
localized lymph node metastasis or disease that is
refractory to RAI therapy, which can put patients at
increased risk for a SPM of the surrounding
structures.29
The Journal for Nurse Practitioners - JNP 241
 Compared with the general population, thyroid
cancer survivors have an elevated risk for cancers of
the breast, central nervous system, prostate, kidney,
stomach, salivary gland, and colon, as well as leuke-
mia, Hodgkin’s lymphoma, non-Hodgkin’s
lymphoma, melanoma, and myeloma.29,30 The
cumulative incidence of SPM is higher in patients
treated with RAI than those who are not.30,31 RAI
tends to accumulate in the salivary glands and
stomach because these tissues have a high number of
sodium-iodide symporters (transmembrane surface
protein controlling transport of sodium and iodine
ions into the cell), leading to an increased risk for
cancer in both sites.31,32 Patients treated with RAI are
also at an elevated risk for leukemia; the incidence of
leukemia correlates with a higher dose of RAI.32
Breast and kidney cancer risk are elevated in all
thyroid cancer survivors and do not correlate with
RAI use.33
Thyroid cancer has been linked to genetic
mutations in the RET proto-oncogene, which has
been connected to the development of leukemia,
prostate, colon, kidney, and breast cancer; however,
this relationship has not been fully characterized.29
Certain RET mutations are associated with the
development of multiple endocrine neoplasia
(MEN), a hereditary cancer syndrome linked to the
development of medullary thyroid cancer.
Individuals with MEN1 are at risk for pancreatic,
thymic, and bronchial neuroendocrine tumors, while
individuals with MEN2 are predisposed to the
development of adrenal tumors.34 Patients with
either syndrome require ongoing surveillance
throughout their lives.
IMPLICATIONS FOR NURSE PRACTITIONERS
Evidence suggests that cancer survivors require
ongoing surveillance for SPMs for decades following
their diagnosis. For this reason, it is important to
acknowledge the role that NPs working in oncology,
survivorship, and primary care have in screening for
and identifying SPMs. Because certain cancer thera-
pies are linked to specific SPM risks, it is essential for
NPs caring for survivors to know the type of cancer
therapy patients received. Care coordination between
healthcare providers is essential; the introduction of
survivorship care plans in recent years has helped to
242 The Journal for Nurse Practitioners - JNP
facilitate collaboration between oncology and
primary care providers. A survivorship care plan is a
formal document containing a patient’s cancer
treatment summary including: diagnosis, stage, grade,
results of diagnostic testing, and outline of treatment
received.35 It also includes vital information on
potential short- and long-term side effects of the
individual’s cancer therapy.
While cancer survivors may have an increased risk
for malignancy based on their initial diagnosis and
treatment, they also have cancer risks because of age
or other characteristics. NPs should advocate for
cancer survivors to adhere to age-appropriate cancer
screening guidelines. Early detection of any new
cancer is the goal, allowing for early medical
intervention and the best treatment outcomes.5
Few guidelines exist that dictate specific surveil-
lance for SPMs in the survivorship setting. The ACS
and American Society of Clinical Oncology (ASCO)
developed breast cancer survivorship guidelines that
include information on screening for SPMs. Women
should continue to undergo breast imaging annually
with mammography to monitor for primary disease
recurrence, as well as development of a SPM.
Women who underwent a unilateral mastectomy
should continue to have annual screening
mammography of their intact breast, while women
who underwent a lumpectomy should continue with
annual mammography of both breasts.36 If the patient
meets high-risk criteria, described as a lifetime risk of
breast cancer of greater than 20%, annual breast
magnetic resonance imaging (MRI) is recommended
in addition to mammography.36 Women taking
tamoxifen need to be evaluated if they develop any
unexpected vaginal bleeding or spotting because
these can be the early signs of endometrial cancer.36
Periodic pelvic imaging in the absence of symptoms is
not indicated and may contribute to
unnecessary biopsies.
The National Comprehensive Cancer Network
(NCCN) has published screening guidelines for
Hodgkin’s lymphoma survivors that provide
direction on screening for SPMs. For patients who
received chest or axillary irradiation, annual breast
screening should begin 8 to 10 years after the patient
finishes treatment, or at age 40, whichever occurs
first.19 The ACS also recommends annual breast MRI
Volume 14, Issue 4, April 2018
in addition to mammography for women who
received radiation therapy to the chest before age
30.19 These patients should perform monthly breast
self-examinations and receive annual clinical breast
exams by a healthcare provider. Survivors with a
greater than 30 pack-year history of smoking qualify
for lung cancer screening with annual low-dose CT
of the chest.16 NCCN recommends screening
colonoscopy every 10 years for survivors over the age
of 50; however, patients at elevated risk for colorectal
cancer based on treatment history should begin
screening at age 40.16 Hodgkin’s lymphoma survivors
who received radiation therapy should be counseled
on skin cancer risk and receive an annual
dermatologic evaluation.
Currently, there are no national guidelines on
survivorship for melanoma patients, nor consensus on
interventions to prevent and screen for SPMs. Mel-
anoma survivors should continue to have annual skin
and lymph node examinations completed by their
healthcare provider because of the increased risk for a
second melanoma and/or non-melanoma skin can-
cer. Patients should also be encouraged to complete
monthly skin self-examinations and seek medical care
for any significant skin changes. Melanoma survivors
should take steps to limit ultraviolet (UV) exposure,
which can contribute to the development of a second
melanoma and other skin cancers.
The ACS has published survivorship guidelines for
prostate cancer survivors, which addresses evaluation
for SPMs. There is no evidence to support increased
frequency or intensity of colorectal cancer screenings
for prostate cancer survivors; however, patients
should adhere to age-appropriate cancer screening
guidelines to allow for early detection of new
cancers.37 Blood in the stool and/or changes in bowel
habits should be carefully evaluated by the NP, even
if colorectal screening is current. Similarly, hematuria
requires prompt evaluation, although routine
screening with urinalysis is not indicated.37
At this time, there are no specific survivorship
guidelines that address screening recommendations
for testicular or thyroid cancer survivors. Both groups
typically receive frequent surveillance for the first
several years following diagnosis, including imaging
and clinical exams, which are useful in monitoring for
disease recurrence or a SPM. Testicular cancer
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survivors should be encouraged to practice
self-examination of the contralateral testicle because
this is the most common site for a SPM.25
NPs caring for cancer survivors should continue
to endorse practices that help reduce cancer risk, such
as exercise, weight management, dietary modifica-
tions, and smoking cessation. Advocating for tobacco
cessation is a vital component of care for all cancer
survivors because smoking negatively impacts
survival. Patients who continue to smoke after their
cancer diagnosis are at elevated risk for cancer
recurrence and a SPM. A recent study showed that
63.9% of patients continue to smoke after their
cancer diagnosis.38 Only 51.7% of cancer survivors
who currently smoke note that they received
smoking cessation counseling by a healthcare
professional within the past year.39 NPs are
fundamental in connecting cancer survivors to
smoking cessation resources, reducing their risk
for a SPM.
CONCLUSION
More than ever, cancer patients are completing
treatment cured of their disease. Cancer survivors
remain at risk for the development of a SPM, which
varies by primary cancer site, extent of disease, age at
diagnosis, genetic predisposition, and cancer
treatment received. Currently, little education is
provided about the delayed and lasting effects of
cancer treatment in graduate nursing programs. As
the population of cancer survivors continues to rise,
NPs need education and training specific to the risks
of SPMs and issues related to cancer survivorship.
More research is needed to examine survivors’ risks
for SPM and help develop site-specific guidelines that
inform NPs how to shape the care they provide for
these patients.
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Both authors are affiliated with the University of Texas M.D.
Anderson Cancer Center in Houston, TX. Danielle M.
Fournier, MSN, AGPCNP-BC, AOCNP, can be reached at
DMFournier@mdanderson.org. Angela F. Bazzell, DNP,
FNP-BC, AOCNP, is Associate Director, APRN Programs.
In compliance with national ethical guidelines, the authors report
no relationships with business or industry that would pose a
conflict of interest.
1555-4155/17/$ see front matter
© 2017 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.nurpra.2017.09.026
Volume 14, Issue 4, April 2018