Mini-review
Open Access
Respiratory issues in cancer survivors
patients: Mini-review
Luis Mendoza*
*IQVIA Senior Medical Director, Medical Strategy & Science, Oncology-Hematology Therapeutic Science & Strategy
Unit,Czech Republic
*Corresponding author: Luis Mendoza, IQVIA, Senior Medical Director, Medical Strategy & Science, Oncology-HematologyTherapeutic Science & Strategy Unit, Czech Republic, Tel: +420 778 700 845: E-mail:
@
Received: 8 December, 2017; Accepted: 19 December, 2017; Published: 27 December, 2017
Citation: Luis Mendoza (2017) Respiratory issues in cancer survivors patients: Mini-review. Int J Hematol Blo Dis 2(3). 1-4.
Introduction
With the recent success of modern cancer therapy, cancer can
be curable,and in cases where cure cannot be achieved, it can be
treated as a chronic disease. As a result,there are now more than
15.5 million Americans with a history of cancer were alive on
January 1, 2016. By January 1, 2026, this number is projected to
reach 20.3 million [1]. These estimates do not include carcinoma
in situ for any cancer except urinary bladder and do not include
basal cell or squamous cell skin cancers. The respiratory effects
of cancer therapy are critically important to the overall health
of cancer survivors due to higher incidence of pulmonary
disease compared with the general population. Because these
conditions can result in a high degree of morbidity and mortality,
understanding how to improve the prevention, recognition, and
treatment of pulmonary disease is an important medical priority.
Cancer survivors are at increased risk for pulmonary disease that results from treatment with chemotherapy, immunotherapy and radiation therapy. This mini review paper will focus on the long-term respiratory and will also cover respiratory issues related to cancer therapy. These are reviewed below. Finally, practical recommendations will be made for certain principles that may help guide the optimal treatment of respiratory effects in cancer survivors.
Cancer survivors are at increased risk for pulmonary disease that results from treatment with chemotherapy, immunotherapy and radiation therapy. This mini review paper will focus on the long-term respiratory and will also cover respiratory issues related to cancer therapy. These are reviewed below. Finally, practical recommendations will be made for certain principles that may help guide the optimal treatment of respiratory effects in cancer survivors.
Pneumonitis
Several chemotherapeutic agents are associated with
interstitial pneumonitis, including bleomycin, cyclophosphamide,
methotrexate, and carmustine. Of these, the pulmonary
complications associated with bleomycin (an agent commonly
used to treat Hodgkin lymphoma and testicular cancer) have
been best characterized.
While this drug can cause a variety of insults, Bleomycin Interstitial Pneumonitis (BIP) is the most common. Depending on the definition used, BIP has been reported to occur in up to 46 percent of patients [2]. BIP is of particular relevance to the longterm care of cancer survivors, given its potential progression to pulmonary fibrosis and associated increased mortality. For example, a study of 38,907 survivors of testicular cancer treated with bleomycin in the past revealed an increased standardized mortality ratio of 2.53 (95% CI 1.26-4.53) for respiratory diseases alone [3]. Late onset BIP typically develops more than six months after treatment [4,5] presenting as a nonproductive cough, dyspnea, tachypnea, fever, and cyanosis. Radiographic imaging demonstrates variable findings but can show bilateral bibasilar infiltrate [2]. Patients with BIP tend to respond to corticosteroids [4,6].
Pneumonitis can also occur with radiation therapy and typically occurs at least one to three months after completion of radiation therapy for lung, breast, esophageal cancers and bone metastases, Hodgkin and non-Hodgkin lymphoma, or total body irradiation for leukemia. The incidence and extent of radiation damage depends on the volume of lung irradiated, total radiation dose, and radiation fractions [7]. Again, common symptoms include dyspnea, hypoxia, nonproductive cough, and fever. Radiographic imaging tends to show changes confined to the outlines of radiation fields [7]. Steroids can be helpful and patients can have complete resolutionof symptoms after six to eight weeks of treatment. Like BIP, however, radiation pneumonitis can progress to fibrosis, making this particularly relevant to the care of long-term survivors.
While this drug can cause a variety of insults, Bleomycin Interstitial Pneumonitis (BIP) is the most common. Depending on the definition used, BIP has been reported to occur in up to 46 percent of patients [2]. BIP is of particular relevance to the longterm care of cancer survivors, given its potential progression to pulmonary fibrosis and associated increased mortality. For example, a study of 38,907 survivors of testicular cancer treated with bleomycin in the past revealed an increased standardized mortality ratio of 2.53 (95% CI 1.26-4.53) for respiratory diseases alone [3]. Late onset BIP typically develops more than six months after treatment [4,5] presenting as a nonproductive cough, dyspnea, tachypnea, fever, and cyanosis. Radiographic imaging demonstrates variable findings but can show bilateral bibasilar infiltrate [2]. Patients with BIP tend to respond to corticosteroids [4,6].
Pneumonitis can also occur with radiation therapy and typically occurs at least one to three months after completion of radiation therapy for lung, breast, esophageal cancers and bone metastases, Hodgkin and non-Hodgkin lymphoma, or total body irradiation for leukemia. The incidence and extent of radiation damage depends on the volume of lung irradiated, total radiation dose, and radiation fractions [7]. Again, common symptoms include dyspnea, hypoxia, nonproductive cough, and fever. Radiographic imaging tends to show changes confined to the outlines of radiation fields [7]. Steroids can be helpful and patients can have complete resolutionof symptoms after six to eight weeks of treatment. Like BIP, however, radiation pneumonitis can progress to fibrosis, making this particularly relevant to the care of long-term survivors.
Immune-related pneumonitis
Immune-checkpoint inhibitor therapy has emerged as
a promising treatment option for advanced cancers[8-10].
Two PD-1 inhibitors have been approved by the U.S. Food and
Drug Administration (FDA) for the clinical cancer treatment,
including nivolumab for advanced melanoma, NSCLC, and RCC,
and pembrolizumab for melanoma and NSCLC. A combination
therapy using nivolumab and ipilimumab, a CTLA-4 inhibitor,
has also been approved as a treatment for advanced melanoma
[11,12]. Given the evidence for clinical efficacy in a wide spectrum
of tumor types, PD-1 immune-checkpoint inhibitor therapy as
monotherapy or in combination is projected to be increasingly
used by oncologists. Immune-checkpoint blockade by PD-1
inhibitors is associated with unique toxicities,termed immunerelated
adverse events (irAEs), which can involve different organs
throughout the body [13-15]. Among the irAEs, pneumonitis
is a relatively rare, but clinically serious and potentially life
threatening toxicity which might affect the quality of life
specially those patients who achieve a durable response.Time
from initiation of therapy to the development of pneumonitis
had a wide range (0.5- 11.5 months), indicating an importance
of careful observation and follow-up for signs and symptoms
(i.e. cough and dyspnea) of pneumonitis throughout treatment.
Shorter time to onset of pneumonitis in lung cancer compared
to melanoma and lymphoma may be due to a higher pulmonary
tumor burden among lung cancer patients, which can result
in an earlier onset of respiratory symptoms. Immune-related
pneumonitis showed a spectrum of radiographic patterns, which
were associated with toxicity grades. The incidence of immunerelated
mild/moderated pneumonitis is increased in patients
who has previously received lung radiation therapy following
the administration of durvalumab (PDL-1 inhibitor) as it was
demonstrated in the Pacific trial [16].
Radiographic pattern of pneumonitis has a wide spectrum where the most frequently are the ground-glass opacities followed by cryptogenic organizing pneumonia, non-specific interstitial pneumonia, acute interstitial pneumonia/acute respiratory distress syndromeand hypersensitivity pneumonitis[17]. Most cases were responsive to corticosteroids and around one-third of the patients are able to restart therapy, though a few patients experienced recurrent pneumonitis during retreatment. These observations emphasize the importance of increased awareness of the entity for the early diagnosis and treatment.
Radiographic pattern of pneumonitis has a wide spectrum where the most frequently are the ground-glass opacities followed by cryptogenic organizing pneumonia, non-specific interstitial pneumonia, acute interstitial pneumonia/acute respiratory distress syndromeand hypersensitivity pneumonitis[17]. Most cases were responsive to corticosteroids and around one-third of the patients are able to restart therapy, though a few patients experienced recurrent pneumonitis during retreatment. These observations emphasize the importance of increased awareness of the entity for the early diagnosis and treatment.
Fibrosis
Pulmonary fibrosis is a dreaded complication of certain
chemotherapies, including bleomycin, busulfan, and carmustine,
and radiation treatment. In a small study of 17 children who
received carmustine to treat brain neoplasms, 25-year follow-up
revealed that nine (53 percent) died of pulmonary fibrosis. Of
the eight survivors, follow-up was available on seven patients,
who all showed signs of upper zone pulmonary fibrosis [18].
Radiation-induced pulmonary fibrosis develops at least 6 to 24
months after exposure to radiation, with patients presenting
with progressive dyspnea and cough. In some cases, fibrosis is
observed on imaging alone and patients are asymptomatic [19].
Steroids typically are associated with little benefit. The Childhood
Cancer Survivor Study demonstrated that patients exposed to
chest radiation were 4.3 times more likely than their siblings to
have pulmonary fibrosis five years postdiagnosis.Chest radiation
was also associated with a 3.5 percent cumulative incidence
ofpulmonary fibrosis 20 years post-diagnosis [20].
Bronchiolitis obliterans syndrome
Pulmonary complications, specifically Bronchiolitis Obliterans
Syndrome (BOS) and idiopathic pneumonia syndrome, are a
significant source of morbidity and mortality in the Hematopoietic
Stem Cell Transplantation (HSCT) population. Among 438 HSCT
patients surviving more than three months, the incidence of late
noninfectious pulmonary complications was 10 percent and the
five-year survival rate of these patients was significantly lower
compared with patients without pulmonary disease (34 versus
65 percent) [21]. BOS is a complication seen after allogeneic
HSCT and is observed in the presence of chronic graft-versus-host
disease. This syndrome causes airflow obstruction secondary to
progressive circumferential fibrosis with eventual scarring of
terminal bronchioles [22]. It typically occurs within the first two
years after transplant but can occur later, at four or five years. In
2005, the followingNational Institute of Health (NIH) diagnostic
criteria were proposed: forced expiratory volume in one second
(FEV)< 75 percent predicted; FEV /forced vital capacity (FVC)
ratio < 0.7; evidence of air trapping, small airway thickening, or
bronchiectasis on high-resolution computed tomography (HRCT)
or residual volume (RV) >120 percent of predicted normal; and
absence of respiratory tract infection or pathologic confirmation
[23]. Using these criteria for BOS, a single center study of1145
patients revealed a prevalence of 5.5 percent in transplanted
patients and 14 percent in patients with chronic graft-versus-host
disease [23]. However, International Bone Marrow Transplant
registry data on 6275 adult patients with leukemia treated with
allogenic HSCT reported an incidence of only 1.7 percent using
prior diagnostic criteria [25].
In its early stages, patients are rarely symptomatic or have nonspecific symptoms of mild dyspnea on exertion or non-productive cough. However, as the disease progresses, patients suffer from significant dyspnea on exertion, persistent nonproductive cough, and decreased exercise tolerance. If BOS worsens, patients eventually develop significant hypoxia and become oxygen dependent, and alongside this an increased risk for pulmonary infections [26]. Diagnostic evaluation includes pulmonary function tests, HRCT, echocardiography to assess pulmonary artery pressures, infectious work-up, complete graft-versus-host evaluation, bronchoalveolar lavage, and tissue biopsy. Steroids are the mainstay of treatment, although their use has not beenevaluated in large clinical trials. Long-term survival is poor. Among 2859 bone marrow transplant patients, five-year survival of patients with BOS was 10 versus 40 percent in patients without BOS. In patients with BOS who responded to initial treatment with steroids, 79 percent survived at five years versus 13 percent ifthere was no response [27]. A 2011 consensus statement originating from the ConsensusConference on Clinical Practice in Chronic GVHD recommended routing pulmonary function testing screening in asymptomatic patients at 3, 6, 9, 12, 18 and 24 months after allogeneic stem cell transplantation and then annually[26].
In its early stages, patients are rarely symptomatic or have nonspecific symptoms of mild dyspnea on exertion or non-productive cough. However, as the disease progresses, patients suffer from significant dyspnea on exertion, persistent nonproductive cough, and decreased exercise tolerance. If BOS worsens, patients eventually develop significant hypoxia and become oxygen dependent, and alongside this an increased risk for pulmonary infections [26]. Diagnostic evaluation includes pulmonary function tests, HRCT, echocardiography to assess pulmonary artery pressures, infectious work-up, complete graft-versus-host evaluation, bronchoalveolar lavage, and tissue biopsy. Steroids are the mainstay of treatment, although their use has not beenevaluated in large clinical trials. Long-term survival is poor. Among 2859 bone marrow transplant patients, five-year survival of patients with BOS was 10 versus 40 percent in patients without BOS. In patients with BOS who responded to initial treatment with steroids, 79 percent survived at five years versus 13 percent ifthere was no response [27]. A 2011 consensus statement originating from the ConsensusConference on Clinical Practice in Chronic GVHD recommended routing pulmonary function testing screening in asymptomatic patients at 3, 6, 9, 12, 18 and 24 months after allogeneic stem cell transplantation and then annually[26].
Idiopathic pneumonia syndrome
Idiopathic pneumonia syndrome (IPS) includes a spectrum
of noninfectious lung injury that carries a high mortality rate. In
2010, IPS was defined as an “idiopathic syndrome of pneumopathy
after HSCT, with evidence of widespread alveolar injury and in
which infectious etiologies and cardiac dysfunction, acute renal
failure or iatrogenic fluid overload have been excluded”[28].
The median onset is considered to be six to seven weeks but
more recently has been shown to occur as early as 19 days posttransplant
(28), with an incidenceestimated to be on the order of
12 percent. Patients present with dyspnea, nonproductive cough,
and hypoxemia, with non-lobar infiltrates are seen on radiographs
[29].The syndrome typically leads to rapid respiratory failure and
death. In 2003, Fukada et al reported a cumulative incidence of
IPS of 2.2 percent in patients treated with non-myeloablative
versus 8.4 percent in patients who underwent conventional
conditioning prior to allogenic HSCT (p = 0.003) and a mortality
rate of 75 percent [30].Etanercept, a TNF-alpha binding protein,
has shown somebenefit in the treatment of these patients [31,32].
Secondary lung cancer
RT to the chest increases the risk of subsequent lung cancer.
Among 64,782 breast cancer survivors who had surgery, at 10 to
14 years and>15 years from their initial diagnosis, patients who
received radiation were at a significantly higher relative risk of
lung cancer than those who did not (relative risk [RR] 1.62, 95%
CI 1.05-2.54 and RR 1.49, 95% CI 1.05-2.14,respectively) [33].
Other populations who receive chest RT appear to also be at risk;
in anotherstudy of survivors of Hodgkin lymphoma, those treated
with chest RT had a relative risk of 2.7 to 7.0 of developing lung
cancer [34].
Monitoring pulmonary function and follow-up
For patients suspected of having symptomsattributable to
pulmonary toxicity, pulmonary function tests can be used to aid
in the diagnosis ofsubclinical, asymptomatic disease.Despite
the potential discrepancy between pulmonary function tests
and overt clinical symptoms,early identification for pulmonary
disease is important given it is a significant cause of mortality
inadult survivors. In a Childhood Cancer Survivor Study which
included 20,483 five-year survivors ofchildhood cancer, the
cumulative mortality at 30 years from diagnosis was 18.1 percent
(95% CI,17.3-18.9) and survivors were 8.8 times more likely to
die from a pulmonary cause [35].
Summary
In a study of 1713 survivors of childhood cancer, 65.2 percent
(95% CI 60.4-69.8) hadabnormal pulmonary function tests
with the highest prevalence in those treated with lungradiation
(74.4 percent [95% CI 69.1-79.2], bleomycin (73.5 percent
[95% CI 61.9-82.9], andthoracotomy (53.2 [95% CI 44.1-62.0])
[36]. In another study that included 220 five-year childhood
cancer survivors who receivedpotentially pulmonary toxic
chemotherapy, 44 percent had abnormal pulmonary function
testsat a median follow-up of 18 years. Restrictive lung disease
and decreased carbon monoxidediffusion capacity were the most
common abnormality [37].
Long-term follow-up with spirometry and questionnaires of 1049 testicular cancer survivorsshowed that 8 percent had restrictive lung disease. In this study, patients treated with accumulative cisplatin dose greater than 850 mg and patients treated with cisplatin andpulmonary surgery had increased odds of developing restrictive lung disease compared withpatients treated with surgery alone. Interestingly, of the patients diagnosed with restrictivelung disease, only 9.5 percent had selfreported dyspnea and 7.5 percent had prevalentasthma [38].
Pulmonary effects of chemotherapy, immune-check point inhibitors and chest radiation can have an insidious onset and devastating consequences. Providers should be aware of conditions that can present months or years after cancer treatment and are associated with increased bad quality of life and mortality.
Diagnostic evaluation can include pulmonary function tests, echocardiograms to assesspulmonary pressures, and chest radiographic imaging in patients who have been exposed to pulmonary toxic chemotherapy or chest radiation. Cancer survivors who continue to smoke tobacco should be counseled to discontinue tobacco use. Several studies have shown smoking increases the risk of a second malignancy [39,40].
Long-term follow-up with spirometry and questionnaires of 1049 testicular cancer survivorsshowed that 8 percent had restrictive lung disease. In this study, patients treated with accumulative cisplatin dose greater than 850 mg and patients treated with cisplatin andpulmonary surgery had increased odds of developing restrictive lung disease compared withpatients treated with surgery alone. Interestingly, of the patients diagnosed with restrictivelung disease, only 9.5 percent had selfreported dyspnea and 7.5 percent had prevalentasthma [38].
Pulmonary effects of chemotherapy, immune-check point inhibitors and chest radiation can have an insidious onset and devastating consequences. Providers should be aware of conditions that can present months or years after cancer treatment and are associated with increased bad quality of life and mortality.
Diagnostic evaluation can include pulmonary function tests, echocardiograms to assesspulmonary pressures, and chest radiographic imaging in patients who have been exposed to pulmonary toxic chemotherapy or chest radiation. Cancer survivors who continue to smoke tobacco should be counseled to discontinue tobacco use. Several studies have shown smoking increases the risk of a second malignancy [39,40].
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