Hodgkin's
disease (HD), a malignancy of the lymphatic system, occurs in a bimodal
age distribution, with one large incidence in young adults between the
ages of 15 and 40 years and another incidence in those older than 55
years. Through the advancement of diagnostic techniques and treatment
modalities, HD has evolved from a condition that was once frequently
fatal to one that is highly curable. In the 1940s, less than 15% of
patients with HD lived 10 years after diagnosis. Major developments in
therapeutic approaches throughout the 1960s and 1970s-including the use
of radiation and combined radiation and chemotherapy-have dramatically
improved survival. According to the Lymphoma Information Network,
patients with HD diagnosed in its early stages now have a greater than
90% chance of long-term survival and patients diagnosed in the later
stages of disease have an 80% or greater chance of survival.1
Hodgkin's
disease and its treatment are not, however, without consequence to the
survivor. Medical management for HD, although effective against the
cancerous cells, also causes multiple sequelae, including cardiac and
lung toxicity, infertility, and various secondary malignancies.2,3 Such sequelae may affect the survivor's health-related quality of life (HRQOL) for many years after treatment is completed.4
The
purpose of this article was to present an integrative review of
empirical studies designed to examine HRQOL in adult survivors of HD, as
well as to offer suggestions for further study with this population.
For this review, the concept of HRQOL encompasses the impact of the
diagnosis and treatment on the individual survivor's well-being in
physical, psychological, social/functional, and spiritual domains.5,6
Methods
Ganong's7
guidelines for narrative integrative literature reviews direct
researchers to select hypotheses or research questions to focus the
review. Researchers also must identify inclusion criteria for the
research to be reviewed, examine the characteristics of the selected
studies and findings, and interpret the results of the selected
literature. These guidelines were followed to compile, review, and
integrate the literature describing HRQOL in adult survivors of HD.
The final sample encompassed 35 studies (see Table 1), 14 conducted in the United States8-21 and 21 conducted in European countries, including the United Kingdom.22-42
The research questions were addressed using content analysis to
identify and classify study characteristics, including conceptual or
theoretical framework used to guide the study, type of research design
used (correlational or experimental, cross-sectional or longitudinal,
prospective or retrospective, cohort or case-control), sample size,
sampling strategy (probability, nonprobability), source used to recruit
study participants (tumor registry, hospital records), sample
demographic characteristics (gender, age), stage of cancer and years
treated, number of years after diagnosis or treatment completion, when
data were collected, research instruments used, method of administration
of instruments, domains of HRQOL (physical, psychological,
social/functional, spiritual) studied, and summary of findings. Two
members of the review team examined, extracted, and analyzed relevant
information from each of the 35 studies. The 2 team members reached
consensus on selection of the final sample of studies based on the above
characteristics.
 | Table 1 Summary of Studies Examining HRQOL in HD Survivors |
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Results
Conceptual or Theoretical Framework
Just 2 of the 35 studies were guided by an explicit conceptual or theoretical framework. Cameron et al11 used classical conditioning theory42
to examine the prevalence of persistent aversive symptoms, such as
anticipatory nausea and vomiting, in HD survivors. Wettergren et al42 cited the Wilson and Cleary's Model43 of causal relationships between individuals' health characteristics and HRQOL outcomes.
Study Design
Thirty-four of the 35 studies (97%) were correlational,8-38,40-42 and one was experimental.39 Thirty of 35 studies (86%) were retrospective and cross-sectional.8-14,16-22,24,26-28,30-38,40-42 Just 5 of the 35 studies (14%) used longitudinal, prospective designs.15,23,25,29,39 Twenty of the 35 studies (57%) were case-control, and 15 (43%) were cohort studies.
Sample
Sample
size ranged from 42 to 818 participants. In 15 (43%) studies, the
sample included fewer than 100 participants. A nonprobability
convenience sampling strategy was used for all studies. Participants
were enrolled in the studies using hospital-based records and/or tumor
registries. All but 2 of the study reports9,11
provided information about the numbers of patients who were eligible
but did not participate. Study participants ranged in age from teens to
mid-80s; reports of 2 studies did not include an age range.37,38 In 26 (74%) of the studies, 51% to 60% of the participants were male. Only 6 studies8,12,20,21,26,28 included more female than male participants, and 3 studies9,10,13
included only male participants. Twenty-nine (83%) studies focused on
HRQOL in HD survivors who were more than 1 year but less than 35 years
after treatment completion, and 6 (17%) studies focused on HRQOL of
those newly diagnosed or less than 1 year after treatment completion.13,15,23-25,27 A complete description of the diagnostic stages and treatment regimens was included in all but 4 studies.20,21,23,24
Early-stage disease was defined as stage I-II, and late stage, as stage
III-IV. In one study, further extent of disease was defined by
delineating between the absence (substage A) or presence (substage B) of
key prognostic indicators including fever, night sweats, or pruritus to
differentiate between early- and late-stage disease.13
Twenty-seven (77%) studies were conducted in samples with early- and
late-stage disease. Study samples were treated from 1965 to 2003. Length
and type of treatment were dependent on stage of disease and ranged
from 3 to 18 months for the studies in this review.
Research Instruments
A
total of 29 different instruments were used to measure HRQOL in adult
HD survivors; the most commonly used instruments are listed in Table 2. Ten (29%) studies used researcher-constructed questionnaires,8,10,11,13,14,18,22-24,31 and the remainder used valid and reliable standardized instruments (Table 2).
The instruments were administered most frequently as questionnaires
that were mailed or administered via a telephone or face-to-face
interview.
 | Table 2 The Most Commonly Used Instruments |
Domains of HRQOL
The variables reflecting the domains of HRQOL addressed in this integrative literature review are listed in Table 3.
Twenty-seven of the 35 studies (77%) addressed the physical domain
using variables such as fatigue, sexuality, and cognition. Twenty-six
(74%) studies addressed the psychological domain using variables such as
distress, depression, and anxiety. The social/functional domain was
addressed in 16 (46%) studies; variables included relationships, work,
and activities of daily living. The spiritual domain was addressed in
only 2 of the 35 studies (6%)13,42 by focusing on survivors' worldview and life meaning.
 | Table 3 The 4 Domains and Associated Variables to Measure Health-Related Quality of Life |
Physical Domain
FATIGUE
Fatigue remains a common problem for HD survivors, even several years after the completion of treatment. Hjermstad et al29
found that a sample of 476 HD survivors reported higher levels of
fatigue than a sample drawn from a general, healthy population.
Correlates
of fatigue reported by HD survivors include age, education, gender, HD
stage, type of treatment, and the presence of other physical symptoms.
Loge et al36
reported that total fatigue was significantly higher among survivors 60
years or older compared to younger HD survivors. Participants with
fewer years of education also reported greater fatigue than those with
more years of education. Norum and Wist38
found that men reported significantly higher levels of fatigue than
women did. In addition, patients diagnosed with later stages of disease
and those who received combination cancer therapy (both chemotherapy and
radiation therapy) experienced a greater delay in the return of their
energy levels than those who were diagnosed with earlier stages of
disease and those who received monotherapy.14 Furthermore, patients who received combination therapy reported a higher level of fatigue than those who received monotherapy.15,28 In addition, Norum and Wist38
found that patients who received mantle radiation experienced more
fatigue and dyspnea than those who did not receive radiation up to 10
years after completion of treatment.
In
one study, so-called B symptoms, such as fever, night sweats, and
weight loss at diagnosis, were found to be the only defining disease
characteristics that were positively correlated with survivors' fatigue
after treatment.29
In other studies, survivors' reports of cardiac disease, psychiatric
disease, tobacco use, and low exercise frequency were correlated with
relatively high levels of fatigue after treatment.20,40
ANTICIPATORY NAUSEA AND VOMITING
Anticipatory nausea and vomiting are another common physical problem experienced by HD survivors.11,12,17 According to Cameron et al,11
this conditioned response-a feeling of distress experienced in relation
to the typical sights and/or smells in the medical environment-has been
reported by as many as 55% of survivors at one point in time and is
most likely to occur just after diagnosis but may continue up to 2 years
after treatment. Furthermore, Kornblith et al16
reported that 39% of HD survivors continued to experience nausea for at
least a year after treatment in response to sights and smells, but
episodes of vomiting were a rarer occurrence.
OTHER SYMPTOMS
Hodgkin's
disease survivors experience several other symptoms related to the
treatment received in the years after treatment including cardiovascular
and respiratory complications,20,38 shortness of breath and tachycardia,8 and thyroid dysfunction.32 Nevertheless, Adams et al8
reported that although HD survivors reported moderate to severe
problems with fatigue, shortness of breath, chest pain, and dizziness
several years after treatment completion, they scored their health as
good as or better than that before diagnosis.
SEXUALITY
Some researchers studied survivors' sexuality. Cella and Tross13
found significantly lowered motivation for intimacy among 60 male HD
survivors compared with a healthy control group. Kornblith et al18
noted that 37% of 273 HD survivors reported one or more sexual
problems; the most common were decreased interest in sex and loss of
sexual satisfaction. Fobair et al14
found that the most common sexuality problems were infertility and
decreased interest in sexual activity in a sample of 403 HD survivors.
Greil et al28
found that survivors who had received combination therapy reported more
infertility problems and less sexual enjoyment than did those who had
received monotherapy.
COGNITION
A few researchers have studied cognition in HD survivors. Joly et al31
found that cognitive problems manifested as memory impairment and poor
concentration even several years after treatment completion. Similarly,
Devlen et al23
reported that 47 of 120 HD survivors described having difficulty
recalling simple facts, such as their telephone number, after completing
treatment. These memory impairments were attributed to the older age of
the samples and to depression, anxiety, and possibly minor brain damage
secondary to chemotherapy or viral infection during treatment.
Psychological Domain
DISTRESS
The incidence of emotional distress among HD survivors varied across the 35 studies. Cella and Tross13
reported that survivors did not differ significantly from case-controls
with regard to emotional distress. The findings of other studies,
however, revealed that emotional distress was higher in the survivors
than in healthy populations.18,19
Correlates
of emotional distress include gender, stage of HD, and marital status.
Female HD survivors in one study reported lower levels of distress than
their male counterparts did, manifested as symptoms associated with
posttraumatic stress disorder, such as intrusive thinking and avoidance.37 In contrast, male HD survivors in another study reported less emotional distress after treatment than females did.27
Furthermore, HD survivors diagnosed with later stages of disease (stage
IIB, IIIB, IVA, or IVB) were found to be at higher risk for emotional
distress than those diagnosed with earlier stages.13 And HD survivors who were married had lower levels of distress than those who were not married.21
ANXIETY AND DEPRESSION
It
is estimated that up to 50% of HD patients and survivors report anxiety
and/or depression during the first year after diagnosis and treatment.24 The influence of gender on reports of anxiety and depression is unclear. Although both Zabora et al21 and Fobair et al14 reported no correlation between gender and depression in HD survivors, Loge et al34
noted that anxiety was greater for women than for men. Age and
educational level may be related to anxiety and depression. Kornblith et
al17
found that survivors older than 40 years had a higher incidence of
depression than their younger counterparts, and both Loge et al33 and Kornblith et al17
found that HD survivors with limited educational backgrounds
experienced higher levels of anxiety and depression than those with
higher levels of education. Marital status, however, does not seem to be
related to anxiety and depression. Loge et al34 found no significant difference in anxiety and depression between HD survivors who lived alone and those who were married.
Social/Functional Domain
Although
it is common for HD survivors to return to their usual level of
functioning after treatment is completed, many experience changes in
their ability to function in social and occupational roles.14,18,24,41 For example, difficulty returning to work has been reported in up to 42% of HD survivors.14
Many HD survivors who had trouble returning to work noted that they had
a diminished capacity to complete work-related tasks or adjust to the
work environment.10
In addition, when compared to survivors of testicular cancer, HD
patients were significantly more likely to change jobs or stop working.
Flechtner et al25 reported that the main reason for unemployment among HD survivors was early retirement due to the disease and its treatment.
Several
factors associated with permanent disability after treatment have been
identified, including having little education and low income, having
been treated with combined chemotherapy and radiation therapy, being
older than 40 years, having depression and/or anxiety, and having
experienced exertional dyspnea and pain or stiffness in the shoulders
secondary to mantle field radiation.22,40 Gender also influences function. Fobair et al14 reported that women had a greater decrease in activity tolerance after treatment for HD compared to men. Similarly, Loge et al35 found that women survivors scored lower than men did on a measure of the functional domain of HRQOL.
In
addition, stage of HD may influence functioning. Survivors who had been
diagnosed with later stage HD were found to be at highest risk for
functional adjustment problems, such as readapting to premorbid work
schedules during the first 2 years after treatment.13 In contrast, Devlen et al23
found that a large proportion of survivors of both early- and
late-stage HD failed to return to work and to resume normal leisure
activities up to 1 year after completion of treatment. Hodgkin's disease
survivors experienced a greater decrease in leisure and work activities
than did those who had testicular cancer, which was attributed to
limited energy and type of treatment.10
The
physical domain symptom of fatigue has been found to affect HD
survivors' ability to participate in leisure activities for many months
after treatment. Devlen et al23
noted that 48 of the 120 survivors (40%) surveyed continued to report
little interest in leisure activities even 1 year after the completion
of treatment.
Several
researchers identified changes in marital status, with an increased
incidence of divorce and separation, among HD survivors.22,25
Approximately 20% of participants in one study reported changes in
their relationships that they associated with their cancer diagnosis and
treatment.25
Participants in another study reported having fewer children after
diagnosis and treatment for HD compared with healthy controls.31
Spiritual Domain
Only
2 of the 35 studies (6%) addressed the spiritual domain of HRQOL. In
one study, survivors reported that they had a greater appreciation for
life after treatment.13
In the other study, survivors identified family, personal health, work,
and relationships with close friends as the most important aspects of
their lives after HD diagnosis and treatment.42
Discussion
State of the Science
Although
it is encouraging to know that HD is considered a curative illness, the
potential for overtreatment of young adults diagnosed with HD is a
topic of discussion and concern. The long-term impact of curative
treatment on the physical domain of HRQOL is especially problematic for
young adult HD survivors because of factors such as age at the time of
chest irradiation and the use of alkylating chemotherapy agents that
increase the risk of secondary lung and other cancers and cardiac
disease in long-term survivors. In 1988, clinical researchers explored
treatment reductions intended to reduce life-threatening adverse events
caused by radiation while maintaining cure rates. By 1991, this fifth
novel treatment regimen-named Stanford V for late-stage
disease-shortened treatment courses, instituted cumulative toxic dose
reductions, and decreased radiation doses and volume while maintaining
favorable survival outcomes for HD.44
Consequently, current clinical trials have been designed to determine
the efficacy of treatment reductions in patients with lower radiation
therapy doses and less toxic chemotherapy regimens for earlier stage
disease as the risk for late mortality from causes other than HD
continues to threaten survivors many years later.3
However, until more clinical data support favorable long-term HRQOL
outcomes with treatment reductions in early- and late-stage disease,
researchers suggest that caution be taken when considering changes in
standard treatment.45
The
literature revealed that fatigue was the most common problem in the
physical domain of HRQOL. The finding that fatigue was more severe for
HD survivors than for healthy controls even years after treatment
completion is consistent with prior research about cancer-related
fatigue. Indeed, fatigue has been reported to occur in approximately 75%
of all cancer patients and can be a more common adverse effect of
treatment than nausea, depression, or pain.46 The high incidence of cancer-related fatigue has led to proposing that it be considered the sixth vital sign.47
Late
medical complications of HD therapy such as cardiac disease and
abnormal thyroid and pulmonary function may contribute to the prevalence
of fatigue in HD survivors compared to other cancer survivors.45
Whether the occurrence of fatigue in cancer survivors is associated
with treatment modality, disease, or nonclinical factors such as
socioeconomic status, age, or gender, patients report that this
assumption profoundly alters their quality of life before and after
treatment.27,36
Increasingly, research findings support the thesis that increased
physical activity ameliorates the incidence of fatigue during and after
treatment and improves physical functioning and other domains of quality
of life.48,49 For example, Oldervoll et al39 reported that fatigue and physical conditioning improved when HD survivors participated in an aerobic exercise program.
Another common physical domain problem is nausea and vomiting. Since the introduction of 5-Hydroxytryptamine3 (5-HT3)
receptor antagonists in 1991, there has been a significant reduction in
posttreatment vomiting, yet treatment-related nausea continues to be a
recurrent and continuing consequence of chemotherapy and is considered
far more difficult to control than treatment-associated emesis. In one
study of HD survivors, 63% experienced persistent anticipatory nausea
and 5% reported anticipatory vomiting, which were thought to be a
response to reminders of treatment, for as long as 6 to 140 months after
completion of chemotherapy. Although these reactions lessened over
time, anticipatory nausea was experienced by half the patients for more
than 2.5 years.50
Promising prevention strategies for the control of anticipatory nausea
and vomiting include both new guidelines for using antiemetics during
treatment and behavioral therapies such as hypnosis.51,52
With
regard to sexuality, the finding that HD survivors reported lowered
motivation for intimacy, along with a decreased interest in sex and loss
of sexual satisfaction, is consistent with findings from other studies
reporting that older adolescents and young adults who experience
distress, depression, and anxiety may experience or show difficulty in
responding to intimacy and lack sexual motivation when stressed.53
Fertility preservation may also be a concern of young adults with HD
and their partners. Issues surrounding fertility and sexuality concerns
should be addressed and evaluated before, during, and after treatment.54
Studies
of the physical domain of HRQOL focused little attention on memory
impairment and cognitive problems although HD survivors often report
difficulties with memory, attention, and new learning after treatment.
The findings of one meta-analysis of specific cognitive effects of
cancer treatment in adults indicated that executive function, verbal
memory, and motor function were negatively affected by systemic cancer
therapies.55
There is some evidence that chemotherapy negatively affects cognitive
ability, sometimes referred to as "chemo brain" or "chemo fog."56,57
Other factors that may influence cognitive decline include stress,
depression, sleep disturbances, fatigue, or the cancer process itself
with the release of toxic by-products (cytokines). Researchers have
begun to report that there is a stimulation of cytokines in breast and
colorectal cancers that may be implicated in deficits of cognitive
function.58
Other researchers have reported survivor complaints of cognitive
problems that can negatively affect daily functioning, vocational
interests, and other aspects of quality of life. Thus, a better
understanding of cognitive function in HD survivors is an important area
for future research.
The
psychological domain of HRQOL continues to be a frequent focus of
research for long-term survivors of cancer. The most common variables
measured in the psychological domain in the studies in this review were
depression and anxiety. The findings revealed mixed results that may be
attributed to a variety of instruments used to measure psychological
distress and the diverse time points for measurement, ranging from
during treatment to many years after treatment completion. Developmental
level at the time a young adult is diagnosed with a serious illness may
have a significant influence on psychological adjustment. For example,
young survivors face the disruption of developmental milestones such as
establishing intimate relationships, fertility, child rearing, and
financial concerns, whereas older adults are looking forward to
retirement.59,60
Survivor responses in the functional and social domains of HRQOL were frequently investigated as well. Seven researchers24,25,27,28,31,41,42
investigated how HD survivors perceived changes in leisure activities,
finances, and employment in response to medical conditions and treatment
effects. Other investigators focused specifically on how fatigue
compromised energy levels and a decline in physical performance that had
a negative impact on work and leisure time.10,29,32,33,35,39,40
Although some researchers have argued that activities not directly
related to health status are outside the purview of the healthcare
provider, such as the measurement of job satisfaction and economic
factors, the impact of treatment on the social/functional domain of
HRQOL for those with cancer or chronic illness is relevant to morbidity,
mortality, and long-term surveillance.61,62
Functional status has not traditionally included measurements of work
satisfaction and the financial consequences of illness, but as
demonstrated in this review, these issues have become increasingly
important to cancer survivors. Advances in early detection and less
debilitating treatments have led to an increased presence of cancer
survivors as active members in the workplace, reinforcing the need to
include this essential component in the measurement of HRQOL.63
Only
2 studies investigating the spirituality domain of HRQOL in HD
survivors were located. Religious and spiritual coping have been shown
to improve other domains of HRQOL in cancer survivors. In a study of 170
patients with advanced cancer, positive religious coping was related to
better existential QOL dimensions, as well as overall QOL.64 Balboni et al65
reported that 72% of respondents with various types of cancer indicated
that they had little opportunity to discuss spiritual concerns with
their healthcare provider. Further studies are needed to understand the
spiritual and religious needs of cancer survivors.66
Theoretical and Methodological Issues
Researchers are encouraged to use existing frameworks for future studies. For example, Wilson and Cleary62
described a theoretical framework that posits causal relationships
among biological and physiological factors, symptoms, functioning,
general health perceptions, and overall quality of life. Ferrans et al67 further developed and revised this model to describe the influences of HRQOL. The Ferrans et al67
model underscores the importance of patient values and preferences and
internal factors such as developmental stage when designing
interventions that are intended to change or modify behavior and improve
HRQOL. Another framework that may be used to guide future research is
the Roy Adaptation Model. This conceptual model depicts individuals as
bio-psychosocial beings who adapt physically, psychologically,
functionally, and socially to ever-changing environmental stimuli.68
Linkages can easily be made between the modes of adaptation and
variables in each domain of HRQOL, as well as between environmental
stimuli and variables such as age, gender, race, education, type of
treatment, and stage of disease.68
The
findings of this review uncovered numerous methodological issues that
need to be resolved, including using more rigorous study designs and
standardizing the measurement of each HRQOL domain. Most studies
reviewed were correlational and cross-sectional; just 4 (11%) of the
studies in this review used longitudinal designs. Murdaugh69
pointed out that HRQOL is a dynamic and nonstatic construct that cannot
accurately reflect the impact of illness at one point in time,
highlighting the need for longitudinal, prospective study designs.
As can be seen in Table 1,
more than 29 different instruments were used to measure the various
domains of HRQOL. Measurement approaches used in the studies included a
single instrument or a battery of different instruments. The 2 most
commonly used single questionnaires measuring HRQOL domains are the
European Organization for Research and Treatment of Cancer Quality of
Life Questionnaire Core 30 and the Medical Outcomes Study Short Form 36 (Table 2).
The European Organization for Research and Treatment of Cancer Quality
of Life Questionnaire Core 30 was used exclusively in European studies
(n = 6) to measure the multidimensional construct of HRQOL. This
instrument is a cancer-specific measure; subscales measure physical,
emotional, cognitive, and social functioning, as well as global health
status.70
Short Form 36, in contrast, is a generic measure that enables
comparison across various diseases. This instrument was used in 7
studies, most of which were conducted in Europe.8,15,26,30,35,39,41
The use of a brief, single, and concise instrument to measure HRQOL
would aid in reducing respondent burden, especially given the high
incidence of fatigue experienced by HD survivors. In addition, the
uniform adoption of a single instrument for measuring HRQOL would allow
for direct comparison of findings across studies and contribute to the
advancement of knowledge.
Researchers
rarely reported categorization of study participants' race, which may
be related to the low incidence of HD in nonwhite persons. Yet in 2005,
HD incidence rates were similar in African American and white,
non-Hispanic populations.71 Only 8 (23%) US studies in this review included descriptions of participant racial/ethnic identity. Zabora et al21
reported that a sample of 680 African American cancer survivors, as
well as those of lower socioeconomic status, experienced greater
distress than did cancer survivors of other races. Addressing HRQOL in
culturally diverse populations cannot be ignored, as evidence suggests
that certain groups may be at risk for decreased HRQOL.
Conclusion
Although
cure rates and survival statistics for patients with HD have improved
dramatically in the last decade, curative treatments have been
implicated in the multiple medical sequelae that occur after treatment,
including second malignancies, cardiac and pulmonary disease, and other
late effects such as infection and endocrine disorders.45
Because HD survivors have had an excellent prognosis for disease-free
survival, this population can be used as a model for investigating the
HRQOL of cancer patients transitioning to survivorship. Implementation
of innovative programs that will improve survivors' adjustment and
gradual return to previous levels of functioning should be a priority.
The results of this systematic review suggest that there is a growing
body of literature that describes the HRQOL problems that occur after
treatment for HD. Gaps in the literature identified through this review
include the lack of longitudinal studies and explicit theoretical
frameworks, inconsistent measurement of HRQOL, and exclusion of minority
groups in study samples. Consensus about standardized HRQOL instruments
would enable researchers to compare findings across studies. As the
evidence related to HRQOL in HD survivors grows, development and testing
of theory-guided interventions are needed to improve the transition
from acute care and enhance the long-term goal of the highest possible
HRQOL.
References and the Originating Source Page- http://www.nursingcenter.com/library/journalarticleprint.asp?Article_ID=940995
1. Lymphoma information network. http://www.lymphomainfo.net/ . Accessed November 2008. [Context Link]
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