According to the World Health Organization, 9.6 million people worldwide died from cancer in 2018 [1]. Considering the progressive ageing of the population worldwide [2] and that most forms of cancer have the highest frequency among the elderly, cancer remains a major public health issue [3].

Receiving the diagnosis of cancer, as well as being in long-term and painful treatments, adversely impact the Health-related Quality of Life (H-QoL) and the psychological wellbeing of people suffering from cancer [4-12].

H-QoL is a complex and multidimensional construct that doesn’t simply deal with the concept of standard of living, which primarily concern income and employment status [13]. In fact, indicators of subjective perception of H-QoL range between the built environment, physical and mental health, education, including elaborate psychological components of wellbeing like, satisfaction with recreation and leisure time, social belonging satisfaction with cares, mood, sleep and rest, energy, vitality [14, 15].

Research evidence show that H-QoL may predict survival in people with several kinds of cancer [16] and could be a prognostic factor of clinical outcome and adherence to treatment [14, 16-18]. Thus, the measure of H-QoL in people suffering from chronic diseases such as solid cancer has become relevant in both prognostic and outcome indicators flanking the traditional outcomes measures, such as adherence to treatments, therapy response and survival rates, to compare different treatment strategies in clinical trials and cohort studies [10, 11, 16, 18-20]. Hence, interest in factors associated with enhancing H-QoL, alleviating psychological distress and facilitating positive adaption to the illness has increased [21, 22], as well the search for accessible and simple ways to measure the H-QoL of large patient cohorts such as the adoption of e-Health based instruments [23, 24].

Among factors associated with a lowering of the H-QoL, an important role has been recognized in several chronic diseases at the co-occurrence of Major Depressive Disorders [25-29]. Although some research has sought to elucidate the relationship between Major Depressive Disorders, H-QoL and cancer [18, 30, 31], this relationship has so far been little studied.

The primary outcome of the present study is to assess H-QoL in patients diagnosed with solid cancers and compare the results with the general population and with other chronic pathologies. Furthermore, another aim is to clarify the role of depressive episodes and the relationship between cancer stage and depression and H-QoL.

The SS consists of 151 people, including 82 females (54.3%) and 69 males (45.7%). The matched CS from a sample of people declaring they do not have cancer and are representative of the Italian population [39] include, 604 people, 328 females (54,3%) and 276 males (45.7%). The mean±sd age of the SS was 63.14±11.548 years and 63,31±11.718 years for the CS (Table 1). The socio-demographic and clinical-oncological characteristics of the SS are illustrated in Table 2. In the SS, the mean±sd of the SF-12 total score was 32.34±6.764; in the CS the mean±sd of the SF-12 total score was 37.01±6.561, the difference reached the statistically significant difference of (F= 60.539, df 1,753,754, p <0.000).

As shown in Table 3, the impact on H-QoL of the burden attributable to the solid cancer was 4.67±6.64 points (as the difference between healthy control matched sample and Study Sample on the SF-12). The H-QoL profile in patients diagnosed with a solid cancer was comparable to that with other chronic diseases such as Major Depression (F=0.6753; df=1,186,187; p=0.4123), Wilson’ Disease (F=0.0375; df=1,172,173; p=0.8467), Carotidal Atherosclerosis (F=2.0799; df=1,195,196; p=0.1509), Obsessive Compulsive Disorder (F= 1.619; df 1,175,176; p=0.205), and Post-Traumatic Stress Disorder (F= 0.347; df 1,175,176; p=0.557). The impact on H-QoL was significantly greater than that due to Celiac disease (F=6.9304; df=1,209,210; p=0.0091) and to Specific Phobia (F=10.497 df 1,77,178

p=0.001) and significantly lower than that due to Multiple Sclerosis (F=18.0766; df= 1,350,351; p=0.000) and Fibromyalgia (F=48.8075; df= 1,220,221; p=0.0000).

Table 4 shows the Association between H-QoL (as a score of SF-12) and moderate-severe depressive symptoms (PHQ-9≥14). The table also shows the difference in the staging of tumors (mean±standard deviation, stage 1, 2, 3, 4) in the two groups of people with and without depression, to verify the possible confounding factor due to a different level of severity in the two groups (i.e., that the different level of depression and consequently the different quality of life may depend on the different severity of the tumors). The two samples are perfectly balanced as regards the distribution of stage severity of the tumors (F=0.59; p= .690, mean differences 0.07).

Table 5 shows the Attributable Burden on worsening H-QoL due to Major Depressive Disorder in people with solid cancers in comparison to the Attributable Burden on worsening H-QoL due to Major Depressive Disorder in other chronic diseases. Attributable burden caused by Major Depressive Disorder in people with solid cancer is higher than the burden due if having Major Depressive Disorder in all chronic diseases examined: Multiple Sclerosis (F = 98.85, 1,350,351 df, p <0.0001); Fibromyalgia (F = 47.27, 1,220,221 df, p <0.0001); Wilson Disease (F = 19.56, 1,150,156 df, p <0.0001); Celiac Disease (F = 61.09, 1,201,210 df, p <0.0001); Carotid Atherosclerosis (F = 39.07, 1,195,196 df, p <0.0001).

The present study shows that people with solid cancers have significantly worse H-QoL than people living in the community without cancer, confirming some previous pieces of evidence [4, 47-49]. The result partially disagrees with the work of Lee and Cartmell [50] in which scores on PHQ-9 (the same tool used by our study to measure depression) and EQ-5D (a H-QoL measure) reported by cancer survivors which were not different from the general population.

As already pointed out in a recent study regarding hematological cancers [4], another important finding of the present research is that solid cancers have a similar impact on the patient H-QoL, along with other chronic diseases such as Major Depression, Wilson’ Disease, Carotid Atherosclerosis, Obsessive Compulsive Disorder and Post-Traumatic Stress Disorder. A significantly higher impact of solid cancers on H-QoL was reported compared with Celiac Disease and Specific Phobia, but lower compared with Multiple Sclerosis and Fibromyalgia [26-28, 41-46]. Despite the considerable impact that having a tumor can imply on the life of an individual, nonetheless highly disabling chronic diseases that do not have an equally “quoad vitam” prognosis, such as Multiple Sclerosis [51] or Fibromyalgia [52], present a burden attributable to worsening the H-QoL much higher than solid cancer.

In this respect, it is interesting to note that Fibromyalgia, as cancers and their treatments, is connoted by high levels of perceived pain [53], such that the significantly higher level of the impact on H-QoL observed by the comparison with that of solid cancer could be due to the different nature of somatic, cognitive and emotional components of pain in Fibromyalgia [54] than those in cancer [55, 56].

The fact that fibromyalgia only recently in the biomedical field and in the regulations concerning the recognition of the condition of disability caused by somatic diseases has been identified as “true” illness may have caused that situation of “being strongly misunderstood”, which has been complained of by people with Fibromyalgia [52, 57]. On the other hand, being affected by a tumor is probably less stigmatizing, unlike what happened a few decades ago, also in relation to the improvement of treatments and the possibility of a good outcome. In fact, more and more often we read of show media and business people, politicians or, in any case, people in view of public opinion who speak openly about their events related to a cancer diagnosis, while until a few years ago, all this was hidden. This may have improved the impact of the disorder [58].

The presence of a depressive episode lowers the SF-12 score on average by 10 points in people with solid cancer regardless of the level of cancer staging; thus, the study indicates that comorbidity with a depressive episode is a powerful factor associated with worsening H-QoL in people with solid tumors. This potential of the depressive episode to worsening the H-QoL is much higher in tumors than in any other chronic disease examined.

We hypothesize that living with solid cancers poses the problem of the awareness of the possibility of the end of life, and in this condition, the equilibrium can be governed on the one hand by a renewed hope in survival due to the improvement of treatments and on the other by the acceptance of the end of life when the health worsens, the onset of a depressive episode can catastrophically break this balance more than in other disorders where the worsening is given by pain, functional disability and stigma (factors having a role even in cancer but in addition of the above described condition). However, future studies will have to clarify these aspects, verify the hypothesis and possibly generate others. To our knowledge, ours is in fact, the first study that highlights these very important aspects.

The causal direction of the association between depression and low H-QoL is not obvious. If it is intuitive, but also reported by the literature, that a depressive episode can dramatically lower the H-QoL of an individual [59], it is also plausible that the stressful impact of having a tumor may be more important in a person who perceives a low H-QoL [60]. It is, therefore possible that a person who receives the diagnosis of cancer and lives the daily life of the struggle for survival and seeks to cope in the new condition may be more vulnerable to depression if, even before the tumor event, he perceives a low H-QoL.

However, while it is very difficult to identify effective tools to modify the perception of H-QoL, the depressive episode can be prevented and cured, and it is shown that the improvement of depression leads to an improvement in the perception of H-QoL [61].

Therefore, considering that both factors (depression and low H-QoL) have been associated with a worsening of the outcome. Prevention, early identification and therapy of the depressive episode become essential in people with solid cancer.

The study also suggests that in people with solid tumors, it is essential to identify the conditions of compromise in H-QoL and to take charge of these aspects, firstly by verifying whether depressive symptoms coexist.

The present study has several limitations. The first one regards the small sample size that decreases the power of the difference in the associations between H-QoL and Depressive Episodes. Another limitation is relative to the observational nature of the cross-sectional study that does not allow to evaluate the causal direction of the association links (i.e., between depression and low H-QoL). Cohort studies on large samples are needed to consolidate the evidence and clarify if the SF-12 score is comparable among cases and controls but apparently not among pathologies without taking into consideration some potential risk factors that characterize each pathology, such as the different gender and age distribution or different comorbid conditions. However, having conducted the comparison not between different pathologies directly, but between differences for each specific pathology of the SF-12 in a sample with diagnosis and with a specific control group extracted from the same database but balanced for sex and age on the specific pathology, may have attenuated this potential bias.

The study confirms a strong impact of solid cancer, but also shows that H-QoL in solid cancer was higher than in chronic diseases with better “quoad vitam” outcome. Since depression was a strong determinant, its prevention, early detection and therapy are the main objectives that must be reached in patients with cancer.