Diminished quality of life in patients with cancer correlates with tryptophan degradation

Introduction

Quality of life (QoL) is often deteriorated in patients suffering from malignant disease in comparison to the normal population. In addition to other consequences of tumor progression like metastasis or tumor-cachexia, immune response was also suggested earlier to be involved in the impairment of QoL (Earlam et al. 1996). In patients suffering from colorectal liver metastasis, QoL was even shown to be related more closely with the extent of immune activation than with liver metastasis volume or the serum level of the tumor marker carcinoembryonic antigen (Allen-Mersh et al. 1998). However, the underlying mechanisms are only poorly understood. Fatigue is another frequent symptom in cancer patients, and it was also proposed to represent a result of chronic immune system activation (Kurzrock 2001; Bower et al. 2002). By contrast, a more recent study on patients with hematological malignancy failed to find such a relationship (Dimeo et al. 2004).

Signs of inflammation and immune activation are often found in patients with malignant disease, and higher concentrations of immune activation markers like neopterin have been shown to predict disease progression in patients with, e.g., gynecological cancer, hepatocellular and colon cancer (Lewenhaupt et al. 1986; Reibnegger et al. 1986, 1987; Weiss et al. 1993; Kronberger et al. 1995; Murr et al. 1999). Well in line with this data, increased concentrations of C-reactive protein (CRP) are also associated with worse outcome in cancer patients (Mahmoud and Rivera 2002). Increased amounts of neopterin are released by human macrophages upon stimulation with Th1-type cytokine interferon-γ, which induces GTP-cyclohydrolase I, the key enzyme for the formation of neopterin. In parallel, interferon-γ triggers expression of the enzyme indoleamine (2,3)-dioxygenase (IDO) (Carlin et al. 1989; Werner et al. 1989; Taylor and Feng 1991; Brown et al. 1991), which converts the essential amino acid tryptophan to kynurenine. Tryptophan is not only important for protein biosynthesis but also serves as precursor for neurotransmitter 5-hydroxytryptamine, serotonin (Wirleitner et al. 2003, see also Fig. 1). Decreased availability of tryptophan and serotonin is discussed to be crucial in the pathogenesis of mood disturbances and depression (Widner et al. 2002).

Enhanced degradation of tryptophan, in parallel with increased production of neopterin is observed in several clinical conditions like virus infections, autoimmune disorders and also malignant diseases (Fuchs et al. 1991; Widner et al. 2000; Denz et al. 1990; Huang et al. 2002; Giusti et al. 1996; Schroecksnadel et al. 2005). QoL is often impaired in patients suffering from such chronic disorders, and susceptibility for mood disturbances or depressive episodes is increased (Cruess et al. 2003). Decreased availability of tryptophan could thus play an important role. Indeed, tryptophan degradation was found recently to be associated with impaired QoL in patients suffering from colorectal cancer (Huang et al. 2002) and in patients with malignant melanoma treated with interferon-α (Capuron et al. 2003). In this study, we compared QoL and fatigue with tryptophan metabolism and cellular immune activation in patients suffering from malignant disease.

Methods

Results

Median tryptophan concentration in patients was 42.9 μmol/l (interquartile range: 31.1–51.5 μmol/l), median kynurenine concentration was 2.21 μmol/l (1.57–3.24) and median kyn/trp was 55.7 μmol/mmol [41.4–78.9, reference ranges, as published by Widner et al. (1997) are shown in the left column of Table 2]. When compared to all other groups, patients with gastrointestinal tumors presented with lowest tryptophan concentrations (median: 36.6 μmol/l) and highest kyn/trp (median: 68.9 μmol/mmol), levels being significantly different from patients with hematologic malignancy and gynecological cancer (both P < 0.05).

Concentrations of neopterin were highly elevated in comparison to reference ranges (see Table 2). Patients with hematologic/lymphatic malignancy had highest neopterin concentrations (median: 25.0 nmol/l), and they were significantly higher compared to patients with gynecological cancer (median: 12.7 nmol/l) and tumors of other localization (median: 15.7 nmol/l; both P < 0.05). Similarly, concentrations of CRP (median: 2.1; interquartile range: 0.6–5.3 mg/dl) and erythrocyte sedimentation rate after one (ESR-1) and 2 h (ESR-2) were elevated in patients: ESR-1: 33 mm/h (16–52), ESR-2: 65 mm/2 h (35–88).

Patients suffering from progressive malignancy had significantly higher concentrations of CRP, ESR-1 and ESR-2 and kyn/trp than patients who had stable or remitting disease (all P < 0.05, Table 2). Tryptophan concentrations and kyn/trp depended on the stage of disease: lower tryptophan concentrations and higher kyn/trp were observed in patients with progressive disease (both P < 0.01). Kynurenine concentrations did not differ in patients with stable or progressive disease, but were significantly higher in patients who died within 3 months (both P < 0.01).

Median QoL score of patients was 3—17.8% of patients rated their QoL as bad (score 4; n = 18) or very bad (score 5; n = 8). Median fatigue score was 3—17.1% of patients rated it high (score 4; n = 18) or very high (score 5; n = 7). Fifty-four patients suffered from depression and had to take antidepressant medication. Rather unexpectedly, the diagnosis of depression and also of anemia was not associated significantly with QoL and fatigue scores (see Table 3), however, a correlation existed between fatigue feeling and hemoglobin counts (r _s = −0.204, P < 0.05). On the other hand, a significant correlation was observed between QoL and fatigue scores (r _s = 0.555; P < 0.001), which were both strongly associated with the performance status of patients (r _s = −0.510 for QoL and Karnofsky-Index, r _s = 0.519 for QoL and WHO/ECOG score; r _s = −0.651 for fatigue and Karnofsky-Index, r _s = 0.666 for fatigue and WHO/ECOG score, all P < 0.001). Patients with different types of cancer did not differ regarding QoL and fatigue scores; however, significantly lower QoL and fatigue scores were observed in patients suffering from more advanced disease in comparison with patients suffering from remitting or stable disease (both P < 0.001).

Both, QoL and fatigue scores, were associated with the clinical stage and also the prognosis of tumor disease in our study: patients with more advanced stages were more likely to suffer from impaired QoL (r _s = 0.362; P < 0.001) and increased fatigue feeling (r _s = 0.456; P < 0.001, see Table 3). While patients suffering from remitting disease had QoL scores of 2.25 ± 0.67 (mean ± SD) and fatigue of 1.97 ± 0.70, patients with stable disease had a mean QoL score of 2.54 ± 0.74 and fatigue of 2.39 ± 0.88. Patients with progressive tumor disease had the worst QoL (QoL score 3.04 ± 0.92) and fatigue feeling (2.98 ± 0.96; both P < 0.001). Furthermore also patients who died within 3 months of the study had decreased QoL (mean ± SD: 3.47 ± 1.22) and suffered more often from fatigue (3.58 ± 1.02) compared to patients still alive after 3 months (QoL score: 2.66 ± 0.80; P < 0.01; fatigue: 2.49 ± 0.89; P < 0.001).

QoL and fatigue as well as Karnofsky index were better in patients with an ETS above 1 year, WHO/ECOG score was worse (all P < 0.001) in comparison to patients with an ETS below 6 months. Patients with an ETS between 6 and 12 months had a lower ESR compared to an ETS of below 6 months (P < 0.01). Patients with an ETS below 6 months had significantly lower tryptophan and hemoglobin concentrations (both P < 0.001); in parallel they presented with higher CRP (P < 0.001), and higher neopterin (P < 0.001) concentrations than patients with an ETS above 1 year and kyn/trp was significantly higher in patients with an ETS lower than 6 months (see Fig. 2).

QoL was better in patients under CHT (median 2 vs. 3, P < 0.01), who also had higher tryptophan (median: 45.5 vs. 41.1, P < 0.01) and lower neopterin (9.6 vs. 20.0 nM, P < 0.001) and CRP (1.3 vs. 2.9 mg/dl, P < 0.001) concentrations. Interestingly, neither age nor disease stage or ETS were different in patients under CHT, whereas Karnofski index was higher in patients under CHT (P < 0.05), indicating that patients under CHT were in a better physical condition than the other patients.

Table 3 shows all parameters that were predictors of impaired QoL and fatigue, respectively, in binary logistic regression analysis (univariate). In multivariate regression analysis, when all laboratory parameters that were predictive for impaired QoL in univariate analysis were included, neopterin concentrations, in combination with tumor stage and ESR were the best indicators of impaired QoL: (Z = −7.459 + 1.309 × stage + 0.023 × ESR-2 + 0.024 × neopterin; P < 0.01 for neopterin, P < 0.05 for ESR-1 and stage).

Lower tryptophan concentrations coincided with decreased QoL (r _s = −0.256; P < 0.01) and increased fatigue feeling (r _s = −0.179; P < 0.05). Similarly, significant correlations were observed between fatigue scores and kyn/trp (r _s = 0.276; P < 0.01). Furthermore, fatigue scores correlated with concentrations of neopterin (r _s = 0.274; P < 0.01), CRP (r _s = 0.375; P < 0.001), ESR-1 (r _s = 0.234; P < 0.01) and ESR-2 (r _s = 0.241; P < 0.01), and QoL correlated with concentrations of neopterin (r _s = 0.307; P < 0.001) and CRP (r _s = 0.508; P < 0.001) (Fig. 3). After adjustment for tumor stage, (partial) correlations between QoL scores and concentrations of tryptophan, neopterin, CRP and kyn/trp remained significant (all P < 0.05).

Immune activation status was strongly related to enhanced tryptophan degradation: Elevated concentrations of neopterin correlated with increased kyn/trp (r _s = 0.586); furthermore, also CRP (r _s = 0.453) and ESR-1 (r _s = 0.326) were strongly related to increased kyn/trp (all P < 0.001, Fig. 4). In line with this finding, lower tryptophan concentrations coincided with higher neopterin and CRP concentrations (both P < 0.001) and higher ESR-1 (P < 0.01). CRP correlated with neopterin (r _s = 0.410; P < 0.001), ESR-1 (r _s = 0.435; P < 0.001) and ESR-2 (r _s = 0.406; P < 0.001), and also neopterin and ESR-1 were weakly associated (r _s = 0.187; P < 0.05).

Discussion

Our patients, suffering from malignant disease, experienced deteriorating QoL and fatigue feeling dependent on disease progression, data confirming and extending earlier observations. The investigation of tryptophan catabolism indicates that depletion of this essential amino acid may, among other factors, contribute to impairment of both, QoL and feeling of fatigue. Tryptophan degradation was found to be accelerated in our patients and correlated with immune activation. Immune-mediated tryptophan degradation has already been shown earlier to be associated with impaired QoL when psychological questionnaires were applied (Huang et al. 2002). In our study, a less objective but more practicable method was performed, namely the subjective view of patients was asked for to judge their QoL and fatigue feeling. Nevertheless, results appear to confirm existing data, the query used was obviously suited rather well to assess psychological status of patients in a more general sense. Both scores were associated with clinical outcome and correlated significantly with tumor stage as well as survival/death within 3 months. Certainly, more sophisticated psychological questionnaires can define better which specific problems may impair the patient’s QoL, e.g., whether the patient suffers rather from physical or mental health disturbances.

QoL and fatigue scores were also strongly associated with markers of inflammation and immune activation and with the degradation of tryptophan. Enhanced conversion of tryptophan to kynurenine in patients coincided with enhanced concentrations of neopterin. Thus, immune activation appears to underlie degradation of tryptophan, and thus most likely IDO is involved. Data are consistent with and extend earlier studies in patients with hematologic and gastrointestinal malignancy (Denz et al. 1993; Giusti et al. 1996; Iwagaki et al. 1995).

Tumor-mediated IDO-expression was recently proposed as effective evasion strategy of tumors to escape immune response (Uyttenhove et al. 2003). However, the coincidence of tryptophan degradation with neopterin formation suggests that mostly interferon-γ-stimulated monocytes are responsible for enhanced tryptophan conversion. Well in accordance with this observation, elevated interferon-γ concentrations were found to correlate with increased neopterin concentrations in patients with hematologic disorders earlier (Denz et al. 1993). However, in a few patients, very high kyn/trp, together with only moderately elevated neopterin levels were observed. Data may indicate that, in addition to macrophages and dendritic cells, also tumor-associated IDO activity may be of some relevance in these patients. Such data agree well with observations made earlier in a pilot study of patients with gynecological tumors (Schroecksnadel et al. 2005). Interestingly, increased tryptophan degradation was found in this study in nearly all cancer patients. Thus, this phenomenon appears not to be confined to special types of tumors. Anti-tumor immune response was earlier suggested to lead to impaired QoL in cancer patients (Earlam et al. 1996), one study in patients with colorectal cancer even observed that QoL was associated stronger with immune activation than with liver metastasis or tumor marker elevation (Allen-Mersh et al. 1998).

Reduced QoL was recently shown to be associated with low tryptophan concentrations in patients suffering from colorectal cancer (Huang et al. 2002). Our data confirm that decreased tryptophan availability in parallel with impaired QoL is also found in patients suffering from other types of cancer. Immune activation cascades with on-going production of pro-inflammatory cytokines like interferon-γ and TNF-α (= cachectin) may in fact account for “cancer symptoms” of patients: most cancer patients show symptoms, which resemble cytokine-induced sickness behavior in animal models and impair QoL severely (Cleeland et al. 2003). After the administration of infectious or inflammatory agents or certain pro-inflammatory cytokines, reduced food intake and decreased social activities were observed in animals (Dantzer et al. 1998), cytokine antagonists were in some cases able to inhibit these reactions. Similarly, treatment of cancer patients with interferon-α and interleukin-2 was described to impair their mood (Capuron et al. 2001). Notably, cytokine-induced decrease of tryptophan concentrations was found to be more expressed in patients who developed depressive symptoms (Capuron et al. 2003).

Tryptophan depletion as a consequence of immune activation cascades may also be of importance in the pathogenesis of mood disturbances and depression (Iwagaki et al. 1997; Murr et al. 2000; Widner et al. 2002; Myint and Kim 2003). Limiting serotonin biosynthesis, lowered serum tryptophan might increase the susceptibility for depressive episodes/depression and decreased social activities. Findings of this study may provide an explanation for the relationship between impaired QoL and increased fatigue in cancer patients. Associations between tryptophan metabolic changes and QoL and fatigue were rather weak, however, associations between other markers, like hemoglobin (which has been proposed as marker for QoL earlier) and QoL or fatigue were even less expressed, e.g., there was no significant correlation between haemoglobin and QoL or fatigue. Of course, enhanced tryptophan metabolism only represents one among several metabolic changes in cancer patients, but it appears to be also of some clinical relevance: the psychological and maybe also the physical status of patients can be influenced by modification of tryptophan metabolism, e.g., by successful antitumor treatment. Follow-up studies investigating the role of tryptophan regarding QoL, mood, fatigue and also survival analysis in cancer patients under treatment may thus also provide important new insights for future treatment of patients. At least in patients with multiple sclerosis, therapeutic benefit was observed by the use of IDO inhibitors (Platten et al. 2005). However, a potential positive influence of IDO inhibitors on psychological status of patients does not rule out an adverse effect of such compounds on the underlying malignant process.