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Health-related quality of life in patients with metastatic colorectal cancer, association with systemic inflammatory response and RAS and BRAF mutation status

European Journal of Cancer, August 2017, Volume 81, Pages 26-35

Abstract

Background

The aim of this study was to evaluate the effect of cetuximab on health-related quality of life (HRQoL) in the NORDIC-VII trial on metastatic colorectal cancer (mCRC), and to assess HRQoL in relation to RAS and BRAF mutation status and inflammatory biomarkers.

Patient and methods

HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, after every fourth cycle of chemotherapy, and at the end of treatment. HRQoL during 12 cycles of chemotherapy was evaluated over time, compared between treatment arms, and assessed for association with tumour mutation status and inflammatory markers.

Results

QLQ-C30 was completed by 512 patients (90%) before start of treatment. HRQoL variables were well balanced across treatment arms at baseline, and no statistically significant differences during treatment were seen. Patients with BRAF -mutated tumours reported poorer HRQoL at baseline and subsequent time points than patients with RAS -mutated or RAS / BRAF wild-type tumours. Patients with high serum interleukin-6 (IL-6) or C-reactive protein (CRP) had markedly impaired HRQoL compared to patients with normal levels. There was a statistically significant association between reduction in IL-6 and CRP levels and improvement in HRQoL during treatment from baseline to cycle 4.

Conclusion

The addition of cetuximab to chemotherapy did not affect HRQoL in mCRC patients. Patients with BRAF -mutated tumours have both a worse prognosis and a poor HRQoL. The associations between levels of systemic inflammatory markers and reduced HRQoL suggest that the patients might benefit from anti-inflammatory treatment.

Highlights

  • Adding cetuximab to oxaliplatin-based chemotherapy did not influence health-related quality of life (HRQoL).

  • Patients with BRAF -mutated tumour had worse HRQoL scores than those with RAS / BRAF wild-type or RAS -mutated tumours.

  • Patients with high inflammatory biomarkers, indicating systemic inflammation, had markedly worse HRQoL.

  • C-reactive protein as biomarker of systemic inflammation, can be useful in the management of metastatic colorectal cancer.

Keywords: HRQoL, mCRC, Chemotherapy, RAS and BRAF mutation status, Inflammation.

1 Introduction

Colorectal cancer (CRC) is the second most common cancer in females and the third most common in males worldwide. Almost half of the patients with CRC have or will develop distant metastases [1] . The treatment options for patients with metastatic colorectal cancer (mCRC) have evolved with more effective combination chemotherapy, targeted therapies and more extensive surgery, resulting in prolonged survival [2] . The main goal of chemotherapy is improved survival. However, health-related quality of life (HRQoL) is also an important outcome for patients with mCRC [3] .

Mutation status of RAS and BRAF in primary tumours or metastases are important biomarkers in mCRC [2] . Presence of RAS and particularly BRAF mutations are associated with impaired prognosis 4 5 6 . Furthermore, RAS mutations are an established biomarker for lack of effect of epidermal growth factor receptor (EGFR) antibody therapy, while this is still debated for BRAF mutations [2 7 8 9 10 .

Inflammation is one of the hallmarks of cancer [11 12] , and there is growing evidence for the role of inflammation in cancer development and tumour progression [13] . Some pro-inflammatory factors exert effects beyond the local tumour, causing a state of systemic inflammation [13 14] , which is an important cause of cancer-associated morbidity in terms of pain, fatigue, functional disability, anorexia and cachexia, and is also associated with poor treatment response and impaired survival 15 16 17 18 .

The NORDIC-VII study [19] was a randomised phase III trial investigating the effect of cetuximab in the first-line therapy of mCRC, in combination with continuous or intermittent chemotherapy with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (Nordic FLOX) [20] . There were no statistically significant differences in outcomes regarding progression-free survival or overall survival (OS) between the treatment arms, irrespective of RAS mutation status [19 21] . Recently, in an analysis across the treatment arms in NORDIC-VII, we demonstrated that patients with high serum levels of the inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP) had reduced median survival [22] .

The aim of the present study was to compare HRQoL between the treatment arms, and to investigate the associations between HRQoL and RAS and BRAF mutation status and between HRQoL and inflammatory biomarkers.

2 Materials and methods

2.1 Patients and study design

The NORDIC-VII study [19] is a phase III randomised trial of first-line chemotherapy with cetuximab in mCRC. Patients were randomly assigned to receive Nordic FLOX (arm A), cetuximab and Nordic FLOX (arm B), or cetuximab combined with intermittent Nordic FLOX (arm C). The Nordic FLOX regimen was administered every 2 weeks with oxaliplatin 85 mg/m 2 on day 1, and 5-FU 500 mg/m 2 bolus injection followed 30 min later by FA 60 mg/m 2 bolus on days 1 and 2. Cetuximab was administered with an initial dose of 400 mg/m 2 and thereafter 250 mg/m 2 weekly [19] . Treatment continued until progression of disease (PD) or unacceptable toxicity in arms A and B. In arm C, Nordic FLOX was paused after 8 cycles if there was treatment response or stable disease. Weekly cetuximab was continued as maintenance therapy until PD, and then Nordic FLOX was reintroduced and continued with cetuximab until PD or unacceptable toxicity. Assessment of HRQoL in the different treatment arms according to mutation status was a secondary end-point.

2.2 HRQoL measurement

Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), version 3.0 [23] . The QLQ-C30 is a cancer-specific self-report questionnaire consisting of 30 items, constituting five functioning scales, one overall quality of life (QoL) scale, three symptom scales and six single items covering the past week. All but two items are scored on a categorical scale ranging from 1 (not at all) to 4 (very much), whereas the two assessing overall health and QoL are scored from 1 to 7, and constitute the global QoL score. Higher scores on the functioning and global QoL scales indicate better functioning, while higher scores on the symptom scales and single items indicate more symptoms. Scores were transformed into a scale from 0 to 100, as described in the EORTC scoring manual [24] .

2.3 Mutation analyses of KRAS , NRAS and BRAF

Genomic DNA was extracted from formalin-fixed paraffin-embedded 10 μm tissue sections with 65–70% (median) tumour cells using QIAamp DNA Micro Kit (Cat.56304, Qiagen). Tumour DNA was screened for the presence of KRAS mutations (Q61H, Q61L, Q61R, K117X (K117N 351A > C, K117N 351A > T, K117R, K117E) and A146X (A146T, A146P, A146V)) using the KRAS Mutation Analysis Kit (EntroGen). NRAS mutations (G12C, G12D, G12S, G13V, G13R, Q61K, Q61R, Q61L, Q61H and A146T) were analysed using the NRAS Mutation Analysis Kit (EntroGen). Input in the KRAS and NRAS assays were 10 ng and 20 ng, respectively. BRAF V600E mutation analysis was performed as previously described [25] .

2.4 Markers of systemic inflammation

Serum concentrations of IL-6 were determined in samples stored at minus 80 °C by a commercially available human IL-6 high-sensitive enzyme-linked immunosorbent assay (ELISA, Quantikine HS, high sensitive, R&D Systems, Abingdon, Oxon, UK) at baseline and after cycle 4. IL-6 levels were dichotomised as high or low at the median 6.1 pg/ml, as there is presently no consensus regarding a clinically relevant cut-off value [26] . Serum concentrations of CRP were measured at each participating hospital, at baseline, after one week, before every cycle for four cycles, and every fourth cycle thereafter. CRP levels were dichotomised as high or low at 10 mg/L, as used in the modified Glasgow Prognostic Score [27] .

2.5 Statistical analyses

Statistical analyses were performed using IBM SPSS (version 18.0. Chicago, SPSS Inc.). Demographic data were described with median and range (continuous variables) or with proportion and percentages (categorical variables).

A difference of ≥10 points on the 0–100 scale of the HRQoL scores was considered clinically relevant [28] and a P value <0.05 was considered statistically significant. Mean scores in mutation subgroups were compared with one-way analysis of variance (ANOVA). Differences in scores over time were compared between treatment arms and mutation subgroups by linear mixed models including fixed main effects as well as the interaction with time, assuming an unstructured covariance matrix. The associations between the selected HRQoL variables and IL-6 and CRP were estimated with linear regression analysis. Two-way ANOVA was used to assess the interaction between inflammation and mutation status.

2.6 Ethics

The NORDIC-VII study ( http://clinicaltrials.gov/show/NCT00145314 ) was approved by the national ethics committees and governmental authorities in each country and was conducted in accordance with the Declaration of Helsinki. All patients had provided written informed consent.

3 Results

3.1 Baseline characteristics

Of all patients in the NORDIC-VII study, 512 (90%) completed the QLQ-C30 before the start of treatment ( Fig. 1 ). Baseline patient and tumour characteristics were well balanced between the treatment arms ( Table 1 ). Information on RAS and BRAF mutations was available for 411 patients, and the prevalence of mutations did not differ between treatment arms. Measurements of serum IL-6 and CRP at baseline were available in 447 and 490 patients, respectively.

gr1

Fig. 1
Number of patients in the NORDIC-VII study and patients with completed EORTC QLQ-C30 questionnaires at different time points. EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.

Characteristics Nordic FLOX (arm A) Cetuximab and Nordic FLOX (arm B) Cetuximab and intermittent Nordic FLOX (arm C)
n = 172 n = 171 n = 169
Median (range) Median (range) Median (range)
Age
Years 60.1 (29.9–74.8) 59.5 (26.9–74.4) 62.2 (35.7–74.9)
n (%) n (%) n (%)
Sex
Male 94 (54.7) 105 (61.4) 105 (62.1)
Female 78 (45.3) 66 (38.6) 64 (37.9)
WHO performance status
0 116 (67.4) 116 (67.8) 114 (67.5)
1 48 (27.9) 49 (28.7) 48 (28.4)
2 8 (4.7) 6 (3.5) 7 (4.1)
Location of primary tumour
Colon 101 (58.7) 88 (51.5) 108 (63.9)
Rectum 71 (41.3) 83 (48.5) 61 (36.1)
Number of metastatic sites
1 45 (26.2) 55 (32.2) 43 (25.4)
>1 127 (73.8) 116 (67.8) 126 (74.6)
Liver metastases only
Yes 33 (19.2) 35 (20.5) 28 (16.6)
No 139 (80.8) 136 (79.5) 141 (83.4)
Primary tumour resected
Yes 118 (68.6) 113 (66.1) 115 (68.0)
No 54 (31.4) 58 (33.9) 54 (32.0)
Tumour mutation status n = 135 n = 140 n = 136
RAS / BRAF wild type 57 (42.2) 58 (41.4) 55 (40.4)
RAS mutation 60 (44.4) 65 (46.4) 66 (48.5)
BRAF mutation 18 (13.3) 17 (12.1) 15 (11.1)
HRQoL n = 172 n = 171 n = 169
Mean (95% CI) Mean (95% CI) Mean (95% CI)
Functioning scales*
Global QoL 68 (65–72) 67 (64–70) 66 (63–70)
Physical functioning 84 (82–87) 82 (80–85) 83 (80–86)
Role functioning 72 (67–76) 68 (63–73) 68 (63–73)
Emotional functioning 75 (72–79) 76 (73–79) 75 (71–78)
Cognitive functioning 88 (85–91) 91 (89–93) 87 (84–90)
Social functioning 79 (76–83) 80 (76–84) 80 (76–84)
Symptom scales and single items*
Fatigue 32 (28–35) 35 (31–39) 32 (28–36)
Nausea and vomiting 8 (6–10) 7 (5–9) 7 (5–10)
Pain 21 (17–25) 23 (19–27) 21 (17–24)
Dyspnoea 15 (12–19) 19 (15–23) 16 (12–20)
Insomnia 25 (22–29) 26 (22–31) 27 (23–31)
Appetite loss 20 (15–24) 22 (17–26) 19 (15–23)
Constipation 13 (10–17) 14 (10–17) 13 (9–16)
Diarrhoea 19 (15–23) 17 (13–21) 16 (12–19)
CI, confidence interval; QoL, quality of life; HRQoL, health-related quality of life; WHO, World Health Organisation.
*Higher scores on the functioning scales indicate better function, while higher scores on the symptom scales and single items indicate more symptoms.

Table 1Clinical and tumour characteristics and HRQoL at baseline in patients who completed QoL questionnaires in the different treatment arms (n = 512).

3.2 HRQoL in different treatment arms

No relevant differences in HRQoL were found between the treatment arms in any of the HRQoL scales or items at baseline ( Table 1 ). The mean scores of global QoL, physical functioning, fatigue and pain for the different treatment arms, from baseline through 12 cycles of chemotherapy are shown in Fig. 2 . There were only small differences over time and between treatment arms from baseline to cycle 12. In all arms a statistically significant reduction in the mean pain score was observed from baseline to after cycle 4 of treatment (arm A: 21–11; arm B: 23–6; and arm C: 21–12), however, there was no statistically significant mean difference between treatment arms ( P = 0.061). No statistically significant differences were seen in any of the other scales.

gr2

Fig. 2
Mean score of global QoL (A), physical functioning (B), fatigue (C) and pain (D) from baseline through 12 cycles of chemotherapy, for the different treatment arms. Higher scores on the functioning scales indicate better functioning, while higher scores on the symptom scales indicate more symptoms. Arm A, Nordic FLOX; Arm B, cetuximab and Nordic FLOX; Arm C, cetuximab and intermittent Nordic FLOX; QoL, quality of life. P-values refer to mean differences between groups.

Since no significant differences in HRQoL were observed between the treatment arms, data were pooled for subsequent analyses of associations with mutation status and systemic inflammation.

3.3 HRQoL and mutation status

Patients with BRAF -mutated tumours had significantly worse baseline scores for global QoL, social functioning, fatigue, dyspnoea and diarrhoea than patients with RAS / BRAF wild-type or RAS -mutated tumours ( Table 2 ). During the first 12 treatment cycles, patients with double wild-type tumours reported the best mean HRQoL scores, while patients with BRAF -mutated tumours reported the worst scores, as demonstrated in Fig. 3 for global QoL, physical functioning, pain and fatigue.

HRQoL Total n = 411 RAS / BRAF WT n = 170 (41%) RAS Mut n = 191 (47%) BRAF Mut n = 50 (12%) P -value**
Mean (95% CI) Mean (95% CI) Mean (95% CI) Mean (95% CI)
Functioning scales*
Global QoL 69 (67–71) 71 (68–75) 68 (65–71) 63 (57–69) 0.05
Physical functioning 84 (82–86) 86 (83–88) 83 (81–86) 80 (75–85) 0.09
Role functioning 71 (68–74) 73 (68–78) 71 (66–75) 63 (54–72) 0.14
Emotional functioning 77 (75–79) 77 (74–80) 77 (74–80) 74 (68–80) 0.56
Cognitive functioning 90 (88–91) 89 (87–92) 90 (88–93) 87 (83–92) 0.53
Social functioning 80 (78–83) 85 (81–88) 79 (75–82) 73 (66–81) 0.007
Symptom scales and single items*
Fatigue 31 (29–34) 29 (26–32) 31 (28–35) 39 (32–46) 0.03
Nausea and vomiting 7 (5–8) 7 (5–9) 6 (4–8) 9 (4–13) 0.49
Pain 21 (18–23) 19 (16–23) 20 (16–23) 28 (20–36) 0.09
Dyspnoea 16 (13–18) 13 (10–16) 16 (12–19) 25 (17–33) 0.007
Insomnia 25 (22–28) 23 (19–27) 26 (22–30) 29 (20–38) 0.34
Appetite loss 18 (16–21) 19 (15–23) 18 (14–21) 20 (12–28) 0.84
Constipation 13 (11–15) 15 (11–19) 12 (8–15) 11 (4–17) 0.26
Diarrhoea 16 (13–18) 14 (11–18) 14 (11–17) 27 (19–36) 0.001
Mut, mutant; WT, wild type; CI, confidence interval; HRQoL, health-related quality of life; QoL, quality of life.
*Higher scores on the functioning scales indicate better function, while higher scores on the symptom scales and single items indicate more symptoms.
**Mean scores in RAS / BRAF WT, RAS Mut and BRAF Mut compared with one-way ANOVA.

Table 2Health-related quality of life at baseline in patients with RAS / BRAF wild type, RAS -mutated and BRAF -mutated tumours.

gr3

Fig. 3
Mean scores of global QoL (A), physical functioning (B), fatigue (C), pain (D) from baseline through 12 cycles of chemotherapy, in subgroups of patients with RAS / BRAF wild type, RAS- mutated and BRAF -mutated tumours. Higher scores on the functioning scales indicate better functioning, while higher scores on the symptom scales indicate more symptoms. Mut, mutant; WT, wild type; dbl WT, RAS / BRAF WT; QoL, quality of life. P-values refer to mean differences between groups.

3.4 HRQoL and systemic inflammation

The proportions of patients with reduced performance status, abnormal alkaline phosphatase, non-resected primary tumour and poor HRQoL at baseline were higher in patients with high serum levels of CRP and IL-6 ( Tables 3 and 4 ).

Characteristics IL-6 <6.1 pg/ml IL-6 ≥6.1 pg/ml
n = 223 n = 224
Median (range) Median (range)
Age
Years 59.8 (26.9–74.9) 60.9 (29.9–74.8)
n (%) n (%)
Sex
Male 126 (56.5) 139 (62.1)
Female 97 (43.5) 85 (37.9)
WHO performance status
0 179 (80.3) 124 (55.4)
1 42 (18.8) 82 (36.6)
2 2 (0.9) 18 (8.0)
Location of primary tumour
Colon 119 (53.4) 137 (61.2)
Rectum 104 (46.6) 87 (38.8)
Number of metastatic sites
1 69 (30.9) 60 (26.8)
>1 154 (69.1) 164 (73.2)
Primary tumour resected
Yes 176 (78.9) 123 (54.9)
No 47 (21.1) 101 (45.1)
Liver metastases only
Yes 41 (18.4) 46 (20.5)
No 182 (81.6) 178 (79.5)
ALP level
Normal 164 (73.5) 70 (31.3)
Abnormal 59 (26.5) 154 (68.8)
Tumour mutation status n = 185 n = 169
RAS / BRAF WT 75 (40.5) 74 (43.8)
RAS Mut 93 (50.3) 71 (42.0)
BRAF Mut 17 (9.2) 24 (14.2)
HRQoL n = 223 n = 224
Mean (95% CI) Mean (95% CI)
Functioning scales*
Global QoL 72 (70–75) 63 (60–66)
Physical functioning 88 (86–90) 78 (76–81)
Role functioning 80 (76–83) 60 (55–64)
Emotional functioning 76 (73–79) 76 (73–79)
Cognitive functioning 89 (87–91) 89 (86–91)
Social functioning 84 (81–87) 77 (73–80)
Symptom scales and single items*
Fatigue 25 (23–28) 39 (36–43)
Nausea and vomiting 4 (3–6) 10 (8–13)
Pain 15 (13–18) 28 (24–32)
Dyspnoea 12 (9–14) 21 (17–25)
Insomnia 24 (20–27) 27 (24–31)
Appetite loss 14 (11–18) 26 (22–30)
Constipation 11 (8–13) 14 (11–17)
Diarrhoea 15 (12–18) 19 (15–22)
IL-6, interleukin-6; WT, wild type; Mut, mutation; ALP, alkaline phosphatase; CI, confidence interval; QoL, quality of life; HRQoL, health-related quality of life; WHO, World Health Organisation.
*Higher scores on the functioning scales indicate better function, while higher scores on the symptom scales and single items indicate more symptoms.

Table 3Clinical and tumour characteristics and HRQoL at baseline in relation to IL-6 level.

Characteristics CRP <10 mg/L CRP ≥10 mg/L
n = 181 n = 309
Median (range) Median (range)
Age
Years 60.5 (28.5–74.8) 60.6 (26.9–74.9)
n (%) n (%)
Sex
Male 104 (57.5) 189 (61.2)
Female 77 (42.5) 120 (38.8)
WHO performance status
0 151 (83.4) 181 (58.6)
1 29 (16.0) 108 (35.0)
2 1 (0.6) 20 (6.5)
Location of primary tumour
Colon 97 (53.6) 184 (59.5)
Rectum 84 (46.4) 125 (40.5)
Number of metastatic sites
1 52 (28.7) 85 (27.5)
>1 129 (71.3) 224 (72.5)
Primary tumour resected
Yes 155 (85.6) 176 (57.0)
No 26 (14.4) 133 (43.0)
Liver metastases only
Yes 27 (14.9) 64 (20.7)
No 154 (85.1) 245 (79.3)
ALP level
Normal 143 (79.0) 117 (37.9)
Abnormal 38 (21.0) 192 (62.1)
Tumour mutation status n = 157 n = 234
RAS / BRAF WT 63 (40.1) 101 (43.2)
RAS Mut 75 (47.8) 106 (45.3)
BRAF Mut 19 (12.1) 27 (11.5)
HRQoL n = 181 n = 309
Mean (95% CI) Mean (95% CI)
Functioning scales*
Global QoL 73 (70–76) 64 (62–67)
Physical functioning 88 (86–90) 81 (78–83)
Role functioning 79 (75–83) 64 (61–68)
Emotional functioning 77 (74–80) 76 (73–78)
Cognitive functioning 89 (87–92) 89 (87–91)
Social functioning 84 (81–87) 78 (75–81)
Symptom scales and single items*
Fatigue 25 (22–28) 37 (34−40)
Nausea and vomiting 4 (3–6) 9 (7–11)
Pain 14 (11–17) 26 (23–29)
Dyspnoea 13 (10–16) 19 (16–22)
Insomnia 23 (19–27) 27 (24–30)
Appetite loss 13 (9–16) 24 (21–28)
Constipation 11 (8–14) 15 (12–17)
Diarrhoea 16 (13–20) 18 (15–21)
CRP, C-reactive protein; WT, wild type; Mut, mutation; ALP, alkaline phosphatase; CI, confidence interval; QoL, quality of life; HRQoL, health-related quality of life; WHO, World Health Organisation.
*Higher scores on the functioning scales indicate better function, while higher scores on the symptom scales and single items indicate more symptoms.

Table 4Clinical and tumour characteristics and HRQoL at baseline in relation to CRP level.

Patients with high IL-6 or CRP had significantly poorer HRQoL for several scales and items, including global QoL, physical functioning, role functioning, social functioning, fatigue, nausea and vomiting, pain, dyspnoea, appetite loss and constipation (only IL-6) at baseline ( Tables 3 and 4 ). During treatment, there were statistically significant associations between reductions in IL-6 or CRP values after 4 cycles and improvements in global QoL, physical functioning, fatigue, and appetite loss ( Supplementary Tables 1 and 2 ). There was no significant interaction between RAS / BRAF mutation status and IL-6 or CRP for global QoL, physical functioning, fatigue or pain.

4 Discussion

This study shows no differences in patient-reported HRQoL between the treatment arms in the NORDIC-VII trial. For the whole study cohort, analysed across the different treatment arms, patients with BRAF -mutated tumour had poorer HRQoL scores than patients with RAS / BRAF wild-type or RAS -mutated tumours, both at baseline and during treatment. Furthermore, patients with high serum concentrations of IL-6 or CRP had markedly worse HRQoL scores.

The finding that cetuximab did not significantly influence HRQoL during treatment in the NORDIC-VII trial is in accordance with results in other trials of EGFR antibody therapy in mCRC. Some studies have demonstrated improved survival by addition of cetuximab or panitumumab to chemotherapy without improved or impaired HRQoL 29 30 31 . The present results show that also in NORDIC-VII, where cetuximab did not improve survival when added to a 5-FU plus oxaliplatin regimen [19] , cetuximab had neither a beneficial nor a negative impact on patient-reported HRQoL. In the NORDIC-VII publication [19] skin toxicity was reported, and as expected was more common in the groups receiving cetuximab. The EORTC QLQ-C30 does not address skin toxicity, however if skin toxicity had significant impact on HRQoL, it would be expected that the HRQoL scores would differ between the treatment arms. In line with a recent publication [32] our data do not indicate difference in HRQoL dependent on grade of skin toxicity.

A statistically significant reduction in pain score was observed in all three treatment arms. We did not observe any clinically relevant or statistically significant difference in pain relief in arms B and C (which included cetuximab) as compared to arm A (without cetuximab). Hence, the effect could not be attributed to cetuximab. Since use of analgesics was not registered, we could not determine whether the reduced pain was a result of the anticancer therapy or a more adequate analgesic treatment after study inclusion.

RAS and BRAF mutations are genetic driver lesions in mCRC. Patients with tumours harbouring RAS or, particularly, BRAF mutations have impaired outcomes compared to those with RAS/BRAF wild-type tumours [4 5 21] . We found that patients in NORDIC-VII with BRAF -mutated tumours had poorer HRQoL both at baseline and during treatment. Since BRAF mutation is associated with markedly impaired prognosis and often rapidly progressing disease, it was expected that these patients would also report worse HRQoL throughout treatment. Chemotherapy does provide meaningful improvements in outcome in subgroups of patients harbouring BRAF -mutated tumours, although post-progression is markedly worse in these patients [33] . We need to identify patients who will and those who will not benefit from chemotherapy, hopefully inflammatory markers might help us in this respect [22] .

There is a large body of evidence indicating that an inflammatory microenvironment is essential for the development and progression of a tumour [11 13] and that a systemic inflammatory response has a profound impact on the clinical symptoms and course of the cancer 16 17 18 . Systemic inflammation is most likely a major cause of cancer-associated morbidity, especially for general symptoms like pain, fatigue, and appetite loss [15] . We recently reported that in NORDIC-VII, increased levels of IL-6 or CRP were associated with markedly impaired survival in mCRC. Patients with high versus low IL-6 levels (dichotomised at median 5.6 pg/ml) had median OS of 16.6 versus 26.0 months, and stratified according to increasing CRP levels, median OS varied from 24.3 months to 12.3 months [22] . In the present study, these observations are further explored. Patients with elevated serum IL-6 or CRP levels were found to have significantly worse HRQoL almost to the same extent, both at baseline and after two months of chemotherapy. No statistically significant interaction between inflammation biomarkers at baseline and mutation status was found. During treatment, there was an association, although moderate, between reduction in inflammatory markers and improvement in HRQoL from baseline to cycle 4.

CRP is a readily available biomarker, which can be measured routinely and inexpensively in daily clinical practice, IL-6 is so far not routinely measured. The present and the previously reported results [22] indicate that CRP levels can assess the degree of an inflammatory condition of importance for HRQoL and for OS. Our findings are in line with those of Laird and co-workers [34] who in a recent publication demonstrate a relationship between deterioration of HRQoL and systemic inflammation in a large cohort of patients with advanced cancer and point out that attenuation of a systemic inflammatory response may improve HRQoL in cancer patients. The above results could have implications for choice of treatment [15 35 36] . It is possible that patients with increased systemic inflammation could benefit from anti-inflammatory treatment to improve HRQoL, either as an add-on to chemotherapy or for patients not fit enough to receive chemotherapy but in need of effective palliation 37 38 39 40 .

This report presents results on HRQoL in mCRC in a large randomised prospective study. The baseline patient and tumour characteristics among those who completed the QoL questionnaire, including performance status, were well balanced across treatment arms and did not differ from the study population in the NORDIC-VII study. However, the study has some limitations. While a large proportion of the patients in the NORDIC-VII study responded to the QLQ-C30 questionnaire at baseline, we do not have information about the patients who did not complete the QLQ-C30 or about concomitant medication such as anti-inflammatory drugs and analgesics.

In conclusion, we found no difference in HRQoL, assessed by the EORTC QLQ-C30, between treatment arms in this randomised phase III study. The addition of cetuximab does not negatively influence HRQoL. In contrast, HRQoL was impaired both at baseline and during treatment in groups of patients with poor prognosis, patients having BRAF -mutated tumours in particular and patients with elevated systemic inflammatory markers. These poor prognostic groups might benefit from active symptom palliation with drugs targeting interleukin signalling in addition to NSAIDs and steroids and this might be a future treatment option in subgroups of patients with mCRC.

Funding

The NORDIC-VII study was supported financially by Merck KGaA , Darmstadt, Germany and Sanofi , Oslo, Norway. This work was supported by The Norwegian Cancer Society and The Swedish Cancer Society .

Conflict of interest statement

None declared.

Acknowledgements

Merck KGaA reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication solely reflect those of the authors.

Appendix A Supplementary data

The following are the supplementary data related to this article: Attached file Attached file

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