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Web Supplement: Summary of the Results of the Systematic Review of

Circulating IL-6 Concentrations and Cancer, by cancer type

Multiple myeloma

22 publications contained data on IL-6 concentrations in multiple myeloma patients

and cancer-free individuals (Table W1). Compared to healthy people’s, multiple

myeloma patient’s IL-6 concentrations in were higher in 15 studies (1-15). In one

study no difference was reported between these groups (16). In some of the studies

the findings may have been exaggerated as the healthy control group consisted of

blood donors and medical staff (3, 17-20). Also, in two studies the results were

imprecise due to the small numbers of newly diagnosed cancer cases (9 and 32 cases,

respectively) (3, 21). Furthermore, in three studies, the elevated IL-6 concentrations

found in cancer patients may have been influenced by prior cancer treatment (22-24)

and for one study we were unable to establish from the article (translated from

Chinese) whether this was a possibility (25). Only two studies had adjustment for age

and sex (26, 27); the remaining studies were unadjusted.

12 studies contained data on IL-6 concentrations in multiple myeloma patients and

people with benign plasma cell diseases, such as monoclonal gammopathies of

unknown significance (MGUS). Cancer patients’ IL-6 concentrations were higher

than MGUS patients’ in six studies (28-33), yet in five studies equally elevated IL-6

concentrations were found in individuals with multiple myeloma and those with

benign plasma cell conditions (34-38). One study had opposing findings, with higher

IL-6 in patients with Sjögren’s syndrome or MGUS than in those with multiple

myeloma (39). However, none of these studies had adjustment for potential

confounders.

Taken together, these findings suggest that multiple myeloma patients’ IL-6

concentrations are elevated when compared to healthy individuals’ but the evidence

for a difference in IL-6 concentrations between individuals with malignant and benign

plasma cell diseases is contradicting. It is possible that the elevated IL-6

concentrations observed in multiple myeloma patients in some studies were caused by

prior cancer treatment or other confounders, rather than cancer.

Lymphatic cancers

IL-6 concentrations were investigated in 21 studies lymphomas (Table W2).

Hodgkin’s lymphoma patients’ IL-6 concentrations were reported to be higher than

healthy controls’ in all studies of this comparison (40-44), although in one of these

studies some cancer patients’ IL-6 concentrations may have been increased by prior

cancer treatment (45). Only one had adjustment for age and sex (46). The remaining

studies were unadjusted. Similarly, when compared to healthy controls, elevated

circulating IL-6 concentrations were reported in patients with non-Hodgkin’s

lymphoma in seven studies (47-53). However, prior treatment may have increased the

cancer patients’ IL-6 concentrations in two of these (54, 55), and only one study had

adjustment for potential confounders (age and sex) (47). Similar IL-6 concentrations

were reported in non-Hodgkin’s lymphoma patients and in controls who had benign

plasma cell disorders (56) or were healthy (57), but in the latter study some of the

cancer patients had received radiotherapy prior to IL-6 measurement.

Elevated IL-6 concentrations were reported in mixed groups of Hodgkin’s and non-

Hodgkin’s lymphoma patients when compared to healthy controls (58, 59) and

controls with benign lymphadenopathy (58) or hepatitis C-associated

cryoglobulinemia (60). The findings were similar in both studies of diffuse large cell

lymphoma (61, 62). None of these studies included a description of the selection of

the healthy controls or adjustment for confounding, but pre-treatment IL-6

concentrations were measured in all but one (63). Equally elevated IL-6

concentrations were found in a patients with Burkitt’s lymphoma and AIDS (64). One

study had mixed results, with higher IL-6 concentrations reported in aggressive non-

Hodgkin’s lymphoma and adult T-cell leukaemia but not in indolent lymphomas

when compared to healthy controls (65).

Thus overall, lymphatic cancer patients have higher circulating IL-6 concentrations

than healthy controls or patients with benign lymphatic diseases, but it is possible that

these findings have been influenced by confounding, although in most studies the

possible effect of cancer treatment had been minimised.

Lung cancer

We identified eight publications of IL-6 concentrations in patients with non-small cell

lung cancer (NSCLC) and ten publications of IL-6 in patients with other types of

lung cancers (Table W3). IL-6 concentrations were measured in people with an

established cancer in all but one study, a prospective cohort (66). In all but three

studies (67-69) IL-6 was measured prior to or at least four weeks after any invasive

treatment.

Higher IL-6 concentrations were reported in NSCLC patients than in healthy controls

in five studies (70-74) and similar IL-6 concentrations in NSCLC patients and healthy

controls in three (75-77). In one study the healthy controls were individuals with a

family history of cardiovascular disease, who may have had higher IL-6

concentrations than healthy people in general (78). However, in this study the

NSCLC patients’ IL-6 concentrations were also found to be elevated when compared

to those of controls with a benign pulmonary disease (79). Only one of these studies

had adjustment for smoking, but in this study the NSCLC patients’ elevated IL-6

concentrations may have been influenced by their aggressive, inoperable disease or

radiotherapy (80).

Elevated IL-6 concentrations were reported in patients with other types of lung cancer

when compared to healthy controls (81-83) or participants with benign lung

conditions (84-86). In three studies the investigators found no difference in IL-6

concentrations between lung cancer patients and healthy people (87) or individuals

with benign lung conditions (88-90). All of these studies were unadjusted. The

findings of the only prospective study (multivariable-adjusted hazard ratio for lung

cancer: 1.22, 95% CI: 0.75, 1.97), were based on only 42 cases (91). Thus overall, due

to limitations in these studies, particularly lack of adjustment for smoking, it is

difficult to determine whether circulating IL-6 concentrations are associated with lung

cancer.

Colorectal cancer

17 studies included data on circulating IL-6 in colorectal cancer patients and cancer-

free people (Table W4). 16 compared prevalent colorectal cancer patients to healthy

controls or controls with benign colorectal diseases and one prospective study

investigated the association of IL-6 with colorectal cancer risk. Cancer patients’ IL-6

concentrations were measured before the onset or at least four week after any

treatment in all of these studies, and were elevated in most studies when compared to

those of healthy controls (92-104) or controls with benign colorectal disease (104).

However, the findings in some of the studies may have been exaggerated by the

selection of the healthy controls from blood donors (104-106). The results were

similar in direction but varied in magnitude in the six studies with adjustment for age

and sex (107-112) and in the rest of the studies that were unadjusted. The point

estimates from the only prospective study, although imprecise, suggested that IL-6

was associated with an increased colorectal cancer risk (multivariable-adjusted hazard

ratio: 1.44, 95% CI: 0.90, 2.31) (113). Thus overall, there is some evidence that

elevated IL-6 is associated with colorectal cancer.

Ovarian cancer

16 studies contained data on IL-6 concentrations in prevalent ovarian cancer cases and

cancer-free individuals (Table W5). Ovarian cancer patients’ IL-6 concentrations

were reported to be higher in all 11 studies with a healthy control group (114-124).

The findings in four of these studies, however, may have been exaggerated as the

healthy controls were blood donors who are likely to have had lower IL-6

concentrations than the general population (125-128).

Ovarian cancer patients’ IL-6 concentrations were also elevated when compared to

women with benign ovarian tumours or cysts (116, 129-134). In one study the

investigators reported similarly elevated IL-6 concentrations in women with

malignant and benign ovarian tumours, but these results were based on a small

number of cancer cases (n=8) (135). Prior treatment may have increased the cancer

patients’ IL-6 concentrations in one study (136) and for two studies it was unclear

whether this was a possibility (133, 137). Only two studies had adjustment for age

(138, 139); the remaining studies had no adjustment for potential confounders.

In conclusion, these findings suggest that ovarian cancer patients have higher IL-6

concentrations than healthy women or women with benign ovarian tumours, but these

findings may be due to confounding, particularly from prior treatment, age or

hormonal factors.

Leukaemias

Twelve studies contained data on IL-6 concentrations in people with leukaemias and

cancer-free people (Table W6). IL-6 concentrations were elevated in patients with

acute myeloid, acute lymphocytic, chronic lymphocytic, chronic myeloid and adult T-

cell leukaemias (140-148) when compared to healthy controls or people with benign

plasma cell diseases (149, 150) or lymphotropic viral infection (151). In order to

avoid confounding from inflammatory conditions, in two of these studies participants

with infections (152) or other immune diseases (153) had been excluded. However, it

is possible that prior treatment had increased the cancer patients’ IL-6 concentrations

in two studies (154, 155) and only one study had adjustment for age and sex as

potential confounders (144). The remaining studies were unadjusted.

Two studies had discordant findings. In one study similar median IL-6 concentrations

were reported in chronic lymphocytic leukaemia and healthy controls (156). In

another study higher IL-6 concentrations were found in healthy children than in those

with acute myeloid leukaemia, but IL-6 concentrations were similar in healthy

children and children with other types of leukaemia (157). These findings may be

specific to the young age groups in this study. Thus there is some evidence that

circulating IL-6 concentrations are elevated in leukaemia patients, but the findings of

some of the studies described here may have been exaggerated by prior cancer

treatment or other confounding factors.

Pancreatic cancer

11 studies contained data on IL-6 concentrations in patients with established

pancreatic cancer and cancer-free individuals (Table W7). It is unlikely that any

treatment had influenced the cancer patients’ IL-6 concentrations in any of these. In

most of the studies cancer patients’ IL-6 concentrations were higher than healthy

controls’ (158-163) or individuals’ with chronic pancreatitis (164) or benign

abdominal diseases (165), although the elevated IL-6 concentrations may have been

due to cancer cachexia in the three studies of weight-losing cancer patients (166-168).

In one study no difference was found between cancer patients and healthy controls

(169) and another study had opposing findings: lower IL-6 concentrations were

reported in pancreatic cancer patients than in controls who were healthy or had benign

pancreatic diseases (170), although these results may have been diluted by the

inclusion of seemingly healthy individuals with a family history of pancreatic cancer

in the control group. However, in only one study had the investigators recruited age-

and sex-matched controls (171); the remaining studies were unadjusted.

Thus pancreatic cancer patients have elevated IL-6 concentrations when compared to

cancer-free people, but it is possible that these findings are due to confounding from

age or cancer co-morbidities, such as cachexia, rather than cancer pathology.

Gastric cancer

IL-6 concentrations in gastric cancer patients and cancer-free people were assessed in

ten studies (Table W8). Gastric cancer patients’ IL-6 concentrations were elevated in

all seven studies with a healthy control group (172-178). Of the five studies

comparing IL-6 concentrations in gastric cancer patients and controls with benign

gastric or liver conditions (179-183), cancer patients’ IL-6 concentrations were

reported to be elevated in three (184-186). Similar IL-6 concentrations were found in

people with gastric cancer and gastric ulcers in one study (187) and in those with

gastric cancer and benign liver conditions in another (188). However, it was unclear

whether prior treatment could have increased the gastric cancer patients’ IL-6

concentrations in six studies (172, 177, 189-192). Furthermore, the findings in six of

the studies described here were unadjusted and only four studies had adjustment for

age and sex (177, 193-195). Hence although these findings suggest that gastric cancer

patients have elevated IL-6 concentrations when compared to healthy individuals or

those with benign gastrointestinal conditions, it is possible that in most studies the

cancer patients’ high IL-6 concentrations have been increased by cancer treatment or

other confounding factors.

Prostate cancer

We identified 11 studies of IL-6 in prostate cancer patients and cancer-free men: IL-6

concentrations were measured in prevalent cancer cases in nine studies and two

studies had a prospective design (196, 197) (Table W9). Overall, the studies were

well-conducted and in six of them the cancer-free controls were men attending

prostate cancer screening at the same clinics as the cases, and were thus representative

of the population from which the cases came (198-203). In the remaining studies the

healthy controls were selected from a hospital sera bank or their recruitment was

unclear (204-207).

The studies of prevalent cases had contradicting findings. In six studies circulating IL-

6 concentrations were elevated in prostate cancer patients when compared to healthy

men (208-212) or to men with benign prostate disease (213-216). However, in some

of these studies cancer patients had received hormone-therapy or undergone surgery,

which may have increased their IL-6 concentrations (217-219). In three studies the

investigators found no difference in IL-6 concentrations between cancer patients and

healthy men (220, 221) or only borderline higher IL-6 concentrations in cancer

patients compared to those with benign prostate disease (222). The researchers found

no association between circulating IL-6 concentrations and incident prostate cancer in

the multivariable-adjusted analyses of either of the two prospective studies (223, 224).

Based on this evidence men with a prevalent prostate cancer have higher IL-6

concentrations than cancer-free men but it is possible that these results are related to

age, treatment or some other attribute of the cancer patients rather than to the

malignant pathology. Furthermore, the null findings from the two prospective studies

suggest that circulating IL-6 is not causally associated with prostate cancer.

Liver cancer

IL-6 concentrations in liver cancer patients and controls were examined in nine

studies (Table W10). IL-6 concentrations were reported to be elevated in cancer

patients when compared to healthy controls in eight studies (225-232) and when

compared to individuals with benign hepatic diseases in five studies (225, 233-236).

In two studies IL-6 concentrations were similar in liver cancer patients and

individuals benign liver diseases (232, 237), although in one of these studies the

benign disease group also included four cancer cases (232). None of the studies

described here had adjustment for potential confounders and in only four studies we

were able to ascertain that pre-treatment IL-6 concentrations had been measured (238-

241). Thus based on these findings it is difficult to determine whether the elevated IL-

6 concentrations observed in liver cancer patients are associated with the malignancy

or related to age or lifestyle factors, such as alcohol use, which predispose to liver

cancer.

Head and neck squamous cell carcinoma

Eight studies contained data on IL-6 concentrations in patients with squamous cell

carcinoma of the head and neck and cancer-free individuals (Table W11). When

compared to healthy controls’, cancer patients’ IL-6 concentrations were elevated in

seven studies (242-248). In one study the investigators reported no difference in IL-6

concentrations between the cancer cases and controls (249). Lack of control for

potential confounders, such as prior treatment, age or smoking, limited our ability to

draw conclusions from the findings of four studies (250-252). Of the remaining

studies, the controls were matched for age in two (253, 254) and for age and sex in

another two (255, 256). However, only one study included a group of controls who

were similar to the cancer cases in terms of smoking history (257) and in another

study all controls were smokers (258). In both of these studies the cancer patients’

mean IL-6 concentrations were reported to be higher than the controls’. Thus due to

the lack of adjustment for potential confounders, particularly tobacco chewing or

smoking, in most of the studies, it is difficult to draw conclusions of their findings.

Breast cancer

We identified eight studies comparing IL-6 concentrations in breast cancer patients

and healthy controls (Table W12). In six studies higher IL-6 concentrations were

reported in women with an established cancer (259-264), yet in one study the

investigators reported similarly elevated IL-6 concentrations in healthy women and

women with current or recently surgically removed breast cancer (265). In two studies

the investigators had recruited controls from among healthy women attending breast

cancer screening (266, 267), although one of these, designed to investigate insulin

resistance in breast cancer patients, only included participants with a BMI exceeding

25 (268). The selection of the cancer-free controls was not described in the remaining

four studies. No association was found between circulating IL-6 and incident breast

cancer in the only prospective study (HR: 0.95, 95% CI: 0.54, 1.65)(269). Hence

women with breast cancer seem to have elevated IL-6 concentrations when compared

to healthy women but due to lack of control for confounding in the majority of the

studies and the small number of cases in the only prospective study (n=30), some of

these findings could be explained by chance, bias or confounding.

Kidney cancer

Seven studies of renal cell carcinoma were identified (Table W13). Higher IL-6 was

reported in renal cancer patients in all five studies with healthy control group (270-

274), although in one of these all cancer cases had a metastatic disease, which may

have increased their IL-6 concentrations (275). Of the three studies comparing IL-6

concentrations in renal cell cancer patients and people with benign renal diseases, the

researchers reported higher IL-6 concentrations in cancer patients in two studies (276,

277) and similar IL-6 concentrations in cancer patients and those with benign renal

cysts in one (278). However, IL-6 had been measured prior to any treatment in only

four studies (272, 279-281) and none of the studies had adjustment for any potential

confounders. Thus based on this evidence it is difficult to determine whether the

elevated circulating IL-6 concentrations in renal cell carcinoma patients are related to

the malignancy or due to the extent of the disease, prior treatment or other

confounding factors.

Melanoma

Six studies contained data on IL-6 concentrations in melanoma patients and healthy

controls (282-287) (Table W14). The investigators found elevated IL-6 concentrations

in melanoma patients in all of these studies. However, the selection of the healthy

controls was not described in any of the studies and I was only able to ascertain from

the published reports that pre-treatment IL-6 had been measured in four of them (288,

289). In only one study had the investigators adjusted for age and sex as potential

confounders (290) and the rest of the studies were unadjusted. Furthermore, in two

studies all melanoma patients had metastatic disease (287, 291), which may have lead

to systemic elevation in IL-6 concentrations. Thus based on this evidence I was

unable to determine whether elevated IL-6 concentrations observed in melanoma

patients are related to cancer or due to prior treatment, the extent of the disease or

other confounding factors.

Other cancers and cancer in general

As the number of studies of each of the other cancer types was small, we were unable

to determine whether elevated circulating IL-6 concentrations were associated with

other cancers (Web Tables W15-W21). Elevated IL-6 concentrations were reported in

bladder cancer patients when compared to healthy controls (292) or patients with

cystitis (293) (Table W18). IL-6 was also reported to be higher in soft tissue and bone

sarcoma patients (294, 295) and those with HIV-associated Kaposi’s sarcoma (296,

297) than healthy controls, as well as in bone sarcoma patients than in controls with

benign bone tumours (298) (Tables W16, W20). Circulating IL-6 was elevated in

women with uterine (299, 300) (Table W17) and cervical (301) (Table W19) cancers

when compared to healthy controls. Higher IL-6 concentrations were also observed in

choriocarcinoma patients when compared to women with vesicular moles (302)

(Table W17) and in patients with malignant ascites when compared to those with non-

malignant ascites (303, 304) (Table W21). In one study IL-6 concentrations were

higher in patients with parapneumonic pleural effusions than in those with malignant

effusions (305) (Table W21). IL-6 concentrations were similar in patients with solid

cancers and healthy controls (306) or controls with autoimmune disease (307) (Table

W21). However, higher IL-6 was reported in bacterial peritonitis than in abdominal

cancers (308, 309) and in depressed participants, irrespective of whether they had

cancer or were healthy (310) (Table W21). Overall, pre-treatment circulating IL-6

was reported to be elevated in and cancer in general (311-317) (Table W21).

Uncertain results

We were unable to ascertain the results of 10 studies: IL-6 was undetectable in all or

most of the cases and controls in seven studies with healthy controls (318-324) and

four studies with controls including benign conditions (325-328), thus making any

meaningful comparison difficult. In one study it was unclear whether the controls

were healthy or had non-malignant diseases (329).

Table W1 Summary of the studies of the relationship between circulating IL-6 concentrations and multiple myeloma (MM)

Study,(author, year)

Study design

N participants Age of participants

N (%) female

Main aim of the study Main results relating to IL-6 Comments

Studies with IL-6 and cancer as a main aimInnsbruck, Austria

[Nachbaur et al., 1991]

Case-control

MM: 47Monoclonal gammopathy of unknown significance (MGUS): 24Myelo-proliferative disorders: 8Healthy controls: 10

Not cited. Not cited. PrognosisTo assess the role of IL-6 in the network of cytokine involved in pathophysiology of multiple myeloma.

Median (range) IL-6, pg/ml:

MM (progressive): 6 (2-33)MM (plateau): 3 (1-10)MGUS: 4 (1-7)MPD: 2 (1-2)Healthy controls: <5

Advanced MM vs. plateau MM or MGUS: p<0.01

For complete results see Table W21.

Selection of healthy controls not described.

No adjustment for potential confounders.

Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy.

Dijon, France

[Solary et al., 1992]

Case-control

MM: 55MGUS: 28Waldenström’s disease: 19Castleman’s disease: 2Healthy controls: 66

Not cited. Not cited. Evaluating an assay To evaluate a radioimmunoassay for investigating IL-6 concentrations in patients with monoclonal gammopathies at diagnosis and during the course of the disease.

Median (range) IL-6, pg/ml, p vs. controls:

MM: 317 (153-947) p=0.05MGUS: 351 (142-668) p=0.05Waldenström’s disease: 356 (174-568) p=0.05Controls: 287 (113-520)


Selection of healthy controls not described. No demographic detail of the participants given.


Possible that cancer patients’ IL-6 influenced by previous treatment.

Table W1, continued. Summary of the studies of the relationship between circulating IL-6 concentrations and multiple myeloma (MM)Study,(author, year)

Study design


N (%) female

Main aim of the study

Main results relating to IL-6 Comments

Studies with IL-6 and cancer as a main aimJapan

[Yamagishi et al., 1992]

Case-control

MM: 61Benign monoclonal gammopathy: 43Healthy controls: 200

Unclear from the Japanese article.

Unclear from the Japanese article.

DiagnosisTo investigate the use of serum IL-6 concentrations measured by ELISA in differential diagnosis in patients with benign and malignant monoclonal gammopathies.

Mean (SD) IL-6, pg/ml:

MM by type:With Bence Jones protein (BJP): 12.3 (12.70BJP and IgG: 11.5 (5.8)IgM: 11.1 (17.5)IgA: 4.0 (1.4)IgG: 9.0 IgD with BJP: 7.0Lymphoma: 16.5

Benign monoclonal gammopathies by type:IgM: 10.5 (4.4)IgG: 5.0 (5.5)IgA: 4.5 (4.9) Percentage of participants with IL-6>10.0 pg/ml:MM: 32.8% Monoclonal gammopathy: 16.3%

Abstract only available in English. Selection or demographic detail of the participants unclear from the Japanese article.

Unclear from the abstract if cancer patients’ IL-6 measured before the onset, or at least 4 weeks after, any treatment.

Subgroup analyses based on small numbers, with fewer than 15 participants in any group. Data presented in a figure; SD not given for all participant groups. No p values cited.


Study design


N (%) female


Main results relating to IL-6 relating to IL-6

Comments


[Thaler et al., 1994]

Case-control

MM: 71MGUS: 57Healthy controls: 40

Not cited. Not cited. Prognosis To analyse serum concentrations of IL-6 in people with MM and MGUS and correlation between IL-6 and BM plasma cells proliferation index.

Mean IL-6, pg/ml:

Overt MM: 5.64Stable MM: 3.21MGUS: 3.95Controls: <3

Overt MM vs. controls p=0.0001Overt MM vs. MGUS p=0.0028Overt MM vs. stable MM p=0.0018

Disease progression associated with elevated IL-6: progressive vs. stable/remission p<0.0001.

Recruitment or demographic details of any participants not described.


Cancer patients’ IL-6 measured before any surgery. 17 MM cases had chemotherapy 4+ weeks previously.

Dijon, France

[DuVillard et al., 1995]

Cross-sectional

MM: 66MGUS: 128Waldenström’s disease: 27

Mean (range):

MM: 68 (36-94)MGUS: 72 (36-96) Waldenström’s disease: 68 (44-92)

Not cited. DiagnosisTo measure IL-6 and other biological markers in patients with monoclonal gammopathies.

Median (range) IL-6, ng/ml:

MM: 0.284 (0.053-0.734)MGUS: 0.200 (0.062-1.090)Waldenström’s disease: 0.212 (0.078-0.592)No p cited.

IL-6 had no positive predictive value for MM; negative predictive value was 0.71.


Participants were consecutive patients at the same hospital.




Study design


N (%) female


Studies with IL-6 and cancer as a main aimBarcelona, Spain

[Filella et al., 1996]

Case-control


MM by stage: Smouldering: 9 Newly diagnosed: 9 Stable: 25 Progressive: 12.

No cited. Not cited. PrognosisTo assess the value of IL-1α, TNF-α, IL-6 and soluble IL-2 receptor as markers of disease progression in patients with MM and MGUS.


MM by stage: Smouldering: 2 (2-31) Newly diagnosed: 2 (2-31) Stable: 2 (2-22) Progressive: 34 (2-210)MGUS: 2 (2-55)Controls: <3 (<2-6)Progressive MM vs. controls p<0.001Stable vs. progressive MM p<0.001MGUS vs. controls p=0.021

Healthy controls were blood donors.

No demographic details of the participants cited.


Some cancer patients had received treatment before IL-6 measurement.

Lodz, Poland

[Wierzbowska et al., 1999]

Case-control

MM: 67Healthy controls: 24

MM by stage: Newly diagnosed: 32 Stable MM: 21 Progressive MM: 14

Median (range):

MM: 64 (37-84)Controls: 58 (42-78)

MM: 35 (52.2)Controls: 15 (62.5)

PrognosisTo investigate the associations between leukaemia inhibitory factor, oncostatin M and various cytokines and disease activity and prognostic biomarkers in multiple myeloma.


All MM: 13.2 (0.0-306.0) p<0.001Newly-diagnosed MM: 14.2 (0.0-306.0) p<0.006Stable MM: 5.7 (0.5-45.5) p>0.05Progressive MM: 29.1 (9.8-160.5) p<0.006Controls: 5.3 (0.5-16.6)





Study design N participants Age of participants

N (%) female


Main results relating to IL-6

Comments

Studies with IL-6 and cancer as a main aimMidwestern Netherlands

[Schaar et al., 1999]

Cross-sectional

Lympho-proliferative disease: 39Myelo-proliferative disease: 7Solid tumour: 35Autoimmune disease: 17MGUS: 54MM: 60

No cited. Not cited.

DiagnosisTo evaluate the diagnostic value of serum IL-6 in paraproteinaemias and its prognostic value in multiple myeloma.


Lymphoproliferative: 25 (7-100)Myeloproliferative: 55 (6-303)Solid tumour: 58 (7-1990)Autoimmune: 29 (18-540)MGUS: 31 (7-474)

Non-MM vs. MGUS p=0.5Non-MM vs. MM p= 0.01MGUS vs. MM p=0.1

MM by stage:Indolent: 22 (6-56)I: 39 (6-220)II: 48 (6-186)III: 25 (6-96)

Median survival in MM patients: IL-6≥ 50 pg/ml: 23 mthsIL-6 < 50 pg/ml: 33 mths, p=0.24

Participants were patients registered in a community-based paraproteinaemia registry who had definite diagnosis, clinical data and serum samples available.



Non-MM group consisted of participants with benign and malignant haematological and autoimmune diseases. IL-6 results based on 50 cases of MM, 39 of MGUS and 81 other diseases

Excluding 42 participants with fever or infection did not alter the results.


Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimBerlin, Germany

[Sezer et al., 2001]

Case-control

MM: 56 MGUS: 11 (Healthy controls: 20)

Median (range):

MM and MGUS: 61 (39-86)

Not cited. Biological mechanism To evaluate serum concentrations of bFGF, VEHF, HGF and IL-6 in patients with multiple myeloma or monoclonal gammopathies and to analyse the effect of chemotherapy on these.

Median IL-6, pg/ml, by cancer stage:

MM I: 3.2MM II: 7.3MM III: 6.2

MGUS: 3.1p=0.25

Selection of controls with MGUS not described. Healthy controls were blood donors.



IL-6 not measured in healthy controls.

Changsha, China

[Shen et al., 2005]

Case-control

MM: 37Solid tumours with bone metastasis: 8Healthy controls: 18

Median (range):

MM: 52.5 (25-75)Solid tumours: 52 (31-60) Controls: 31.3 (31-60)

MM: 8 (21.6)Solid tumours: 3 (37.5)Controls: 10 (55.6)

PrognosisTo examine the clinical significance of concentrations of IL-6 and VEGF in multiple myeloma and solid tumours resulting from metastasis.


MM: 7.14 (3.21)p vs. controls: <0.01Solid tumours: 10.09 (5.11)p vs. controls: <0.01Controls: 3.04 (1.34)

MM by stage: I: 1.84 (0.45)II: 7.78 (3.01)III: 5.81 (2.08) (n=19)




Most MM patients (n=22) had stage III disease.


Study design

N participants

Age of participants

N (%) female Main aim of the study


Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsHelsinki, Finland

[Pettersson et al., 1992]

Case-control

Sjögren’s syndrome: 22MGUS: 12MM: 16Healthy controls: 32

Mean (range):

SS: 51 (26-80)MM: 65 (41-85)MGUS: 62 (44-86)Controls: 35 (21-54)

SS: 21 (95.5)MM: 6 (37.5)MGUS: 8 (66.7)Controls: 7 (21.9)

Biological mechanismTo measure serum immunoreactive IL-6 in patients with various lymphoproliferative diseases.

Mean (SD) IL-6, ng/l-1:

SS: 299 (100)MM: 113 (58)MGUS: 337 (92)Controls: 92 (77)MM vs. controls: p >0.5SS vs. MM or controls p<0.001MGUS vs. MM or controls p<0.001





Participants were free of concomitant infections.

Torino, Italy

[Merico et al., 1993]

Case-control


Range:

MM: 43-77MGUS: 50-71

MM: 16 (53.3)MGUS: 4 (66.7)

Biological mechanism To investigate the production of cytokines by bone marrow stromal cells to generate a microenvironment favourable to the expansion of plasma cells.

No. (%) of participants with IL-6 >0.1 ng/ml:

MM: 4 (13.3)MGUS: 0 (0)Controls: 0 (0)

IL-6 undetectable in both groups of controls.

Selection of healthy controls not clearly described but they were matched for age and sex.



Unclear why serum IL-6 only measured in 4/6 MGUS patients.


Study design


N (%) female Main aim of the study Main results relating to IL-6

Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsRome, Italy

[Greco et al., 1994]

Case-control

MM: 39MGUS without cancer: 22

Median (range):

MM male: 58 (41-760MM female: 68 (46-82)MGUS male: 65 (23-83)MGUS female: 62 (35-86)

Median (range):

MM: 21 MGUS: 45 (45.9)

Diagnosis and biological mechanismTo analyse serum cytokine abnormalities due to different types of cancer in monoclonal gammopathy of unknown significance (MGUS).


MM: 25.0 (1.0-160.0)MGUS without cancer: 9.0 (0.5-50.0)p<0.005

Controls selected from patients undergoing screening for multiple myeloma at the same institute as the cases.



22 cancer-free MGUS patients only included as 80% of eligible controls with MGUS (n=98) also had cancer.


Study design


N (%) female

Main aim of the study Main results relating to IL-6

Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsLondon, UK

[Thavasu et al., 1995]

Case-control, with partial follow-up

Active MM: 42MGUS or indolent or stable MM: 20Healthy controls: 80

Median (range):

MM: 60 (28-85)

Not cited. Prognosis and treatment To study the role of immunological parameters in prognosis and response to treatment.

Proportion of participants with pre-treatment IL-6>50 pg/ml:

Active MM by stage: I-II: 3/5III: 15/17Healthy controls: 0/80Active MM vs. healthy: p=0.0001

MGUS, indolent MM or stable MM: 1/13Active vs. inactive MM: p=0.0001

Healthy controls selected from hospital staff. Controls with MGUS were hospital patients.



Results presented in a figure.

Greece

[Kyrtsonis et al., 1996]

Case-control with follow-up


Not cited. Not cited. PrognosisTo evaluate the prognostic value of sIL-6R in MM.


MM: 20 (0-800)Controls: 5 (0-13)p not given

IL-6 did not correlate with sIL-6R at diagnosis or during the course of MM.





Study design




Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsMarburg, Germany

[Kaiser et al., 1996]

Case-control

MM: 125MGUS: 25Waldenström’s disease: 20Healthy controls: 50

Median:

MM: 61Controls: 46MGUS and Waldenström’s disease: not given.

MM: 58 (46.4)Controls: 23 (46.0)MGUS and Waldenström’s disease: not given.

PrognosisTo determine the diagnostic and prognostic value of the soluble embryonic neural cell adhesion molecule (NCAM) in paraproteinemia by comparing it to other biochemical prognostic markers.

Mean IL-6, pg/ml:

MM: 9.36MGUS: 2.89Waldenström’s: 6.45Controls: 0.9

MM vs. controls: p<0.001MM vs. MGUS: p=0.081 MM vs. Waldenström’s: p=0.167

Selection of none of the controls described.


Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy.Healthy controls seem to have been younger than MM cases.

Lodz, Poland

[Urbanska-Rys et al., 2000]

Case-control


Mean (range):

MM: 66 (37-90)Controls: 63 (40-80)

MM: 62 (51.2)Controls: 16 (25.4)

PrognosisTo test the concentration of IL-10 in MM patients at different phases and stages of the disease.

Mean (SD) IL-6, ng/ml, p vs. controls:

MM, by stage:I: 4.68 (4.60)II: 8.60 (10.17) p=0.03III: 25.05 (52.64) p=0.02Controls: 4.49 (2.91)

Selection of healthy controls not described. Controls were “comparable for median age and gender distribution” to the cases.




Study design




Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsPrague, Czech Republic

[Spicka et al., 2000]


MM: 124MGUS: 29

Median (range):

All participants: 62 (22-91)MM: 62 (not given)

All participants: 72 (46.2)MM: 58 (46.8)

PrognosisTo assess the value of clinical features and cytokines for differential diagnosis, assessment of myeloma activity, prediction of survival and duration of remission in multiple myeloma and monoclonal gammopathies.

Median IL-6, pg/ml:

MM: 3.45MGUS: 2.45p≤0.05

IL-6 reported as higher in stage III MM than stage II (p=0.03) or stage I (p=0.01), as well as in progressive compared to stable MM (p=0.04), but no means cited.

Controls recruited from the same clinics as the cases. No demographic details of controls cited.


34.7% of the MM cases also had a kidney condition.


Two participants with extramedular plasmacytoma and 1 with amyloid disease excluded

Ankara, Turkey

[Yagci et al., 2003]

Case-control


Mean (SD):

MM: 57.61 (1.1)Controls: 57.48 (1.9)

MM: 30 (45.5)Controls: 9 (50.0)

Prognosis To investigate fibrinolytic action in multiple myeloma.

Mean (SE) IL-6, pg/ml:

MM: 8.27 (0.74)Controls: 2.64 (0.66) p<0.001



Cancer patients aged 70+ received chemotherapy prior to IL-6 measurement.


Study design



Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsHeraklion, Greece

[Alexandrakis et al., 2003a]

Case-control


Median (range): Male MM: 66 (41-87)Female MM: 64 (36-81)

MM: 18 (75) PrognosisTo evaluate IL-6 and various acute phase proteins, other prognostic markers and erythrocyte sedimentation rate in a multivariate model in order to identify those with independent prognostic significance in MM.


MM: 6.9 (6.8)Controls: 0.8 (0.4)p=0.0001

Controls were hospital staff and matched for age and sex.

Duplicate publication of the same data used in the study by Alexandrakis and colleagues, 2003b.

Heraklion, Greece

[Alexandrakis et al., 2003b]

Case-control


Median (range):

MM: 64 (38-83)

MM: 21 (44.7) PrognosisTo evaluate serum concentrations of hepatocyte growth factor in MM patients at different disease stages, and the relationship between HGF at diagnosis and some prognostic markers and markers of bone resorption.


MM stage I: 1.72 (0.62-5.08)MM stage II: 2.83 (0.81-5.99)MM stage III: 6.56 (1.94-26.70)Controls: 0.67 (0.38-2.17)p MM vs. controls<0.01

Controls were hospital staff and matched for age and sex.



Study design

N participants

Age of participants

N (%) female


Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsAthens, Greece

[Terpos et al., 2003]

Case-control


Median (range):

MM: 65 (51-89)Controls: 62 (50-74)

MM: 24 (55.8)Controls: 20 (44.4)

Biological mechanismTo investigate the association between PNH phenotype and various biochemical markers in multiple myeloma.


MM: 31.0 (27.2)Controls: 2.1 (0.8)p<0.001

Selection of healthy controls not described but they were matched for age and sex.


56% of MM cases had CD55 and/or CD59 deficient red blood cells.

Heraklion, Greece

[Alexandrakis et al., 2004]

Case-control


Median (range):

MM: 67 (39-84)

MM: 24 (47.1)

PrognosisTo determine whether proliferating cell nuclear antigen (PCNA) and microvascular density (MVD) from bone marrow provide additional information on MM activity, and whether angiogenic potential correlates with proliferative activity and other parameters before and after chemotherapy.


MM: 6.73 (5.63)Controls: 1.46 (1.16)p<0.01

Pre-treatment PCNA, MVD, plasma cell infiltration and IL-6 were higher than post-treatment or control values and correlated with one another.

Healthy controls were hospital staff or blood donors, and matched for age and sex.


Apparently the same cases but at least partly different controls as the studies by the same group of authors in 2003.


Study design



Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsMalatya, Turkey

[Kuku et al., 2005]

Before-and-after study


Median (range):

MM: 63.4 (42-71)

MM: 8 (58.0) PrognosisTo investigate circulating mediators of inflammation in MM patients before and after chemotherapy treatment with vincristine-adriamycin-dexamathasone.


MM: 11.4 (3.2)Controls: 4.4 (0.2)p<0.001

CRP, IL-6 and other inflammatory markers were lower in MM patients after chemotherapy




Table W2 Summary of studies of circulating IL-6 concentrations and lymphatic cancersStudy,(author, year)

Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimHodgkin’s lymphoma (HL)Istanbul, Turkey

[Karter et al., 2002]

Case-control

Hodgkin’s lymphoma: 13Rheumatoid arthritis: 12Healthy controls: 23

Mean (SD):

HL: 34 (16)Rheumatoid arthritis: 43 (12)Controls: 32 (12)

HL: 6 (23.1)Rheumatoid arthritis: 7 (58.3)Controls: 12 (52.2)

Biological mechanismTo investigate differences in IL-1, IL-6 and TNF-α concentrations in Hodgkin’s lymphoma, rheumatoid arthritis and healthy controls to explore whether the two diseases might have similar inflammatory profiles.


HL: 89.6 (104.36)Rheumatoid arthritis: 66.52 (109.32)Controls: 3.53 (0.93)HL vs. controls: p<0.001




Non-Hodgkin’s lymphoma (NHL)Innsbruck, Austria


Case-control

NHL: 25 MGUS: 24Myeloproliferative disorders: 8Healthy controls: 10



NHL: 3 (2-10)MGUS: 4 (1-7)MPD: 2 (1-2)Healthy controls: <5





IL-6 measured in 101/104 participants. NHL patients had low-grade disease.

Table W2, continued. Summary of studies of circulating IL-6 concentrations and lymphatic cancersStudy,(author, year)

Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimNon-Hodgkin’s lymphoma (NHL)Rome, Italy

[Stasi et al., 1993]

Case-control

NHL: 14Healthy controls: 174

Median (range):

NHL: 35 (21-55)Controls: 41 (14-65)

AML: 7 (36.8)NHL: 9 (64.3)Controls: 92 (52.9)

Prognosis and response to treatmentTo determine the extent to which antiphospholipid antibodies can be found in newly diagnosed acute myeloid leukaemia and non-Hodgkin’s lymphoma patients and whether they change during treatment.


NHL: 13.8 (10.1)p vs. controls=0.043

No. (%) participants with IL>7pg/ml: NHL: 10 (71.4)


Selection of healthy controls not described, but those with hereditary coagulation deficiencies or history of thrombosis were excluded.



Dijon, France


Cross-sectional

NHL: 11MGUS: 128Waldenström’s disease: 27

Mean (range):

MGUS: 72 (36-96) Waldenström’s disease: 68 (44-92)NHL: 75 (57-90) CLL: 67 (52-90)



NHL: 0.201 (0.073-2.464)MGUS: 0.200 (0.062-1.090)Waldenström’s disease: 0.212 (0.078-0.592)No p cited.






Study design

N participants

Age of participants

N (%) female



Comments

Studies with IL-6 and cancer as a main aimNon-Hodgkin’s lymphoma (NHL)Houston, TX, US

[Fayad et al., 1998]

Case-control, with follow up


Not cited. Not cited. Prognosis To examine the correlation between serum IL-6 and phenotypic characteristics as well as survival in patients with non-Hodgkin’s lymphoma.


NHL: <0.9 (<0.9-225.97)Controls: <0.9 (<0.9-4.31)

% of participants with IL-6 ≥2 pg/ml:NHL: 25%Controls: 9%p=0.0118




NHL patients had low- grade lymphoma.

Switzerland

[Kovacs and Kuehn, 2002]

Case-control


Range:

NHL: 45-79Controls: 31-62

NHL: 12 (44.4)Controls: 11 (39.3)

TreatmentTo investigate how short-term and long-term viscum album treatment influences concentrations of IL-6, sIL-6r and sgp130 in patients with NHL.

Mean (SE) IL-6. pg/ml: NHL: 1.6 (0.3)Controls: 2.8 (0.3)p>0.05

Selection of healthy controls not described but they were matched for age.

All cancer patients had B-cell- derived NHL. 21 of the 27 cases had received chemo- or radiotherapy before the study. Pre-therapy IL-6 measured only in the 15 participants who went on to receive short-term viscum album therapy.

Same controls as in the study by Kovacs and colleagues, 2001.


Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimNon-Hodgkin’s lymphoma (NHL)Mansoura, Egypt

[el-Far et al., 2004]

Case-control


Mean:

NHL: 28.5Controls: 26.3

NHL: 10 (25.0)Controls: 9 (45.0)

PrognosisTo examine the relationship between IL-6 and IL-10 and other prognostic factors and disease outcome in non-Hodgkin’s lymphoma


NHL: 134.725 (5.85)Controls: 16.25 (5.85)p<0.001




Participants were free of inflammatory conditions.Cases included adults and children.

Croatia

[Duletic-Nacinovic et al., 2006]

Case-control

Indolent NHL: 43Aggressive NHL: 46

Not cited. Not cited. DiagnosisTo investigate the diagnostic value of serum IL-6 in non-Hodgkin’s lymphoma and to establish its expression in the cancer cells.


All NHL: 10.3 (ND– 486.0)Controls: ND (ND-27.9) p=0.002

Indolent NHL: ND (ND-170.2)Aggressive NHL: 26.85 (ND-486.0) p=0.018

Selection of participants not described. No demographic details of any of the participants. Unclear who controls were.



ND: non-detectable


Study design


N (%) female


Studies with IL-6 and cancer as a main aimMix of Hodgkin’s lymphoma (HL) and NHLVarious locations, German Hodgkin Study Group, Germany

[Gause et al., 1991]

Case-control

HL: 147NHL: 65Healthy controls: 20

Median (range):

Cancers: 29 (16-60)

Cancers: 26 (46.0)

Biological mechanismTo examine the clinical significance and the role of IL-6 in the pathogenesis of Hodgkin’s lymphoma.

No. (%) participants with IL-6>10 pg/ml:

HL without systemic symptoms: 14 (48%)HL with B symptoms: 18 (66.7)Controls: 1 (5)

Selection of healthy controls not described, but they are reported having the same age distribution as the cases.


Some cancer patients had received treatment <4weeks before IL-6 measurement.

Dijon, France


Case-control

HL: 5NHL: 8MGUS: 28Waldenström’s disease: 19Castleman’s disease: 2Healthy controls: 66

Not cited. Not cited.

Evaluating an assay To evaluate a radioimmunoassay for investigating IL-6 concentrations in patients with monoclonal gammopathies at diagnosis and during the course of the disease.


HL: 548 (223-8271) p=0.005NHL: 401 (219-8887) p=0.01MGUS: 351 (142-668) p=0.05Waldenström’s disease: 356 (174-568) p=0.05Controls: 287 (113-520)






Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimMix of Hodgkin’s lymphoma (HL) and NHLHouston, TX, US

[Kurzrock et al., 1993]

Case-control

Lymphoma: 60Healthy controls: 20

Not cited. Not cited. PrognosisTo investigate the relationship between cancer symptoms and serum concentrations of TNF-α IL-1β, IFN-γ and IL-6 in lymphoma patients.


Cancer with B-symptoms: 28.9 (0-173)Cancer without B-symptoms: undetectable (0-54)Controls: undetectable (0-21)p<0.001

Selection of healthy controls not described. No adjustment for potential confounders.


B-symptoms defined as fever, night sweats and weight loss.

IL-6 was measured in 57 cancer patients and 19 controls. Unclear why some were excluded. Lymphoma cases included 28 patients with Hodgkin’s lymphoma and 32 with non-Hodgkin’s lymphoma.


Study design




Comments

Studies with IL-6 and cancer as a main aimMix of Hodgkin’s lymphoma (HL) and NHLAssiut, Egypt

[el-Deen et al., 1995]

Case-control

Lymphoma: 56NHL: 28 HL: 28

Benign lymphadenopathy: 21Healthy controls: 21

Mean (range):

Lymphoma: 37.4 (20-54)Healthy: 36.8 (22-49) Lymphadeno-pathy: not given.

Lymphoma: 15 (26.8)Healthy: 7 (33.30Lymphadeno-pathy: not given.

Biological mechanismTo investigate IL-6 concentrations in people with lymphoma and to compare them to those of people with benign lymphatic disease or healthy people.


Lymphoma: 643 (66.9)Lymphadenopathy: 342 (44.7)Healthy: 139 (26.8)

Lymphoma vs. lymphadenopathy p<0.01Lymphoma vs. healthy p<0.001




Participants were free of inflammatory conditions.

Adult Lymphoma Treatment Study Group, Japan

[Niitsu et al., 2002]

Case-control

NHL: 184aggressive: 149 indolent: 35

HL: 9T-cell leukaemia/Lymphoma (ATLL): 8Healthy controls: 20

Median (range):

Cancers: 64 (18-78)Controls: 58 (18-64)

Not cited. PrognosisTo examine VEGF and IL-6 as potential prognostic factors in aggressive NHL.

Mean (SD) IL-6. pg/ml, p vs. healthy controls:

Aggressive NHL: 19.6 (30.6), p=0.0001Indolent NHL: 6.19 (8.52), p>0.5HL: 2.21 (1.58) p>0.5ATLL: 71.5 (57.8) p=0.00001Controls: 1.6 (1.08)


No adjustment for potential confounders in the comparative analysis.




N (%) female



Comments

Studies with IL-6 and cancer as a main aimBurkitt’s/small non-cleaved cell lymphomaMulti-centre AIDS cohort study (MACS),US

[Breen et al., 1999]

Prospective case-control nested in a cohort

Lymphoma: 50AIDS: 44HIV+: 48HIV-: 44

Not cited. 0 (0) Aetiology To examine whether serum IL-6 and soluble CD23 predict lymphoma of the Burkitt’s /small non-cleaved cell subtype.


Lymphoma: 42 (18)AIDS: 9.8 (6.5)HIV+: ≤ 1.0HIV-: 3.9 (1.7)p>0.05

Median IL-6, pg/ml, per lymphoma type:Burkitt’s/small non-cleaved cell: 12Large cell: ≤ 1Immunoblastic: ≤ 1Central nervous system: ≤ 1p=0.01

Controls selected from participants in the same cohort as cases, and three controls, one with AIDS, one HIV+ and one HIV- were matched to each case by visit number and where possible by CD4+ T cell count.


Results may have been influenced by the large number of participants with undetectable IL-6 (≤1pg/ml) concentrations in all participant groups.


Study design N participants

Age of participants

N (%) female



Comments

Studies with IL-6 and cancer as a main aimDiffuse large cell lymphoma (DLCL)Houston, TX, US

[Seymour et al., 1995]


DLCL: 58Healthy controls: 33

Median (range):

DLCL: 57 (26-78)

22 (40) PrognosisTo ascertain whether serum IL-6 is associated with specific clinical and laboratory features and has prognostic significance in diffuse large cell lymphoma.


DLCL: 4.37 (0.35-110.2)Controls: 0.35 (0.35-1.87)p<0.0001

IL-6 <1.9 pg/ml associated with less treatment failure (p=0.042) and longer overall survival (p=0.05) (Data presented in figures.)




DLCL patients had intermediate or high-grade disease and poor prognosis, which were selection criteria for subsequent chemotherapy.

Houston, TX, US

[Preti et al., 1997]


DLCL: 118Healthy controls: 45

No. of DLCL patients aged ≥60 years: 53and <60 years: 65

DLCL: 51 (43.2)

PrognosisTo examine the relationship between pre-chemotherapy IL-6 and outcome in diffuse large cell lymphoma.


DLCL: 11.1 (24.3)Controls: 0.7 (1.20p<0.009

IL-6 ≤4.3 pg/ml vs. >4.3 pg/ml:

Selection of healthy controls not described, but exclusion criteria were fever within a week, other illness, medication or pregnancy.




Study design


N (%) female



Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsHodgkin’s lymphoma (HL)Various locations, Germany

[Gorschluter et al., 1995]

Case-control

HL: 210Newly relapsed HL: 9Complete remission after chemo- or radiotherapy: 52Healthy controls: 95

Not cited. HL: 93 (44.3)

PrognosisTo investigate the concentrations of various cytokines and whether their expression correlates with other clinical parameters or survival in Hodgkin’s lymphoma.

Median (% above 2.4 pg/ml, upper limit in healthy controls) IL-6, pg/ml:

HL: 6.7 (72.3) (n=177)Controls: <1 (2.1%) (n=47)p=0.00001

HL by stage:I +II: 4.7 (65.3) (n=98)III + IV: 12.4 (79.7) (n=79)p=0.0036

HL with and without B-symptoms: B symptoms: 12.4 (87.7) (n=95)No B-symptoms: 2.9 (58.9) (n=82)p=0.0001

Selection of healthy controls not described, but they were age and sex-matched.



Unclear why IL-6 concentrations only cited for some of the participants.

B –symptoms were unexplained fever, night sweats or weight loss of >10% of body weight within 6 mths.


Study design


N (%) female


Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsHodgkin’s lymphoma (HL)Houston, Texas, US

[Seymour et al., 1997]

Case-control

HL: 65Healthy controls: 33

Median (range): HL: 29 916-73)

HL: 30 (46.2)

Biological mechanism and prognosisTo examine the role of IL-6 in Hodgkin’s lymphoma and its relationship with clinical and pathological features of the disease.


HL: 2.7 (0.35-38.4)Controls: 0.35 (<0.35-1.87)p=0.0001

Selection of healthy controls not described. No demographic details of controls given.



Greece

[Passam et al., 2006]

Case-control

HL: 60Healthy controls: 19

Mean (range):

HL: 41 (16-80)Controls: 39 (22-58)

HL: 25 (41.70Controls: 5 (26.3)

PrognosisTo assess the influence of radio- and chemotherapy on concentrations of angiogenic markers in Hodgkin’s lymphoma.


HL: 14.1 (3.4-150.0)Controls: 3.1 (2.1-14.8)p<0.001

Median (range) IL-6, pg/ml, by cancer stage:

I-II: 9.18 (3.36-150.0)III-IV: 14.83 (6.61-150.0)p>0.5





Study design



Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsNon-Hodgkin’s lymphoma (NHL)France

[Blay et al., 1994]

Case-control


Median (range):Lymphoma: 38 (16-74)

9 (37.5) Biological mechanismTo investigate serum cytokine concentrations in people with non-Hodgkin’s lymphoma.

No. (%) or participants with IL-6>70pg/ml:

NHL: 12 (50)Controls: 2 (8)p=0.003

Selection of healthy controls not described, but they were matched for age and sex.


Germany

[Feldmann et al., 2006]

Case-control

Uncomplicated Hepatitis C (HCV): 12HCV + cryoglobulinemia (MC): 14HCV +B-cell non-Hodgkin’s lymphoma (B-NHL): 12Healthy controls: 12

Median (range)HCV: 45 (21-830 HCV-MC: 62 (37-77)HCV-B-NHL: 68 (41-860Controls: 33 (24-54)

HCV: 5 (41.7)HCV-MC: 7 (50.0)HCV-B-NHL: 7 (58.3)Controls: 6 (50.0)

Pathogenesis To investigate whether the recognition of hepatitis C virus proteins by pattern recognition receptors is involved in the pathogenesis of hepatitis C-associated cryoglobulinemia and cancer.

Mean IL-6, pg/ml (data presented in a figure):

HCV: 5HCV-MC: 12HCV-B-NHL: 5Controls: 3

HCV-B-NHL vs. controls p=0.041HCV-B-NHL vs. HCV-MC p=0.028




Table W3 Summary of studies of circulating IL-6 concentrations and lung cancerStudy,(author, year)

Study design




Studies with IL-6 and cancer as a main aimNon-small cell lung cancer (NSCLC)Naples, Italy

[De Vita F. et al., 1998]

Case-control

NSCLC: 60Healthy controls: 40

Range:

NSCLC: 41-70

NSCLC: 12 (20.0)

PrognosisTo investigate the role of IL-6 as a prognostic marker in NSCLC.


NSCLC by stage:All: 10.19 (0.31)III: 9.40 (0.14)IV: 12.46 (0.75)Control: 5.86 (0.33)Cancer vs. controls: p<0.0001Stage IV vs. III: <0.006

Progressive NSCLC: 8.05 (18)Newly-diagnosed NSCLC: 11.92 (0.38) p<0.005

Healthy controls were blood donors and matched for age and sex.


Rome, Italy

[Guadagni et al., 2004]

Case-control

NSCLC: 65COPD: 65Healthy controls: 65

Mean (range): NSCLC: 65 (48-82)COPD: 67 (46-85)Healthy controls: 61 (47-83)

NSCLC: 12 (18.5)COPD: 14 (21.5)Healthy controls: 14 (21.5)

PrognosisTo analyse the possible associations between TNF-α, IL-6 and D-dimer or TATc concentrations in people at different stages of NSCLC.

Median (IQR) IL-6, pg/ml:

NSCLC: 8.8 (3.7-21.6)COPD: 4.7 (2.7-6.8)Healthy controls: 1.5 (0.5-3.80NSCLC vs. COPD p<0.01NSCLC vs. controls p<0.0001

Healthy controls selected from individuals with family history of cardiovascular disease attending a prevention programme. Controls were chosen to be similar to the cases in terms of age, sex and smoking habit.


Table W3, continued. Summary of studies of circulating IL-6 concentrations and lung cancerStudy,(author, year)


N (%) female


Comments

Studies with IL-6 and cancer as a main aimNon-small cell lung cancer (NSCLC)Istanbul, Turkey

[Tas et al., 2005a]

Case-control NSCLC: 28Healthy controls: 15

Median (range):NSCLC: 65 (41-80)

NSCLC: 2 (7.2)

Diagnosis and prognosisTo investigate the diagnostic and prognostic roles of IL-6, CRP and TNF-α and leptin in patients with advanced non-small cell-lung cancer, and the effects of chemotherapy on these cytokines.


NSCLC: 20.3 (14.4-62.0)Controls: 20.1 (18.9-24.6)p=0.693

High IL-6 concentrations found to be associated with poorer prognosis (p=0.0636).

Healthy controls were personnel at the institute where the cases were treated. No demographic details of controls given.



All cancer patients had advanced, non-surgically treatable disease, but no brain metastases or non-malignant chronic diseases.


Study design




Comments

Studies with IL-6 and cancer as a main aimNon-small cell lung cancer (NSCLC)Ankara, Turkey

[Kayacan et al., 2006]

Case-control

Cachectic NSCLC: 23Non-cachectic NSCLC: 21Healthy controls: 12

Mean (SD):

Cachectic NSCLC: 59.9 (11.8)Non-cachectic NSCLC: 55.9 (10.7)Controls: 52.1 (12.3)

Cachectic NSCLC: 1 (4.3)Non-cachectic NSCLC: 2 (9.5)Controls: 2 (1.7)

PrognosisTo investigate the role of IL-6 and TNF-α in development of cachexia in newly diagnosed non-small cell lung cancer patients.

Mean (SD) median IL-6, pg/ml:

All NSCLC: 7.6 (11.6) 5.2Cachectic NSCLC: 6.4 (4.1) 5.7Non-cachectic NSCLC: 8.9 (16.3) 4.4Controls: 4.1 (3.5) 3.3No p-values cited.

Selection of healthy controls not described, but all controls were age-matched smokers.


All cancer patients had an inoperable disease.

Lung cancerTokushima, Japan

[Yanagawa et al., 1995]

Case-control

Lung cancer: 75Benign lung disease: 20

Mean (range):

Lung cancer: 64.5 (44-85)Benign lung disease: 60.0 (23-78)

Lung cancer: 13 (17.3)Benign lung disease: 6 (30.0)

Biological mechanismTo clarify the role of IL-6 in lung cancer and its association with patient characteristics.

No. (%) participants with IL-6>20 pg/ml-1:

Lung cancer: 29 (39%)Benign disease: 0 (0)No p cited.(Data presented in a figure.)

Selection of controls with benign lung disease not described.





Study design




Studies with IL-6 and cancer as a main aimLung cancerJapan

[Yamashita et al., 1995]

Case-control

Lung cancer: 176Diffuse pulmonary infiltrates: 28Benign lung tumours: 15Bronchial asthma: 5

Mean (SD):

65.4 (6.4)

All: 77 (34.4)

Lung cancer: 59 (33.5)Diffuse pulmonary infiltrates: 14 (50.0)Benign tumours: 4 (26.7)Bronchial asthma: 0 (0)

Diagnosis and prognosisTo assess measurability and diagnostic and prognostic significance of IL-6 and CRP in lung cancer patients.

Mean (SD) IL-6, pg/ml, by cancer and stage:

Adenocarcinoma:I: 0.816 (0.354)II: 0.634 (0.144)IIIa: 4.334 (4.299)IIIb: 3.903 (2.796)IV: 7.976 (6.392 ) I & II vs. III & IV, p “significant”

Squamous cell carcinoma:I: 1.178 (0.795)II: 2.390 (1.338)IIIa: 2.902 (1.239)IIIb: 7.175 ( 4.031)IV: 6.194 (3.204)I & II vs. III & IV, p “significant”

Small cell carcinoma: I: 0.557 (0.317)IV: 8.094 (2.908)Diffuse pulmonary infiltrates: 5.063 (3.751)Benign lung tumours: 1.079 (1.425)Bronchial asthma: 2.161 (0.942)




Results on large and small cell carcinoma were based on small numbers, only 4 and 19 cases respectively.


Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimLung cancerLiege, Belgium and Cleveland, OH, US

[Dowlati et al., 1999]

Case-control

Lung cancer: 41Controls with COPD: 24

Mean (SD):

Lung cancer: 67 (7.5)COPD: 63 (9)

Lung cancer: 5 (14.3)COPD: 4 (16.7)

Biological mechanism To determine the relationship between bronchoalvaeolar lavage and serum IL-6 in lung cancer patients, and to compare these with a control group with chronic obstructive pulmonary disease.


Lung cancer: 37.5 (42.4)COPD: 29.5 (40.3)p=0.5

Extensive stage small cell lung cancer 58.2 (34.9)Limited stage small cell lung cancer: 10.4 (8.7)p=0.06

Selection of controls with COPD not described.

No adjustment for potential confounders, but study groups were similar in terms of age and pack-years of cigarettes smoked.


23 patients had non-small cell lung cancer and 9 had small cell lung cancer.

Patients with COPD also had infection (bronchitis or pneumonia), and their IL-6 concentrations may thus have been higher than usual.


Study design




Comments

Studies with IL-6 and cancer as a main aimLung cancerHeraklion, Greece

[Alexandrakis et al., 2000a]

Case-control

Malignant pleural effusion: 32Benign pleural effusion: 33Healthy controls: 15

Median (range):

MPE: 63 (32-86)BPE: 65 (26-92)Healthy: not given.

MPE: 10 (31.3)BPE: 9 (27.3)Healthy: not given.

Diagnosis To evaluate concentrations of cytokines in serum and pleural fluid of patients with malignant and benign pleural effusions and to investigate their use in differential diagnosis.

Mean (SD) IL-6, fmol/ml:

MPE: 7.2 (7)BPE: 8.6 (6.4)Healthy: 2.9 (1.3)

MPE vs. healthy: p<0.05BPE vs. healthy: p<0.01BPE vs. MPE: p>0.05

In all patients the serum/pleural fluid ratio for IL1α, IL1β and IL-2 was >1, whereas for TNF-α, IL-6 and IL-8 the ratio was >1. However, higher pleural IL-6 was found in MPE than in BPE.

Controls with BPE and cases were consecutive patients. Healthy controls were hospital staff or their relatives.



27 participants with malignant pleural effusions had lung cancer; 5 had other cancer. Of the controls with benign pleural effusions, 16 had pneumonia, 7 had tuberculosis and 10 had other inflammatory conditions.

Authors suggest the results indicate local IL-6 production in MPE.


Study design

N participants

Age of participants

N (%) female



Comments

Studies with IL-6 and cancer as a main aimLung cancerMichigan, US

[Brichory et al., 2001]

Case-control

Lung cancer: 54Healthy controls: 51

Median (range):

Lung cancer cases: 64.6 (46-82)Other participants: not given

Lung cancer: 25 (46.3)Other participants: not given.

Biological mechanismTo identify proteins that induce humoral response in lung cancer.


Lung cancer: 60.53 (6.27)Controls: 23.14 (1.88)p=0.003

Patients with autoantibodies against annexin I or II had higher IL-6 concentrations (74.25 (9.27)) than those without antiannexin autoantibodies (48.82 (6.58), p=0.029)




Serum IL-6 measured in a subgroup of 40 cancer cases and 39 healthy controls. Study included participants with other diseases, but they were not compared to other groups in terms of IL-6.

Rijeka, Croatia

[Matanic et al., 2003]

Cross-sectional

Lung cancer: 26Benign lung disease: 15

Range:

Lung cancer: 40-77 BLD: 47-82

Lung cancer: 6 (23.1)BLD: 4 (26.7)

Biological mechanismTo investigate IL-1β, IL-6 and TNF-α releasing capacity in patients with lung cancer and benign lung disease.


Lung cancer: 197 (53)BLD: 157 (101)p=0.1047

Bronchoalveolar lavage IL-6 higher in cancer patients than those with BLD (p=0.0004).

Participants were hospital patients with infiltration changes in the chest radiograph.




Study design




Comments

Studies with IL-6 and cancer as a main aimLung cancerHealth ABCstudy, Memphis, TN and Pittsburgh, PA, US

[Il'yasova et al., 2005]

Cohort Cancer-free participants: 2169Incident cancers: 296Lung cancer: 42

Median (IQR):

Cases: 74 (71-76)Non-cases: 73 (71-76)

Cases: 113 (38)Non-cases: 1193 (55)

Aetiology To analyse the association between circulating inflammatory markers and incident cancer in elderly people.

Multivariable-adjusted HR [95% CI] for lung cancer, per log unit IL-6, pg/ml:

Lung: 1.43 [0.91-2.26]


Participants recruited from Medicare beneficiaries. Exclusion criteria were difficulty walking ¼ mile, climbing 10 steps or doing basic daily activities, life threatening illness or intent to leave area in the subsequent 3 years.

Adjustment for age, gender, race and site.



Study design


N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsNon-small cell lung cancer (NSCLC)Tenerife, Spain

[Aleman et al., 2002]

Case- control


Median (range):

NSCLC: 62.5 (36-75)Controls: 58.5 (38-75)

13 (12.3) Prognosis:To study serum leptin concentrations in relation to nutritional status and acute phase response in advanced-stage non-small cell lung cancer.

Mean (EE (x) ) IL-6, pg/ml:

NSCLC: 34.06 (21.44)Controls: 5.25 (0.08)p=0.002




All cases had advanced cancer. Cases excluded if they had brain metastases, poor performance status or chronic disease, other than cancer, causing malnutrition.

Bristol, UK

[Crown et al., 2002]



Mean (SD):

NSCLC: 68.0 (8.2)Controls: 57.4 (6.8)

NSCLC: 4 913.3)Controls: 15 (50.0)

Biological mechanism and prognosisTo investigate the relationship between components of the IGF system, inflammation and energy balance in NSCLC patients.


NSCLC: 12.5 (4-16)Controls: 6 (1-13.5)p<0.0001(Data presented in a figure)

Selection of healthy controls not described but they were free of metabolic or endocrine disease.

Adjusted for age and current smoking status

Cancer patients had received radiotherapy before the study.

Table A23, continued. Summary of studies of circulating IL-6 concentrations and lung cancerStudy,(author, year)

Study design


N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsNon-small cell lung cancer (NSCLC)Athens, Greece

[Georgiades et al., 2003]

Case-control


Mean (SE):

NSCLC: 62.6 (2.5)Controls: 36.8 (7.80

NSCLC: 13 (43.3)Controls: 7 (46.7)

Response to treatmentTo study the effects of bronchoalveolar lavage (BAL) procedure on clinical changes in NSCLC patients.

Mean IL-6, pg/ml:

NSCLC: 4 hrs after BAL: ca. 1224 hrs after BAL: ca. 8

Controls: ca. 6.7

Data presented in a figure, no p cited.

Baseline IL-6 referred to as higher in cases than in controls but no mean cited.





West of Scotland, UK

[McKeown et al., 2004]

Case-control


Median (range):

Cases: 64 (43-83)Controls: 66 (46-74)

Cases:26 (52.0)Controls:6 (55.0)

Prognosis To examine the relationship between CRP and inflammatory cytokines and cytokine receptors in patients with non-small-cell lung cancer.

Median (range) IL-6, pg/l-¹:

NSCLC: 13 (<2-103)Controls: <2 (<2-<2)p=0.291

Controls selected from healthy volunteers in the same palliative care centres as cases.




Study design

N participants

Age of participants

N (%) female



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsNon-small cell (NSCLC) and unspecified type of lung cancerWest of Scotland, UK

[Jamieson et al., 2004]

Case-control


Median (range):

Cases: 64 (43-79)Controls: 65 (46-74)

Cases: 7 (35.0)Controls: 7 (53.8)

Metabolism To examine the relationship between adiponectin and the systemic inflammatory response in advanced cancer patients.


NSCLC: 14.5 (<2.0-72.6)Controls: <2.0 (<2.0-<2.0)p<0.001

Healthy controls recruited from volunteers in the same palliative care centres as cases and matched for age and sex.


Duplicate publication of the data used by McKeown and colleagues, 2004.

Madrid, Spain

[Arias-Diaz et al., 1994]

Case-control

Lung cancer: 22Benign lung-related disease: 8

Mean (SE):

Lung cancer: 63.8 (1.6)Controls: 64.1 (2.4)

0 (0) Biological mechanismTo investigate the presence of cytokines, nitric oxide and messenger cyclic guanosine 3’5’ monophosphate in bronchoalveolar lavage of lung cancer patients.

Mean IL-6, pg/μg protein:

Lung cancer: 1.4Controls: 0.5p<0.001

(Data presented in a figure.)

Controls randomly selected from people undergoing bronchoscopy as a part of clinical assessment for non-malignant disease.



All participants had smoking history of 5+ years, were smoking >1 pack/day and were asked not to smoke on the day of bronchoscopy.

Table A23, continued. Summary of studies of circulating IL-6 concentrations and lung cancerStudy,(author, year)

Study design

N participants

Age of participants

N (%) female


Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsLung cancerTokyo, Japan

[Katsumata et al., 1996]

Case-control

Lung cancer: 183Healthy controls: 50

Mean:

Lung cancer: 65Controls: 63

Lung cancer: 30 (16.4)

PrognosisTo evaluate the relationships between serum cytokine concentrations and disease manifestations in lug cancer.


Cancer <60yrs: 11.4 (28.0)≥60years: 9.7 (36.9)Controls: 1.3 (3.6), no p cited

Crude HR for IL-6 in cancer survival: 1.009, 95% CI: 1.005-1.013, p<0.0001




Crete, Greece


Case- control

LCRT: 23LCNP: 18BILD: 27Healthy controls: 25

Mean:LCRT: 68LCNP: 62BILD: 64Healthy controls: 39

LCRT: 8 (34.8) LCNP: 8 (44.4)BILD: 9 (33.3)Healthy controls: 11 (44.0)

Biological mechanismTo compare IL-1β, IL-6 and other inflammatory markers in participants with various lung diseases.

Mean IL-6, fmol/ml:(Approximate values: data presented in a figure.)

LCRT: 0.75LNCP: 0.70BILD: 0.95Controls: 0.38

BILD vs. controls p<0.05LCRT and LCNP vs. controls: p cited as not significant.

Healthy controls were blood donors and were younger thaN participants.No adjustment for potential confounders.

Cancer patients’ IL-6 measured before the onset of any treatment but some cancer cases had reactive thrombosis.

LCRT: lung cancer +reactive thrombocytosisLCNP: lung cancer, normal platelet countBILD: benign inflammatory lung disease

Table W4 Summary of studies of circulating IL-6 concentrations and colorectal cancer (CRC)


Study design

N participants

Age of participants

N (%) female



Studies with IL-6 and cancer as a main aimL’Aquila, Italy

[Berghella et al., 1996]

Case-control

CRC: 77Healthy controls: 70

Range:

CRC: 44-85Controls: 43-78

CRC: 33 (42.9)Controls: 30 (42.8)

PrognosisTo investigate the relationship between immunological parameters and cancer stage and prognosis in colorectal cancer.

Mean (SD) IL-6, pg/ml, p vs. controls:

All cancer: 118.8 (278.2)p<0.0001Controls: 16.2 (91.6)

Cancer by stage:I: 23.2 (63.6)p>0.05II: 24.1 (69.3)p=0.015III: 136.6 (141.9)p<0.0001IV: 474.6 (372.2)p<0.0001

Healthy controls were laboratory staff or blood donors.

No adjustment for potential confounders but cases and controls were shown to have similar age and sex distributions.


Unclear why IL-6 measured in a subgroup of 70 cancer cases.

Mie, Japan

[Kinoshita et al., 1999]

Case-control


Mean (range):

CRC: 64.3 (33-86)

CRC: 34 (48.6)

PrognosisTo examine correlation between serum, tissue and tumour concentrations of IL-6 and to determine whether serum IL-6 reflects tumour characteristics or disease status in colorectal cancer patients.


CRC: 35.7 (69.0)Controls: 4.3 (1.0)p=0.0093

Mean (SD) local IL-6, pg/ml:tumour tissue:913.7 (1148.0)normal mucosa: 369.5 (395.1)p=0.0203



11 cancer patients had liver metastases.

Table W4, continued. Summary of studies of circulating IL-6 concentrations and colorectal cancer (CRC)


Study design

N participants

Age of participants

N (%) female



Comments

Studies with IL-6 and cancer as a main aimWarsaw, Poland

[Grotowski and Piechota, 2001]

Case-control


Mean (range):

CRC: 67.9 (45-79)Controls: 62.1 (46-73)

CRC: 11 (36.7)Controls: 4 (40.0)

PrognosisTo investigate the concentrations of IL-4, IL-6, IL-8 and IL-10 and their correlation with tumour stage in colorectal cancer.

Mean (SD) (range) IL-6, pg/ml:

CRC: 5.3 (5.8) (0-20)Controls: 1.5 (1.4) (0-3.2)p<0.02

IL-6 concentrations were higher in patients with tumours at Duke’s stages C and D compared to stages A and B (data presented in a figure).




Malmo, Sweden

[Syk et al., 2002]

Case-control

CRC: 7Benign colonic lesions: 5

Mean (range):

CRC: 70 (55-85)Benign: 50 (33-78)

Not cited. Biological mechanism and treatmentTo test the hypothesis that cytokine production associated with colorectal surgery originates in the bowel and that ongoingIL-6 production happens at the site of colonic cancers.

IL-6 concentrations below the assay detection limit in both cases and controls: CRC: <8 pg/mlBenign: <8pg/ml

All participants were hospital patients undergoing colonic resection for malignant or benign tumours.



Il-6 below the assay detection limit in both cases and controls.



Study design

N participants

Age of participants

N (%) female


Comments

Studies with IL-6 and cancer as a main aimNaples, Italy

[Galizia et al., 2002b]

Case-control CRC: 50Healthy controls: 25

Mean (SD):

CRC: 65.4 (10.5)

CRC: 16 (32.0)

PrognosisTo expand from previous research and investigate the predictive potential of serum cytokine concentrations with regards to possibility of curative surgery and recurrence rate.


CRC: 9.3 (2.1)Controls: 4.4 (0.8)P<0.0001

Patients with higher IL-6 concentrations were less likely to have had potentially curative operation: RR 2.19, p<0.001

Controls were blood donors and matched for age and sex.


Multivariate survival analysis adjusted for tumour size and stage, lymph node involvement, metastasis and resection and IL-10.

Hsin-Chu, Taiwan

[Chung and Chang, 2003a]

Case-control CRC: 164Healthy controls: 20

Range: 18-90

CRC: 71 (43.3)

PrognosisTo investigate the possible role of serum IL-6 in tumour biology and prognosis in patients with resectable colorectal cancer.


CRC: 11.89 (0-440.64)Controls: 3.41 (0-9.12)p<0.01






Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimHsin-Chu, Taiwan

[Chung and Chang, 2003b]

Case-control


Mean (SD):

Cases: 66.2 (10.2)

CRC: 71 (43.3)

Prognosis and survivalTo determine whether serum concentrations of interleukins 1, 2, 6 and 8 and TNF correlate with tumour stage and survival in colorectal cancer.

Median IL-6, pg/L:

CRC: 12.1Controls: 4.3p<0.05

Selection and demographic details of healthy controls not described.


Duplicate publication of the study by Chung and colleagues, 2003a.

Nagasaki, Japan

[Nakagoe et al., 2003]

Case-control


Median (range):

CRC: 67 (29-90)

CRC: 26 (41.9)

PrognosisTo determine whether preoperative serum IL-6 correlates with prognostic indicators in colorectal cancer.

Median (IQR) IL-6, pg/L:

CRC: 4.26 (1.18-6.94)Controls: 0.56 (0-3.38)p=0.0014



Colorectal cancer cases were recruited from patients undergoing cancer surgery at a university hospital.



Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimTokyo, Japan

[Ashizawa et al., 2004]

Case-control


Median (range):

CRC: 65.5 (26-89)

CRC: 19 (29.2)

PrognosisTo investigate possible prognostic role of IL-6 by examining the relationship between IL-6 and lymph node and hepatic metastasis in colorectal cancer.

Mean (SD) IL-6, pg/ml, by Duke’s stage:

D: 18.57 (19.90)C: 7.12 (9.60)B: 3.39 (1.20)A: 3.0 (1.46)Controls: 1.05 (0.46) D vs. all other groups p<0.01C vs. healthy p<0.05

Selection of healthy controls and demographic details unclear from the Japanese article. No English translation available.



Health ABC study, Memphis, TN and Pittsburgh, PA, US


Cohort Cancer-free participants: 2169Incident cancers: 296Colorectal cancer: 40

Median (IQR):

Cases: 74 (71-76)Non-cases: 73 (71-76)

Cases: 113 (38)Non-cases: 1193 (55)


Multivariable-adjusted HR [95% CI] for CRC, per log unit IL-6, pg/ml:CRC: 1.44 [0.90-2.31]







Study design

N participants

Age of participants

N (%) female


Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsEdinburgh, UK

[Fearon et al., 1991]

Case-control


Mean (SE):

Cancer: 60 (5)Controls: 61 (5)

Cases: 1 (16.7)Controls: 6 (100)

Biological mechanism To compare concentrations of circulating biochemical markers and hepatic protein synthesis rates in participants with hepatic metastases and controls.

Range IL-6, U/ml:

CRC: 26-330Controls: <10-16p<0.01

Controls referred to as healthy, but recruited among patients with a history of cholelithiasis, with normal liver function at the time of the study.



Cancer cases had colon cancer with liver metastases.

L’Aquila, Italy

[Pellegrini et al., 1996]

Case-control


Range:


CRC: 33 (42.9)Controls: 30 (42.9)

PrognosisTo examine whether an imbalance of TH1 and TH2 subsets of CD4+ T cells in peripheral blood of colorectal cancer patients is related to development and progression of cancer.

Mean (SD) IL-6, pg/ml (p vs. controls):

By cancer stage I: 23.2 (63.6)p >0.05II: 24.1 (69.3) p=0.015III: 136.6 (141.9) p<0.0001IV: 474.6 (372.2) p<0.0001Controls: 16.2 (91.6)

Healthy controls were laboratory staff, blood donors and patients undergoing surgery for dermic cysts.


Duplicate publication of the data by the same group of investigators in the same year (Berghella 1996).



Study design

N participants

Age of participants

N (%) female


Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsL’Aquila, Italy

[Contasta et al., 1996]

Case-control


Range:


CRC: 14 (38.9)Controls: 30 (42.9)

Immune responseTo examine the apparent immune system malfunctioning in colorectal cancer patients by measuring various immunological parameters and mutant c-Ki-ras oncogene in colorectal cancer patients.

Mean (SD) IL-6, pg/ml, p vs. controls:

CRC with c-Ki-ras mutation: 70.5 (90.0)p=0.0005

CRC without c-Ki-ras mutation: 50.0 (101.9)p= 0.0017

Controls: 24.9 (117.2)



Unclear why IL-6 analysed in subgroups of 32 cases and 42 controls.

Probable partial duplicate publication of the data published by the same groups of investigators in the same year (Berghella 1996).

Brno, Czech Republic

[Zaloudik et al., 1998]

Case-control


Not cited. Not cited. PrognosisTo analyse various immune and inflammatory markers in colorectal cancer patients before and after chemoimmunotherapy and compare these to healthy controls’.

IL-6 was undetectable in controls and in cases before as well as after treatment.




No demographic details of any of the participants given.



Study design

N participants

Age of participants

N (%) female


Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsMie, Japan

[Ito and Miki, 1999]

Case-control


Mean (range):

CRC: 61.2 (22-86)

CRC: 32 (40.0)

Biological mechanismTo investigate the profile of circulating IL-6 and IL-1r in colorectal dancer and to determine their clinical significance.


CRC: 88.9 (24.8)Controls: 4.6 (0.3)p<0.01



Berlin, Germany

[Ordemann et al., 2002]

Case-control


Mean (SD):

CRC: 63.5 (4.620Controls: 65.5 (8.74)

CRC: 19 (47.5)Controls: 8 (44.4)

PrognosisTo analyse associations between various immunological parameters, changes in these parameters and tumour progression in colorectal cancer.

Median [95% CI] IL-6, pg/ml:

CRC: 5.52 [3.9-7.65]Controls: 0.85 [0.7-1.3]p<0.01

By cancer stage:I: 3.28 [3.0-7.0]II: 5.52 [4.0-13.7]7.66 [3.0-12.1]p=0.03

Selection of 10 healthy controls not described, 8 were hospital patients with minor ailments. Controls pair-matched to cases but matching criteria unclear.

Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy. Participants were free of inflammatory conditions.

Warsaw, Poland

[Grotowski and Piechota, 2002]

Case-control


Mean (range):

CRC: 66.9 (45-81)Controls: 60.4 (23-90)

CRC: 31 (38.3)Controls: 19 (47.5)

PrognosisTo analyse preoperative serum concentrations of carcinoembryonic antigen and various cytokines and soluble receptors in colorectal cancer patients in relation cancer stage and other symptoms.

Positive IL-6 test result for cancer: 30/81Sensitivity of IL-6: 37%

No statistical tests reported.






Study design

N participants

Age of participants

N (%) female


Comments

Studies with other primary aims but containing IL-6 data of cancer patients and cancer-free individualsRome, Italy

[Roselli et al., 2003]

Case-control, with follow-up

CRC: 194Benign CR disease: 40Healthy controls: 59

Mean (range):

CC: 58.9 (33-71)BD: 52.7 (32-70)Controls: 52.2 (33-71)

CC: 87 (44.8)BD: 19 (47.5)Controls: 24 (40.7)

PrognosisTo investigate potential prognostic value of preoperative sE-selectin and sVCAm concentrations by analysing and their correlations with inflammatory markers and clinicopathological features in different stages of benign and malignant colorectal tumours.


CRC: 8.3 (20.8)BD: 3.1 (4.9)Controls: 3.0 (5.5)

p CC vs. controls <0.0001p BD vs. controls <0.05p CC vs. BD <0.01

No relationship found between IL-6 and disease-free survival.




Multivariate regression and survival analyses adjusted for age, sex, tumour stage, TNF-α, IL-6, sE-selectin, sVCAM and CEA.

Athens, Greece

[Nikiteas et al., 2005]



Mean (SD):

Male cases 66.83 (10.45)Female cases: 66.83 (1.24)

Cases: 35 (74.3)Controls: not given

Prognosis To investigate the role and prognostic significance of preoperative CRP, TNF-α and IL-6 measurements in colorectal cancer.


CRC: 8.11 (1.09-188.42)Controls: 3.52 (0.45-9.96)p<0.01




Table W5 Summary of studies of circulating IL-6 concentrations and ovarian cancerStudy,(author, year)

Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimLos Angeles, US

[Berek et al., 1991]

Case-control

Epithelial ovarian cancer: 36Healthy controls: 12

Not cited. 48 (100). Biological mechanismTo investigate the production of IL-6 by ovarian tumours and its role as a growth factor in ovarian cancer.


Ovarian cancer: 0.24 (0.04)Controls: 0.12 (0.03)p<0.05

Controls were blood donors.



Participants had more than one blood sample taken. Unclear if the means IL-6 concentrations represent of the mean of all samples (n=90) or mean for participants.

Durham, NC, US

[Moradi et al., 1993]

Case-control

Ovarian cancer: 52Healthy controls: 37

Not cited 89 (100) Diagnosis and prognosisTo evaluate various cytokines measured in serum and peritoneal fluid as potential tumour markers in ovarian cancer.

Median (range) IL-6:

A. First instance ovarian cancer: 110 (0-232)B. Long-term ovarian cancer: 0 (0-670)Controls: 0 (0-2075)

A vs. C p=0.0001A vs. B p=0.0002B vs. C p=0.9

Selection of healthy controls not described. No demographic details of participants given.



Unit of measurement for IL-6 unclear

Table W5, continued. Summary of studies of circulating IL-6 concentrations and ovarian cancerStudy,(author, year)

Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimFrankfurt, Germany

[Schroder et al., 1993]

Case-control

Ovarian cancer: 18Benign ovarian tumours: 32Endometriosis: 15Cervical cancer: 2

Not cited. 67 (100) DiagnosisTo examine clinical usefulness of IL-6 in differentiating between benign and malignant ovarian tumours.

Mean (range) serum IL-6, pg/ml:

Ovarian cancer: 6.2 (0-50.5)Benign tumours: 0.5 (0-8.1)No p cited.

Mean (median) peritoneal fluid IL-6, pg/ml:Ovarian cancer: 20.6 (5.0)Endometriosis: 6.3 (0.6)Range in benign tumour group: 0-85.6.

Controls with benign conditions were consecutive hospital patients.



No statistical test or comparisons reported.

New York, US

[Gastl et al., 1993]

Case-control

Ovarian cancer: 40Controls with benign tumours: 24

Median (range):

Ovarian cancer: 63 (23-87)Benign tumours: 53 (21-85)

64 (100) Biological mechanism and prognosisTo investigate the relationship between tumour-associated IL-6 production and circulating platelet counts in women with malignant and benign ovarian tumours.


Ovarian cancer: 3 (<1-1221)Controls with benign tumours: <1 (<1-4) p<0.005

Generally, IL-6 concentrations from ascitic fluid were higher than serum concentrations in both groups, but IL-6 in matched fluid and serum samples did not correlate.

Controls were women who underwent exploratory laparotomies for benign ovarian conditions.





Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimGroningen, the Netherlands

[van der Zee et al., 1995]

Case-control

Ovarian cancer: 21Benign ovarian tumours: 21

(Cf. Results)

Not cited. 15(100)

Prognosis To evaluate relationship between IL-6 concentrations in cystic fluids and pre-treatment CRP, platelet counts and haemoglobin in women with benign and malignant ovarian tumours.

Median IL-6 (range) U/ml:

Ovarian cancer: 12 (<2-19)Benign ovarian tumours: 5 (<2-20)p reported as non-significant.

IL-6 detectable in 8/13 of the cancer cases and 4/11 of patients with benign tumours.

Controls were patients undergoing surgery for benign tumours in the same hospital as cases.



Pre-treatment serum samples only available for a subgroup of participants.

Galveston, TX, US

[Chopra et al., 1996]

Case-control


Range:

All participants: 30-60

68 (100) PrognosisTo investigate growth factors and cytokines in ovarian cancer and to identify cytokines associated with tumour progression and angiogenesis.


Ovarian cancer by stage, p vs. controls:I: <10II: 89.6 (13.2) p<0.001III: 58.7 (11.9) p<0.001IV: 65.7 (7.8) p<0.001Controls: <10

Selection of healthy controls not described, but they were not pregnant or on any medication.


Some cases had received treatment before IL-6 measurement


Study design

N participants

Age of participants

N (%) female



Studies with IL-6 and cancer as a main aimPrague, Czech Republic

[Svoboda et al., 1996]

Case-control

Ovarian cancer: 38Benign ovarian tumours: 46Healthy controls: 40

Range:

Ovarian cancer: 39-73Benign tumours: 17-72Healthy: 21-60

115 (100) DiagnosisTo assess IL-6 as a diagnostic marker in ovarian cancer

Mean (range) IL-6, pg/ml:

Ovarian cancer: 4.4 (0-61.0)Benign tumours: 2.54 (0-9.6)Healthy: 0.15 (0-4.0)Cancer vs. healthy: p<0.01Benign vs. healthy: p cited as not significant.

% with undetectable IL-6:Ovarian cancer: 58%Benign tumours: 50%Healthy: 50%

Healthy controls were blood donors; controls with benign disease selected from the same clinic as cases.



IL-6 measured in only 29 cancer cases.

Vienna, Austria

[Tempfer et al., 1997]

Case-control


Median (range):

Ovarian cancer: 54.6 (34-69)

Ovarian cancer: 73 (100)

PrognosisTo investigate the prognostic value of serum IL-6 and its correlation with tumour burden in ovarian cancer patients before and after therapy.


Ovarian cancer: 55.6 (0-2869.0)Controls: 0.5 (0-2.14)p=0.0001

Cancer patients before therapy: 158.5 (0-2869.0)Cancer patients 2 wks after therapy: 158.5 (0-252.9)p=0.003

Healthy controls were blood donors. No demographic details of the controls given.

No adjustment for potential confounders.Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy.

Cancer patients subsequently underwent hysterectomy, lymphadectomy, omentectomy and chemotherapy.


Study design


N (%) female



Studies with IL-6 and cancer as a main aimVienna, Austria

[Staal-van den Brekel AJ et al., 1998]

Case-control


Median (range):

Ovarian cancer: 54.6 (34-69)

Ovarian cancer: 73 (100)

Prognosis To investigate the prognostic and tumour-marker value of IL-6 in ovarian cancer and its correlation with tumour burden.


Ovarian cancer: 55.6 (0-2869.0)Controls: 0.5 (0-2.14)p=0.0001

Pre-surgery: 158.5 90-2869.0)2 wks after surgery: 7.4 (0-252.9)p=0.003

Healthy controls were blood donors. No demographic details of controls given.



Lodz, Poland

[Nowak et al., 2001]

Case-control

Ovarian cancer: 17Benign ovarian cysts: 16Healthy controls: 15

Not cited. 48 (100) DiagnosisTo evaluate the usefulness of IL-6, IL-8, TNF-α and IFN-γ as tumour markers in ovarian cancer.


Ovarian cancer: 109.3 (287.7)Benign cysts: 7.7 (20.2)Controls: 2.7 (2.4)p<0.05

Selection of healthy controls not described but they were of similar age to cases. Controls with benign tumours were patients at same hospital as the cases.

No demographic details of any of the participants cited.



Study design


N (%) female



Studies with IL-6 and cancer as a main aimPittsburgh, Pennsylvania, US

[Gorelik et al., 2005]

Case-control

Ovarian cancer: 44Benign pelvic tumours: 37Healthy controls: 45

Median (range):

Ovarian cancer: 46 (34-88)Benign tumours: 44.5 (28-87)Controls: 46 (36-76)

126 (100) DiagnosisTo evaluate the diagnostic usefulness of a panel of cytokines in ovarian cancer.


Ovarian cancer: 64.2 (12.72)Benign tumours: 28.0 (9.3)Controls: 8.8 (2.50)Cancer and benign vs. controls p<0.001

Predictive values for IL-6 for early stage ovarian cancer: Correctly classified: 85.1%Sensitivity: 84.1%Specificity: 86.0%

Controls obtained from case-control research database and matched for age.


Cagliari, Italy

[Maccio et al., 2005]

Case-control


Mean (range):

Cases: 62.1 (45-81)Controls: 61.0 (46-78)

186 (100)

Prognosis To determine the relationship between haemoglobin and various inflammatory markers.

Mean (SD) IL-6, pg/ml, according to ovarian cancer stage:

I-II: 8.7 (5.6)III-IV: 32.8(23.2)Controls: 1 (2.5)p<0.001






Study design


N (%) female



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsAlicante, Spain

[Acien et al., 1994]

Cross-sectional

Ovarian cancer: 18Benign ovarian tumours: 14Borderline tumours: 2

Not cited. Not cited. DiagnosisTo analyse and compare the diagnostic value of several tumour markers in ovarian cancer.


Ovarian cancer: 77.4 (33.5)Benign tumours: 25.2 (13.2)

Sensitivity and specificity for differentiating between malignant and benign ovarian tumours: both 77%.

Participants were consecutive hospital patients receiving treatment for ovarian tumours.



Patients with borderline tumours (n=2) and Meigs syndrome (n=2) were excluded from the analysis.

Cagliari, Italy

[Maccio et al., 1998]

Case-control

Epithelial ovarian cancer: 30Healthy controls: 20

Mean (range):

Cases: 55 (40-650Controls: 57 (40-67)

50(100)

PrognosisTo investigate associations between serum concentrations of CRP and other biochemical markers in women with advanced epithelial ovarian cancer.


Ovarian cancer: 125 (10)Controls: 11 (2)p<0.001

Selection of healthy controls not described, but they were matched for age.



Study design


N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsWroclaw, Poland

[Dobryszycka et al., 1999]

Case-control

Ovarian cancer: 45Benign ovarian tumours: 22Healthy controls: 21

Mean (SD):

Ovarian cancer: 43.1 (18.8)Benign ovarian tumours: 42.6 (18.;5) Healthy controls: 43.0 (12.1)

89 (100) Diagnosis and prognosisTo assess various proteins as possible diagnostic and prognostic markers in ovarian cancer.

Mean (SD) IL-6, pg/ml, by cancer stage:

I-II: 38.3 (29.5)III: 71.5 (103.2)IV: 51.9 (62.7)

Benign tumours: 19.85 (22.1)Healthy controls: 23.7 (35.7)


Controls with benign disease and cancer patients recruited from preoperative patients to a gynaecological clinic.



Paris, France

[Darai et al., 2003]

Cross-sectional

Ovarian cancer: 13Benign ovarian tumours: 30Endometrioma: 34

Mean (range):

Ovarian cancer: 68 (51-82)Benign tumours: 52 (16-88)Endometrioma: 37 (22-540

77 (100) DiagnosisTo compare cytokine concentrations in endometrioma patients to those of women with benign and malignant ovarian tumours to determine whether endometriomas are associated with specific cytokine profiles.


Ovarian cancer: 87 (115)Benign tumours: 5.0 (3.5)Endometrioma: 18.4 (13.5)p=0.001

Participants were consecutive patients undergoing surgery.


Sera sampled before the outset of surgery.

Cancer patients were on average older than controls.

Table W6 Summary of studies of circulating IL-6 concentrations and leukaemiasStudy,(author, year)

Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimChronic lymphocytic leukaemia (CLL)Dijon, France


Cross-sectional

Chronic lymphocytic leukaemia (CLL): 7MGUS: 128Waldenström’s disease: 27

Mean (range):

CLL: 67 (52-90)MGUS: 72 (36-96) Waldenström’s disease: 68 (44-92)

Not cited.

DiagnosisTo measure IL-6 and other biological markers in patients with monoclonal gammopathies.


MGUS: 0.200 (0.062-1.090)Waldenström’s disease: 0.212 (0.078-0.592)CLL: 0.207 (0.146-0.318)No p value cited.





Tampere, Finland

[Hulkkonen et al., 2000]

Case-control

B- cell type CLL: 36Healthy controls: 400

Mean (range):

B-CLL: 65.2 (48-79)

B-CLL: 10 (27.8)

PrognosisTo analyse plasma concentrations of various interleukins and polymorphisms of their genes in CLL patients and assess their associations with the severity of the disease and predisposition to complications.


B-CLL: 3.75 (7.53)Controls: 1.80 (2.53)p<0.005

Mean (SD) IL-6, pg/ml, by Binet stage:A: 1.51 (0.79)B: 3.13 (3.05)C: 8.47 (14.14)p A vs. C <0.05

Healthy controls were blood donors. No demographic details of controls given.


Some cancer patients had received treatment before IL-6 measurement: Nine of them had previously been treated with drugs. IL-6 concentrations were undetectable in 5 cases and 57 controls.

Table W6, continued. Summary of studies of circulating IL-6 concentrations and leukaemiasStudy,(author, year)

Study design


N (%) female


Studies with IL-6 and cancer as a main aimHouston, TX, US

[Fayad et al., 2001]

Case-control

CLL: 177Healthy controls: 55

Median (range):

CLL: 60 (21-82)

CLL: 66 (37.3)

PrognosisTo examine the association between serum IL-6 and IL-10 and outcome in chronic lymphocytic leukaemia.

No. (%) participants with IL-6 <0.09 pg/ml:CLL: 62 (41)Controls: 39 (71), p=0.0001

36 (24%) of CLL patients had values above the upper limit of the normal range, >4.3 pg/ml. p=0.0001 (Data presented in figures.)

High IL-6 correlated with stage, previous treatment, elevated serum LDH and β2-microglobulin and age >60years.

Unclear if healthy controls were blood donors. No demographic details of controls given.



Houston, Texas

[Lai et al., 2002]

Case-control

CLL: 100Healthy controls: 11

Not cited. CLL: 33 (33.0)Controls: not given.

PrognosisTo assess the prognostic value of IL-6 in CLL and to determine whether IL-6 concentrations correlate with other prognostic factors, e.g. CD38 expression and β-2-microglobulin.

Median (range) IL-6, pg/ml:CLL: 6.8 (1.82-35.10)Controls: 2.6 (2.03-4.70)p=0.38

IL-6 higher in CLL cases with β-2-microglobulin>3.5 vs. <3.5: p=0.02, and in CLL cases at Rai stage III or IV vs. Rai stage III-0, p=0.006.

Higher IL-6 associated with shorter survival, p=0.0001.

Selection of healthy controls not described. No demographic details of the controls given.


Some cancer patients had received treatment before IL-6 measurement: only56 cases were newly diagnosed and untreated.


Study design

N participants

Age of participants

N (%) female



Studies with IL-6 and cancer as a main aimAcute myelogenous leukaemia (AML)Lyon, France

[Thomas et al., 1997]


AML: 58Healthy controls: 10

Mean (SD):

AML: 59 (16)

19 (32.8)

PrognosisTo evaluate potential relationship between serum IL-6 and disease manifestations and outcome.


AML: 35 (3-416)

No. (%) of participants with IL-6>3 pg/ml:AML: 54 (93)Controls: 3 (30)

IL-6 did not correlate with achievement of complete remission or with overall survival.

Controls were blood donors. No demographic details of the controls given.



IL-6 detectable in 54 AML cases.

T-cell leukaemiaNagasaki, Japan

[Yamamura et al., 1998]

Case-control

Adult T-cell leukaemia (ATL): 59Healthy human T-lymphotropic virus type-I carriers (HTLV-I): 32Healthy controls: 30.


PrognosisTo evaluate the circulating IL-6 concentrations in adult T-cell leukaemia and their association with survival.


ATL: 8.2 (<1.0-185.7)HTLV-I: 4.2 (<1.0-13.3)Controls: <1.0 (<1.0-3.5)

ATL vs. HTLV-I p=0.002ATL vs. controls p<0.0001

Median survival time in ATL patients: IL-6 >3.5 pg/ml: 277dIL-6≤3.5 pg/ml: 598d, p=0.025

Recruitment and demographic details of the participants unclear.No adjustment for potential confounders.

Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy but participants with infections excluded.

16 healthy controls had IL-6 concentrations below the detection limit of the assay, 1.0 pg/ml.


Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimDijon, France


Case-control

Acute non-lymphoblastic leukaemia (ANLL): 13Acute lymphoblastic leukaemia (ALL): 5MGUS: 28Waldenström’s disease: 19Castleman’s disease: 2Healthy controls: 66




MGUS: 351 (142-668) p=0.05Waldenström’s disease: 356 (174-568) p=0.05ANLL: 625 (351-1774) p=0.005ALL: 544 (424-834) p=0.005Controls: 287 (113-520)





Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsHouston, Texas, US

[Faderl et al., 2005]

Case-control

ALL: 95Healthy controls: not given.

Mean (range):

46 (17-83)

Not cited.

PrognosisTo evaluate the prognostic significance of various angiogenic factors in adult patients with acute lymphoblastic leukaemia.


ALL: 6.31 (1.98-327.54)

No data for the controls given.

Selection and demographic details of controls not described.



IL-6 measurement obtained from 93 participants.


Study design


N %) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsAcute myeloid leukaemiaRome, Italy


Case-control

Acute myeloid leukaemia: 19Healthy controls: 174

Median (range):

AML: 48 (19-74)Controls: 41 (14-65)

AML: 7 (36.8)Controls: 92 (52.9)

Prognosis and response to treatmentTo determine the extent to which antiphospholipid antibodies are found in newly diagnosed acute myeloid leukaemia and non-Hodgkin’s lymphoma patients and whether they change during treatment.


AML: 38.4 (30.6)p vs. controls=0.003

No. (%) participants with IL>7pg/ml: AML: 17 (89.5)





Acute myelogenous leukaemia (AML) and Acute lymphoblastic leukaemia (ALL) Gent, Belgium

[Struyf et al., 2003]

Case-control

AML: 13ALL: 11Precursor B-lineage ALL: 27Healthy child controls: 21Healthy adult controls: 42

Median (range):

All leukemias: 5.5 (7mths-16)

AML: 5 (38.5)ALL: 0 (0)PrepreB-ALL: 5 (31.3)PreB-ALL: 7 (63.6)

Biological mechanismTo evaluate the involvement of pulmonary and activation-regulated chemokine and hemofiltrate CC chemokine in lymphoproliferative disorders.

Mean (SE) IL-6, U/ml:

AML: 6.5 (1.8)PrepreB-ALL: 9.4 (3.1)ALL: 14.8 (3.1)PreB-ALL: 16.9 (5.6)Child controls: 21.1 (2.6) AML and preB-ALL vs. controls p=0.001

Difference between preB-ALL, ALL and controls reported as insignificant.

Selection of healthy child controls not described; healthy adult controls were blood donors.



All cancer cases were children. 3 cases excluded due to high chemokine concentrations.


Study design


N %) female



Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsChronic lymphocytic leukaemiaHelsinki, Finland


Case-control

Sjögren’s syndrome: 22Chronic lymphocytic leukaemia: 9 MGUS: 12Healthy controls: 32

Mean (range):

SS: 51 (26-80)CLL: 66 (43-78)MGUS: 62 (44-86)Controls: 35 (21-54)

SS: 21 (95.5)CLL: 5 (55.6)MGUS: 8 (66.7)Controls: 7 (21.9)

Biological mechanismTo measure serum immunoreactive Il-6 in patients with various lymphoproliferative diseases.


SS: 299 (100)CLL: 120 (32)MGUS: 337 (92)Controls: 92 (77)

SS vs. CLL/controls p<0.001 MGUS vs. CLL/controls p<0.001

CLL vs. controls: p cited as not significant.





Participants with diseases were free of concomitant infections.

Chronic myeloid leukaemiaCzech Republic

[Humlova et al., 2006]

Case-control

Chronic myeloid leukaemia (CML): 24Healthy controls: 24

Median (range):

CML: 44 (24-72)

CML: 15 (62.5)

Immune functionTo determine concentrations of immunological biomarkers in untreated leukaemia patients.

Mean (SD) IL-6, mg/l:

CML: 5.97 (3.24)Controls: 3.04 (0.51)p=0.0003

Healthy controls were blood donors or laboratory staff and matched to cases on age and sex.


Table W7 Summary of studies of circulating IL-6 concentrations and pancreatic cancer (PC)Study,(author, year)

Study design


N (%) female


Comments


[Okada et al., 1998]

Case-control

Pancreatic cancer: 55Chronic pancreatitis: 25Healthy controls: 20

Mean (SD):

PC: 61.2 (7.3)CP: 61.6 (6.8)Controls: 60.2 (6.5)

PC: 17 (30.9)CP: 8 (32.0)Controls: 6 (30.0)

PrognosisTo examine the relationship between IL-6 and clinical status and its potential role in cancer cachexia in pancreatic cancer.

No. (%) participants with IL-6 ≥ 3pg/ml:

PC: 30 (54.5)CP: 2 (8.0)Controls: 1 (5.0)

Selection of controls not described but they had similar gender and age distributions and cases.




IL-6 detectable in only one healthy control.

Table W7, continued. Summary of studies of circulating IL-6 concentrations and pancreatic cancer (PC)Study,(author, year)

Study design

N participants

Age of participants

N (%) female



Comments

Studies with IL-6 and cancer as a main aimLondon, UK

[Ballinger et al., 1998]

Case-control with follow up

Cancer of the head of pancreas: 25Healthy controls: 10

Mean (range):

PC: 74 (48-89)

PC: 13 (52.0)

Prognosis and response to treatmentTo determine whether internal biliary drainage by stent leads to fall in plasma cytokine concentrations in patients with malignant bile duct obstruction.

Median (range) IL-6, ng/l:

PC before stent insertion: 13.2 (<5-36.9)1 wk after stent insertion: <5 (<5-15.6)Controls: <5

Before stent insertion, IL-6 concentrations detectable in 17 (68%) of cases. 1 week after stent insertion they were undetectable in 19 (76%) of cases.



Cases with obstructive jaundice were recruited, but excluded if endoscopy was impossible. Excluded patients were similar to participants in terms of age and biochemical blood markers.

IL-6 below the assay detection limit in all healthy controls.

Padova, Italy

[Fogar et al., 1998]

Case-control


Range:

PC: 46-83CP: 17-75Controls: 27-50

PC: 10 (55.6)CP: 5 (22.7)Healthy controls: 9 (45.0)

PrognosisTo ascertain whether portal and systemic IL-6 influence tumour spread or cancer-associated diabetes in pancreatic cancer.

Median IL-6, mg/L:

PC: 2.1CP: <1Controls: <1PC vs. healthy p<0.01(Data presented in a figure.)

No association between IL-6 and extent of tumour.

Healthy controls were medical staff or blood donors.


Cancer patients had received treatment <4weeks before IL-6 measurement.


Study design

N participants

Age of participants

N (%) female



Comments

Studies with IL-6 and cancer as a main aimEdinburgh, UK

[Barber et al., 1999]

Case-control

Pancreatic cancer: 13Healthy controls: 6

Median (range):

PC: 67 (51-76)Controls: 54 (50-62)

Not cited.

PrognosisTo assess the relationship between serum IL-6, sIL-6r and TNF receptors and the acute phase response in advanced pancreatic cancer patients.

Median IL-6, pg/L:

PC: 5.5Controls: <1p=0.041(Data presented in a figure.)



Cancer patients’ IL-6 measured 14 days after surgeryAll cases had advanced, unresectable cancer.

Houston, TX, US

[Ebrahimi et al., 2004]

Case-control

Pancreatic cancer: 51Healthy controls: 48-62

Median (range):

PC: 65 (43-79)

21 (41.2)

Prognosis and survival To examine the serum concentrations of pro- and anti-inflammatory cytokines and disease outcomes of people with pancreatic cancer.


PC: 3.4 (<0.7-38.0)Controls: <0.7 (<0.7-4.3)p<0.0001

Median survival time:IL-6>5.2 pg/ml: 4.6 mthsIL-6<5.2 pg/ml: 10.9 mths. p=0.002

Unclear whether healthy controls were blood donors.

No adjustment for potential confounders in the comparative analysis. Survival analysia adjusted for tumour location, mesentery vein invasion, metastatic disease and other cytokine concentrations.


No details of controls. Cytokines measured in 48-62 controls, depending on cytokine. IL-6 measured in 50 cancer cases.


Study design

N participants

Age of participants

N (%) female



Studies with IL-6 and cancer as a main aimEdinburgh, UK

[Barber et al., 2004]

Case-control


Median (range):

PC: 59 (56-75) Healthy controls: 54 (50-62)

PC: 3 (42.8)Healthy controls: 3 (50.0)

Prognosis and treatmentTo investigate the relationship between circulating leptin concentrations, IL-6 and fat oxidation during feeding in weight-losing cancer patients and healthy people.

Median (range) IL-6, ng/l¹:

PC: 753 (420-1554)Controls: <2 (<2-<2)p=0.048




All cases were weight-losing cancer patients. All controls were weight-stable. Maybe the same controls as in Barber, 1999.

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsItaly

[Manes et al., 1999]

Case-control


Mean (range):

PC: 54.1 (37-79) Chronic pancreatitis: 45.4 (29-59) Healthy controls: 49.2 (29-59)

PC: 13 (38.2) Pancreatitis: 7 (29.2)Healthy controls:32 (44.4)

DiagnosisTo evaluate the role of neopterin in diagnosis and staging of pancreatic cancer.


PC: 8.2 (0-63.3)Pancreatitis: 3.7 (1-16.9)Controls: 0.9 (0.04-6.2)PC vs. pancreatitis: p<0.05.PC vs. healthy: p<0.001

Cancer vs. pancreatitis (IL-6 cut-off of 5 pg/ml): + predictive value: 69.6%- predictive value: 56%Sensitivity: 67.6%, specificity: 58.3%





Study design

N participants

Age of participants

N (%) female



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsBerlin, Germany

[Wenger et al., 1999]

Case-control


Mean (SD):

PC: 58.3 (9)

PC: 16 (57.1)

PrognosisTo examine the association of immune function and lymph node status and tumour size in pancreatic carcinoma.

Mean IL-6. pg/ml:

PC: 17Controls: 1p=0.01(Approximate values: data presented in a figure)

IL-6 was not associated with tumour stage (p=0.62), tumour size (p=0.08) or lymph node status (p=0.52).

Selection of healthy controls not described, but they were matched for age and sex. Multivariable analysis adjusted for various cell counts and cytokine concentrations.

Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy. Cancer patients were free of infection.

All patients had resectable cancer and had lost weight, but had no immune-modulating illness or treatment. 15 patients had preoperative jaundice.

Groeningen, the Netherlands

[DeJong et al., 2005]

Case-control

Pancreatic cancer: 16Controls with benign disease: 11

Mean (?):

PC: 67 (4)Benign disease: 66 (2)

PC: 6 (37.5)Benign disease: 2 (18.2)

Biological mechanismTo investigate uncoupling proteins and ubiquitin-proteasome pathway activity and their relationship with cytokines in pancreatic cancer patients.


PC: 21.1 (4.1)Benign disease: 7.3 (2.1)p<0.01

Controls were surgery patients benign disease. 8 of them had surgery for gallstones, and 3 for hernia.



Cancer patients recruited from weight-losing pancreatic cancer cases eligible for surgery.


Study design




Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsIllinois and Michigan, US

[Orchekowski et al., 2005]

Case-control

Pancreatic cancer: 61Benign pancreatic disease: 31Healthy controls: 50

Median (SD):

PC: 66.7 (11.9)Controls with benign pancreatic disease: (56.5 (16.8) Healthy controls: 43.0 (13.0)

PC: 49.2%Controls with benign pancreatic disease: 49.1%Healthy controls: 66.6%

Diagnosis To investigate the association of multiple serum proteins with pancreatic cancer and to explore the use of combined measurements for sample classification.

Lower levels of IL-6 antibody found in cancer patients: Cancer vs. healthy Experiment set 1:p<0.005Experiment set 2: p<0.001

Cancer patients not compared to patients with benign disease.

No mean IL-6 concentrations cited.

Controls with benign disease were hospital patients. Healthy controls selected from people attending a cancer screening programme for individuals from high-risk families, or were participants in a liver biomarker study.



Turin, Italy

[Bellone et al., 2006]

Case-control

PC: 65Healthy controls: 30

Median (range):

PC: 65 (50-87) Controls: 40 (24-65)

PC: 28 (43.1)Controls: 17 (56.7)

Survival To investigate the cytokine expression pattern ins people with pancreatic carcinoma in vivo and in vitro and to identify patterns associated with survival.


PC: 55 (38-69)Controls: 59 (50-67)

Difference described as non-significant. Data represented in a figure.




Table W8 Summary of studies of circulating IL-6 concentrations and gastrointestinal (GI) or gastric cancerStudy,(author, year)

Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimOman

[Kabir and Daar, 1995]

Case-control

Gastric cancer: 21Controls with benign gastrointestinal; symptoms: 17

Not cited. Not cited. Biological mechanismTo determine IL-1α, IL-1β, IL-6 and TNF- α concentrations in gastric carcinoma patients in order to understand the biology of the tumour.


Gastric cancer: 120.95 (60-1400)Controls: 17.05 (30-75)p<0.05

Controls were patients undergoing gastrointestinal endoscopies, and matched for age, sex and date of study participation.


Taipei, Taiwan

[Wu et al., 1996]

Case-control

Gastric cancer: 218Benign gastric lesions: 9Hepatitis B: 9Healthy controls: 85

Mean:

Gastric cancer: 66

42 (19.2) Response to treatment:To examine IL-6 as a marker for response to treatment in gastric cancer.


Gastric cancer: 10.0 (9.5)Hepatitis B: 2.8 (0.9)Benign lesions: 2.6 (0.5)Healthy: 2.5 (0.3)

p cancer vs. each other group <0.0001P for difference between benign lesions, hepatitis B and healthy controls cited as non-significant.

Healthy controls recruited from outpatients with no history of gastrointestinal complaints. Selection of controls with benign diseases not described.

No adjustment for potential confounders.Possible that cancer patients’ IL-6 influenced by previous treatment.Participants were free of inflammatory conditions.

Table W8, continued. Summary of studies of circulating IL-6 concentrations and gastrointestinal (GI) or gastric cancerStudy,(author, year)

Study design


N (%) female


Studies with IL-6 and cancer as a main aimKyoto, Japan

[Yamaoka et al., 2001]

Case-control

Gastric cancer without H. pylori infection: 20Gastric cancer with H. pylori infection: 46Gastritis: 66

Mean:

Gastric cancer: 60.8Gastritis: 59.5

Gastric cancer: 26 (39.4)Gastritis: 26 (39.4)

Biological mechanismTo investigate the relationship between IL-1β, IL-6 and IL-8 with the type of gastric cancer, and with active H. pylori infection.


Gastric cancer: 12.2 (2.2)Gastritis: 2.1 (0.2)p<0.0001

Serum IL-6 higher in non-curable PC cases than in curable cases, and highest in those with liver metastases (data not shown).

Selection of controls not described, but they were matched for age and sex.

IL-6 measured before the onset, or at least 4 weeks after, any treatment.

46 gastritis controls were H. pylori-positive and 20 were H. pylori –negative.

Naples, Italy

[Galizia et al., 2002a]

Case-control

Gastric cancer: 28Colon cancer: 50Healthy controls: 25

Mean (range):

Gastric cancer: 62.0 (38-83)Colon cancer: 65.4 (37-83)

Gastric cancer: 12 (42.9)Colon cancer: 16 (32.0)

PrognosisTo investigate prognostic role of preoperative IL-10 and IL-6 in gastric and colon cancer patients.


Gastric cancer: 8.6 (0.9)Colon cancer: 9.3 (2.1)Controls: 4.4 (0.8)

All cancer cases vs. controls: p<0.0001Gastric vs. colon cancer: p=0.181

Unadjusted HR for cancer, IL-6>8.8 pg/ml: 1.208, p=0.786

Healthy controls were blood donors and matched for age and sex.


Colon cancer data also published in the article by Galizia and colleagues, 2002b.


Study design

N participants

Age of participants



Studies with IL-6 and cancer as a main aimSeoul, South Korea

[Kim et al., 2003]

Case-control

Gastric cancer: 109Healthy controls: 29

Median (IQR):

Gastric cancer: 56 (46-63)Healthy controls: 55 (44-61)

Gastric cancer: 34 (31.2) Healthy controls: 11 (37.9)

PrognosisTo investigate the concentrations of platelet microparticles, VEGF, IL-6 and chemokine RANTES and their potential association with metastasis in gastric cancer patients.


Gastric cancer: 4.40 (3.39-6.11) Healthy controls: 2.95 (2.63-3.83)p<0.001

Gastric cancer/stage:I: 3.40 (3.10-4.55)II/III: 3.99 (3.24-5.43)IV: 6.0 (4.52-12.00)p<0.001

Sensitivity and specificity of IL-6 for predicting distant metastasis were 70.0% and 79.7%.

Selection of healthy controls not described, but exclusion criteria included no hospitalisations during the previous three years.



Firat, Turkey

[Ilhan et al., 2004]

Case-control


Median (IQR):

Cases 62 (46-76)Controls 61 (38-82)

Cases:23 (55)Controls:12 (52)

Prognosis To examine the association of IL-6 and other markers with disease stage and related infection in gastric cancer.


Gastric cancer: 4.68 (2.0)Controls: 1.41 (0.34)p<0.0001





Study design




Comments


[Ashizawa et al., 2005]

Case-control


Mean (range):

Gastric cancer: 64.1 (40-83)

Gastric cancer: 17 (28.3)

PrognosisTo examine the prognostic role of IL-6 in gastric cancer.

Mean (SD) IL-6, pg/ml, by cancer stage:

I: 2.14 (1.57)IV: 11.77 (10.58)Healthy controls: 1.05 (0.46)p<0.01

Selection or demographic details of healthy controls not described.



Bangkok, Thailand

[Thong-Ngam et al., 2006]

Case-control

Gastric cancer: 51Controls with gastric ulcers: 17

Mean (range):

Gastric cancer: 64.5 (33-85)

Gastric cancer: 21 (44.7)

Diagnosis and prognosisTo investigate the role of IL-6, IL-10, IL-12 and IL-18 in the diagnosis and spread of gastric cancer.


Gastric cancer: 15.10 (27.7)Controls: 8.03 (7.41)p=0.3

Gastric cancer with metastases: 20.21 (9.37)Gastric cancer without metastases: 10.13 (7.83)p=0.037

Controls with gastric ulcers were patients at the same hospital as the cases but no demographic details of the controls given.



Gastric cancer cases were more likely to smoke and drink alcohol than controls.


Study design


N (%) female Main aim of the study Main results relating to IL-6 Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsKahawa, Japan

[Fukuma et al., 1996]

Case-control

Gastric cancer: 12Chronic hepatitis: 20Cholecystolithiasis: 11Healthy controls: 6

Median (range):

Gastric cancer: 60 (38-72)Chronic hepatitis: 51 930-62)Cholecysto-lithiasis: 56 (35-73)Controls: 61 954-72)

24 (49.0) Immune functionTo investigate the expression and serum concentrations of various cytokines to determine whether the liver has an immunological role in certain extrahepatic disorders.


Gastric cancer: 34.0 (16.0)Chronic hepatitis: 35.4 (25.4)Cholecystolithiasis: 27.6 (3.7)Controls: 16.0 (7.1)p cancer vs. controls <0.01




Glasgow, UK

[Wallace et al., 2002]

Case-control

Gastrointestinal (GI) cancer: 26Healthy controls: 11

Median (range):

GI cancer: 62 (47-88)Controls: 66 (46-74)

GI cancer: 8 (30.8)Controls: 4 (36.4)

PrognosisTo investigate the relationship between circulating free leptin concentrations, fat mass and the systemic inflammatory response in gastrointestinal cancer, and to examine the effect of the appetite stimulant megestrol acetate on these relationships.


GI cancer: 2 (<2-178)Controls: <2 (<2-<2)p<0.05

Free leptin correlated with appetite scores. Treatment with megestrol acetate increased leptin concentrations (p<0.05)



Table W9 Summary of studies of circulating IL-6 concentrations and prostate cancerStudy,(author, year)

Study design


N (%) female



Studies with IL-6 and cancer as a main aimHouston, TX, US

[Shariat et al., 2001]

Case-control

Prostatectomy patients: 120Lymph-metastatic prostate cancer: 19Bone-metastatic prostate cancer: 10Healthy controls: 44

Mean (SD):

Prostatectomy: 61.8 (7.2)Other groups: not given.

Not cited. PrognosisTo determine the relationship between preoperative plasma IL-6 and IL-6r with established markers of cancer invasion, metastasis and progression.


Prostatectomy: 2.07 (0.97)Lymph-metastatic: 2.52 (1.62)Bone-metastatic: 47.41 (21.320Controls: 1.91 (0.61)p-values: bone metastatic vs. lymph metastatic: <0.001lymph-metastatic vs. prostatectomy or healthy: 0.042, 0.039 respectively.

Healthy controls were selected from prostate cancer screening programme in the same city as cases.



Health ACB cohort, Memphis, TN and Pittsburgh, PA, US


Cohort Cancer-free participants: 2169Incident cancers: 296Prostate cancer: 63

Median (IQR):

Cases: 74 (71-76)Non-cases: 73 (71-76)

Cases: 113 (38)Non-cases: 1193 (55)


Multivariable-adjusted HR [95% CI] for prostate cancer, per log unit IL-6, pg/ml:

Prostate: 0.88 [0.59, 1.30]





Table W9, continued. Summary of studies of circulating IL-6 concentrations and prostate cancerStudy,(author, year)

Study design


N (%) female



Studies with IL-6 and cancer as a main aimSan Antonio Center for Biomarkers of Risk or Prostate Cancer cohort, San Antonio, Texas, US

[Baillargeon et al., 2006]

Case-control nested in a prospective cohort

Prostate cancer: 125Healthy controls: 125

Mean (SD):

PC: 63.5 (7.4)Controls: 63.2 (7.6)

0 (0) Aetiology and prognosisTo examine the relationship between obesity and leptin, adiponectin and interleukin-6 with prostate cancer risk and aggressiveness.

Age of participants-adjusted OR [95% CI] by tertiles of IL-6, pg/ml:

Incident prostate cancer:1st: 1.00 (ref.)2nd: 1.09 [0.61, 1.93]3rd: 0.84 [0.46, 1.53], p=0.98

High-grade prostate cancer (Gleason score>7):1st:1.00 (ref)2nd: 1.82 [0.75, 4.44]3rd: 0.84 [0.30, 2.33], p=0.17

Multivariable adjusted OR [95% CI] by tertiles of IL-6, pg/ml:

Incident prostate cancer:1st: 1.00 (ref.)2nd: 1.63 [0.75 , 3.65]3rd:0.93 [0.42, 2.06], p=0.63

High-grade prostate cancer (Gleason score>7):1st:1.00 (ref)2nd: 1.35 [0.52, 3.52]3rd: 0.85 [0.29, 2.47], p=0.52

Cases and controls selected from the participants of a community-based prostate cancer screening cohort. All men were free prostate cancer at study baseline.

Cancer-free participants were age-matched to cancer cases.


Further adjustment for age, race, serum PSA, BMI, leptin and adiponectin in multivariable-adjusted models.


Study design


N (%) female



Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsSeattle, US

[Drachenberg et al., 1999]

Cross-sectional

Prostate cancer: 176Benign prostate disease: 216Healthy controls: 15

Mean: Prostate cancer: 67.7Benign prostate disease: 73.5Healthy controls: 42.1

0 (0) PrognosisTo determine whether differences exist between IKL-6 concentrations in men with different prostatic diseases, to evaluate whether IL-6 correlates with prostate specific antigen and whether it could be a marker of disease progression in prostate cancer.

Mean (SE) IL-6 pg/ml:

Advanced hormone refractory cancer: 5.7 (1.9)Advanced hormone dependent cancer: 3.9 (1.6)Advanced untreated cancer: 0.05 (0.05)Locally recurrent cancer: 0.8 (0.4)Localised cancer: 1.7 (0.4)Prostatic intra-epithelial neoplasia: 1.1 (0.7)Benign hyperplasia: 1.9 (0.5)Chronic prostatitis: 6.2 (2.3)Healthy controls: 0.7 (0.4)

Hormone refractory cancer vs. healthy controls, benign hyperplasia, prostatitis and localised or recurrent cancer p<0.05.

Hormone refractory disease vs. intra-epithelial neoplasia p=0.07 and vs. advanced untreated disease p=0.06

All serum samples selected from sera bank at a hospital.



Some of the participants groups have few people in them, e.g. advanced untreated disease (4 participants).


Study design


N (%) female


Comments


[Adler et al., 1999]

Case-control


Mean (range):

Prostate cancer: 65.0 (48-78)Controls: 55.6 (35-80)

0 Prognosis and Biological mechanismTo define the pattern of cytokine abnormalities in prostate cancer and to investigate the relationship between some cytokines and prostate specific antigen concentrations as well as tumour grade and pathology.


Localised cancer: 1.94 (0.35)Cancer with extra-prostatic/seminal vesicle involvement: 1.51 (0.41)Cancer with lymph node metastases: 2.19 (1.51)Cancer with bone metastases: 93.15 (48.05)Controls: 1.53 (0.3)p=0.0008

Healthy controls selected from men attending prostate cancer screening at the same institute as the cases.


Some cancer cases had received surgery before IL-6 measurement.

Authors report 80% power to detect a difference between groups.

New York, NY, US

[Wise et al., 2000]

Case-control

Cancer 1 (hormone-responsive prostate cancer): 18Cancer 2 (hormone-resistant prostate cancer): 10.Benign prostate hyperplasia: 19Healthy controls: 10

Mean (range):

Cancer 1: 80 (66-93)Cancer 2: 84.5 (76-102)BPH: 73 (55-84)

0 (0) PrognosisTo evaluate the association of pro-inflammatory (Th1) and anti-inflammatory (Th2) cytokines with the response to hormone therapy in prostate cancer.


Cancer 1: 7.7 (5.3)Cancer 2: 20.9 (29.4)BPH: 5.6 (2.3)

Hormone-responsive vs. hormone-resistant cancer p=0.01

Selection of healthy controls not described, but they were matched for age.

IL-6 measured after patients had received hormone treatment for 49 weeks or longer. IL-6 concentrations not cited for healthy participants.


Study design


N (%) female



Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsSeattle, Washington

[Pfitzenmaier et al., 2003]

Case-control


Median:

Localised prostate cancer: 65Advanced cancer: 70Controls: 55

0 (0) Biological mechanismTo determine whether concentrations of various cytokines are elevated in cancer cachexia.

Mean (SD) IL-6:, pg/ml:

Localised prostate cancer: 8.58 (0.60)Non-cachetic advanced cancer: 7.32 (1.02)Cachetic advanced cancer: 3.94 (12.10)Controls: 7.24 (1.00)

Cachetic vs. non-cachetic p=0.019

Selection of healthy controls not described but they had no history of prostatic disease.


Localised prostate cancer patients’ IL-6 measured before the onset of any therapy. Unclear if advanced cancer patients were receiving treatment.

London, UK

[Michalaki et al., 2004]

Case-control

Prostate cancer: 80Benign prostate hyperplasia: 26Healthy controls: 12

Mean (SD): Cancer: 74.5 (7.5)BPH: not given.Controls: 67.5 (6.8)

0(0) PrognosisTo clarify the association of IL-6 and TNF-α with progression and outcome in prostate cancer.

Mean (SD) IL-6, pg/ml-1, p vs. healthy:

All cancer: 5.65 (6.74)p=0.031Localised cancer: 1.27 (0.81)Locally advanced: 3.50 (2.88)Metastatic: 9.26 (7.81)p<0.001BPH: 1.20 (0.49)Controls: 1.13 (0.63)

Healthy controls selected from men attending prostate cancer screening at the same hospital as the cases.




Study design

N participants

Age of participants

N (%) female



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsGlasgow, UK

[McArdle et al., 2004]

Cross- sectional

Prostate cancer: 86Benign prostate disease: 59

Cases 52/34BPD 45/14All participants≤70 /70

0(0)

Biological mechanism To examine correlation of IL-6 and CRP in men with benign and malignant prostate disease.

Median (range) IL-6, pg/ml-1:

Prostate cancer: 2.3 (0.8-28.1)BPD: 2 3 (0.7-12.9)p=0.0526

Participants were consecutive outpatients having prostate biopsies at the same hospital.


Cancer patients’ IL-6 measured before the onset, or at least 4 weeks after, any invasive procedure

Birmingham, UK

[Caine et al., 2004]

Case-control


Mean (SD):

Prostate cancer: 63.5 (7)Healthy male controls: 30 (14)

60 (50) Biological mechanismTo investigate possible relationships between inflammatory and coagulation markers in cancer.

Median (IQR) IL-6,pg/ml:

Prostate cancer: 8.25 (5-12.5)Male controls: 7.25 (5.75-7.88), p=0.405


Selection of controls not described but they were matched for age and sex for both cancer groups.


Participants were free of concomitant infections.

Houston, Texas

[Garcia et al., 2006]

Case-control


Mean (SD):Prostate cancer: 63.1 (8)Controls: 65.7 (12)

0 (0) PrognosisTo measure testosterone and its correlation with other biomarkers and appetite in men with and without prostate cancer.

Mean (SE) IL-6, pmol/L:

Prostate cancer: 0.9 (0.23)Controls: 0.13 (0.020p<0.005

Healthy controls selected from patients attending the same medical centre as cases and they were matched for age, sex and race.


Cancer cases were infection-free

Table W10 Summary of studies of circulating IL-6 concentrations and liver cancerStudy,(author, year)

Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimCordoba, Spain

[Padillo et al., 2002]

Before-and-after

Malignant obstructive jaundice (MOJ): 24Benign obstructive jaundice (BOJ): 11

Mean (SD):

MOJ: 67 (11)

MOJ: 14 (58.3)

PrognosisTo evaluate the effect of preoperative internal biliary drainage on TNF-α, IL-6 endotoxins and CRP in patients with benign or malignant obstructive jaundice.


MOJ: 344 (225)BOJ: 204 (110)p=0.008

Selection of participants not described.



Participants were free of inflammatory conditions.: 8 patients with inflammatory diseases and 2 patients in whom biliary drainage could not be performed were excluded.

Table W10, continued. Summary of studies of circulating IL-6 concentrations and liver cancerStudy,(author, year)

Study design



Comments

Studies with IL-6 and cancer as a main aimChulalongkorn and Udonthani, Thailand

[Tangkijvanich et al., 2004]

Case-control

Cholangio-carcinoma (CCA): 45Hepatocellular carcinoma (HCC): 15Metastatic liver cancer (MLC): 15Benign biliary disease (BBD): 10Healthy controls: 10

Mean (SD):

CCA: 63.0 (10.7)HCC: 50.9 (8.7) MLC: 60.9 (12.8)BBD: 40.3 (16.3)Controls: 34.2 (10.7)

CCA: 21 (46.7)HCC: 3 (20.0) MLC: 7 (46.7)BBD: 6 (60.0) Controls: 4 (40.0)

DiagnosisTo determine the diagnostic usefulness of serum CA 19-9 and IL-6 in cholangiocarcinoma.

Mean (SD) IL-6, pg/ml, p vs. CCA:

CCA: 568.78 (858.65)HCC: 34.27 (58.88) p<0.001MLC: 212.82 (597.34), p=0.01BBD: 0.08 (0.25) p<0.001Controls: 0.00 p<0.001

At cut-off of 0.18 ng/ml, sensitivity and specificity of IL-6 in differentiating CCA from: BBD: 71.1% and 90%Other liver cancers: 71.1 and 26.7.





Controls who were healthy or had benign disease were younger than cholangiocarcinoma cases.


Study design


N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsTaipei, Taiwan

[Hu et al., 1999]

Case-control

Hepatocellular carcinoma (HCC): 34Healthy controls: 23

Mean (range):

HCC: 55.9 (31-77)Controls: (45-66)

HCC: 8 (23.5)Controls: 7 (30.4)

PrognosisTo study the pre- and postoperative HGF, IL-6 and CRP profiles in patients undergoing surgery for HCC and to analyse relationships between these factors and various clinical parameters.

Preoperative IL-6, pg/ml:

HCC: 48 Controls: 20p=0.012(Approximate values: Data presented in a figure).

Concentrations of CRP, IL-6 and HGF did not return to normal level after HCC resection.

Controls recruited from healthy people attending medical check-ups at the same hospital where the cases were treated.


Cancer patients’ IL-6 measured before the onset of any treatment.

Taipei, Taiwan

[Huang et al., 1999]


HCC: 36Acute hepatitis: 29Chronic hepatitis: 43Liver cirrhosis: 40Healthy controls: 30

Mean (SD):

HCC: 58 (12)Acute hepatitis: 49 (10)Chronic hepatitis: 45 (19)Liver cirrhosis: 56 (19) Controls: 42 (15)

HCC: 9 (25.0)Acute hepatitis: 7 (24.1)Chronic hepatitis: 10 (23.3)Liver cirrhosis: 9 (22.5)Controls: 7 (23.3)

PrognosisTo evaluate the change and clinical significance of cytokines in the different stages of hepatitis C infection.


HCC: 25.4 (11.4)Acute hepatitis: 19.3 (9.0)Chronic hepatitis: 22.4 (9.7)Liver cirrhosis: 26.5 (13.2)Controls: 7.2 (1.1)

All disease groups vs. healthy controls p<0.05

Selection of healthy controls not described; controls with non-malignant diseases were patients in the same hospital as the cases.


Unclear if cancer patients’ IL-6 measured before the onset of any treatment.


Study design




Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsCatania, Italy

[Malaguarnera et al., 2000]

Case-control

HCC: 50Chronic hepatitis: 50Healthy controls: 20

Mean (SD):

HCC: 68.7 (10.1)Hepatitis: 91.8 (8.6)Controls: 56.1 (16.3)

HCC: 18 (36.0)Hepatitis: 24 (48.0)Controls: 10 (50.0)

PrognosisTo determine the relationship between serum β2-microglobulin concentrations and as a marker of tumour progression.


HCC: 49.7 (61.2)Hepatitis: 25.5 (8.5)Controls: 12.4 (6.4)p<0.05




Kaohsiung, Taiwan

[Lan et al., 2003]

Before-and-after

HCC: 7Healthy liver donors: 7

Mean (SD):

HCC: 48.4 (14.6)Donors: 34.8 (5.5)

Not cited. PrognosisTo evaluate IL-6 and CRP induced by hepatectomy in patients with healthy and diseased livers.


Pre-surgery:HCC: 11.50 (6.80)Donors: 4.12 (2.10)p=0.01

24 hrs after surgery:HCC: 141.90 (82.00)Donors: 47.51 (37.02)p=0.011

Controls were healthy donors undergoing partial hepatectomy for related living donor transplantation.



Donors were younger than HCC cases.


Study design



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsRepublic of China

[Wan et al., 2004]

Case-control

Liver transplantation: 22Liver cancer: 13Healthy controls: 12

Range (all participants): 35-58

Liver transplantation: 2 (9.1)Other groups: not given.

Immune status after liver transplantationTo elucidate serum cytokine and adhesion molecule concentrations in stable survivors of liver transplantation.


Liver transplantation: 21.63 (24.97)Liver cancer: 14.55 (19.85)Healthy: 2.29 (1.53)

Liver transplantation vs. liver cancer: p=0.842Liver transplantation vs. healthy: p=0.048

Selection of healthy controls not described. Participants in the liver transplantation group were patients at the same hospital as the cancer cases.


Possible that cancer patients’ IL-6 influenced by previous treatment. The liver transplantation group included people with benign liver diseases and 4 liver cancer cases.


Study design

N participants

Age of participants

N (%) female



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsPalermo, Italy

[Soresi et al., 2006]

Case-control

HCC: 93Liver cirrhosis (LC): 72Healthy controls: 42

Mean (range):

HCC: 62.2 (43-76)LC: 56.5 (36-75)Controls: 54.9 (45-61)

HCC: 32 (34.4)LC: 24 (33.3)Controls: 11 (26.2)

PrognosisTo evaluate immunohisto-chemical localisation of IL-6 and its receptor in hepatocellular tumour tissue.


HCC: 14 (3-301)LC: 6.4 (3-155)Controls: 3.6 (3-17)HCC vs. LC: p=0.002HCC vs. healthy p=0.0001

By HCC stage:I: 6.5 (3-270)II: 12 (3-301)III: 32 (3-110)III vs. II p<0.01III vs. I p<0.005

Controls with liver cirrhosis were consecutive in- and outpatients at the same hospital where the cases were treated. Healthy controls were blood donors without any liver disease.



Elazig, Turkey

[Ataseven et al., 2006]

Case-control

HCC: 22Cirrhosis (LC): 23Healthy controls: 25

Mean (SD):

HCC: 59.82 (8.770LC: 45.54 (7.99)Controls: 37.12 (7.57)

HCC: 7 (31.8)LC: 12 (52.2)Controls: 14 (56.0)

PrognosisTo evaluate concentrations of ghrelin and leptin and their associations with IL-6 and TNF-α in people with liver cirrhosis and hepatocellular carcinoma.

Mean (SD):

HCC: 33.27 (16.38)LC: 15.65 (5.19)Controls: 4.56 (2.0)

HCC vs. healthy p<0.01LC vs. healthy: p<0.01



Possible that cancer patients’ IL-6 influenced by previous treatment but participants were free of infection.

HCC patients were older and more likely to be male than controls or cirrhosis patients.

Table W11 Summary of studies of circulating IL-6 concentrations and head and neck squamous cell cancers (HNSCC)Study,(author, year)

Study design


N (%) female



Studies with IL-6 and cancer as a main aimCharleston, SC, US

[Lathers et al., 2003]

Case-control

HNSCC: 101Other cancers: 26Healthy controls: 40

Mean (SE):

HNSCC: 62.7 (11.6)Other cancers: 63.8 (3.9)Controls: 67.2 (13.9)

Not cited

PrognosisTo examine panel of cytokines in HNSCC patients and their relationship with the extent of the disease.

Mean IL-6, pg/ml:

HNSCC: 8.9Other cancer: 4.8Healthy controls: 5.0(Data presented in a figure.)HNSCC vs. healthy p<0.001HNSCC vs. other cancers p<0.02

Healthy controls were patients at an ear, nose and throat clinic, and matched for age.


Other cancers included HCC, lung, thyroid skin cancers and cancers of unspecified location.

Charleston, SC, US

[Lathers and Young, 2004]

Case-control

HNSCC: 101Healthy controls: 40

Mean (SE): HNSCC: 62.7 (11.6)Controls: 67.2 (13.9)

Not cited.

PrognosisTo examine the interrelationship among plasma concentrations of Th1 and Th2 cytokines in HNSCC patients and the influence this may have on prognosis.


HNSCC: 8.9 (0.9)Controls: 4.8 (0.4)p<0.001

HNSCC patients had more Th2 cytokines. Correlation among cytokine concentrations declined with increasing cancer stage.

Healthy controls were patients at an ear, nose and throat clinic, and matched for age.

Duplicate publication of the study by Lathers, 2003.

Table W11, continued. Summary of studies of circulating IL-6 concentrations and head and neck squamous cell cancers (HNSCC)Study,(author, year)

Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimMannheim, Germany

[Riedel et al., 2005]

Case-control

HNSCC: 90Healthy controls: 39

Median (range): HNSSC: 59 (39-83)Controls: not given.

HNSCC: 13 (14.4)Controls: not given.

PrognosisTo investigate the relationship between IL-6 and characteristics of the tumour and the patient in HNSCC.

Mean IL-6, pg/ml:

HNSCC: 19.5Controls: 6.0p<0.001

Selection and demographic details of controls not described.



Oral squamous cell carcinomaZagreb, Croatia

[Vucicevic et al., 2005]

Case-control

OSCC: 33Healthy controls: 23

Mean (range):

OSCC: 55.45 (40-73)Controls: 25

OSCC: 5 (15.2)Controls: 15 (60.0)

Biological mechanismTo evaluate the role of IL-6 and basic fibroblast growth factor (bFGF) in the pathogenesis of oral squamous cell carcinoma by measuring these markers in the saliva and serum of patients and controls.

No significant difference in serum IL-6 concentrations between cases and controls reported (data not shown).

Mean rank salivary IL-6:OSCC: 34.80Controls: 19.46p=0.001

Selection of healthy controls not described, but they had been free of any medication for a month prior to study.



Table W11, continued. Summary of studies of circulating IL-6 concentrations and head and neck squamous cell cancers (HNSCC)


Study design


N (%) female



Studies with IL-6 and cancer as a main aimNasopharyngeal carcinoma (NPC)China and Taiwan

[Chow et al., 2003]

Case-control

NPC: 314Healthy controls: 202

Mean (SD):

Male NPC: 58.9 (12.6)Female NPC: 52.2 (13.4)

NPC: 63 (20.1)

SurvivalTo examine the relationship between serum IL-6, sIL-2Rα and butyrate concentrations and post-therapeutic survival in NPC patients.

Pre-treatment IL-6 concentrations (SD) were above the normal average of 2.76 (SD: 2.06) pg/ml in 217/314 (69.1%) of the cancer patients.




Healthy controls included to define a normal cut-off value for IL-6.

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsPittsburgh, PA, US

[Hathaway et al., 2005]

Case-control

Active HNSCC: 2Remissive HNSCC: 30Healthy controls: 29

Mean (SE):

Active HNSCC: 57.3 (1.79)Remissive HNSCC: 62.5 (2.07)Controls: 63.0 (1.93)

Active HNSCC: 5 (16.7)Remissive HNSCC: 7 (31.8)Controls: 8 (28.6)

Diagnosis and prognosisTo determine the cytokine profile characteristic to patients with active HNSCC compared to that of long term smokers.


Active HNSCC: 46.6 (17.8)Remissive HNSCC: 39.7 (18.7)Controls: 20.0 (11.6)

Predictive accuracy, sensitivity and specificity of combination of IL-6 and other cytokines for HNSCC vs. chronic smokers: 79.2-62.5-93.1%, and vs. HNSCC in remission: 83.1-80.0-86.2%

Controls were smokers under-going lung cancer screening.

Controls matched for age.

Remissive HNSCC patients had been free of cancer for >3 years.




Study design




Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsBethesda, Maryland, US

[Druzgal et al., 2005]


HNSSC: 29Healthy controls: 15

Median (range):

HNSCC: 55 (24-77)Controls: 57 (30-80)

HNSSC: 5 (17.2)Controls: 5 (33.3)

Prognosis and survivalTo investigate potential value of cytokines and angiogenic factors as markers of prognosis, progression, recurrence and survival in HNSCC.

Mean IL-6, pg/ml:

HNSCC: 25Controls: 0.5p=0.005 (Data presented in a figure.)


None of the participants had a history of malignancy, immune diseases, or infections on enrolment.


Pre-treatment IL-6 concentrations presented for the 22 HNSCC patients for whom post-treatment samples were available.

Unable to ascertain exact IL-6 concentrations as data presented in a figure. Unclear if median or mean IL-6 concentrations presented.



Study design

N participants

Age of participants

N (%) female



Comments

Oral cavity and oropharyngeal squamous cell carcinoma (OSCC)Los Angeles, US

[St John et al., 2004]

Case-control

OSCC: 32Healthy controls: 32

Mean (SD):

OSCC: 49.3 (7.5)Controls: 48.8 (5.7)

Not cited. DiagnosisTo investigate whether IL-6 and/or IL-8 could serve as biomarkers for OSCC in saliva and/or serum.

Mean serum IL-6, pg/ml:

OSCC: 86.5Controls: 0p<0.05

At cut-off of 0 pg/ml, sensitivity and specifity for serum IL-6 were 57% and 100%, respectively, and area under ROC curve was 0.824.

IL-8 in saliva and IL-6 in serum were, not associated with sex, age or alcohol or tobacco use (p>0.75).

Selection of healthy controls not described, but they were matched for age and sex, and were similar in terms of smoking history.


Serum measurement of IL-6 only available for 19 OSCC cases.

No participant had previous history of malignancy, immune-function-related disease or hepatitis. Cancer cases had primary disease.

Oesophageal squamous cell carcinoma (OECC)Fukuoka, Japan

[Katsuta et al., 1998]

Case-control

OECC: 19Healthy controls: 10

Mean (range):

OECC: 63 (55-84)Controls: 77 (69-82)

OECC: 4 (21.1)Controls: 4 (40.0)

Response to treatmentTo clarify the association between TNF- α and IL-1β with pulmonary complications during oesophagectomy.


OECC: 19 (7)Controls: 1.1 (0.4)p<0.01



Two cancer cases had received radiotherapy prior to cytokine measurement.

Table W12 Summary of studies of circulating IL-6 concentrations and breast cancer (BC)


Study design

N participants

Age of participants

N (%) female



Studies with IL-6 and cancer as a main aimBialystok, Poland

[Kozlowski et al., 2003]

Case-control

BC: 45Healthy controls: 25

Range:

BC: 25-79Controls: not given.

70 (100) PrognosisTo examine the correlation of IL-6, IL-8 and IL-10 with the clinical stage of breast cancer.

Median (range) IL-6, pg/ml, N/% participants with elevated values:

All BC: 31.7 (6.25-100.0), 39/86.7%Controls: 3.3 (1.56-8.6), 0/0% p<0.05BC according to TNM stage:IIA: 18.6 (6.25-30.6), 5/n=6 IIB: 19.3 (7.8-36.4), 20/n=23IIIA: 40.9 (7.8-96.0), 11/n=12IIIB: 44.1 (5.4-100.0), 3/n=4p<0.05





30 cancer patients had ductal infiltrating carcinoma and 115 had lobular infiltrating carcinoma.

Houston, TX, US

[Pusztai et al., 2004]

Case-control


Median (range):

BC: 47 (25-77)

105 (100)

Response to treatmentTo assess changes in serum cytokines during chemotherapy and whether these correlate with musculoskeletal symptoms.


Current BC: 7.549 (33.18110Had BC: 6.657 (25.5126)Controls: 6.233 (13.0967)p cited as not significant.



Some cancer patients had received treatment before IL-6 measurement. Participants were free of inflammatory conditions.

55 BC cases had intact primary tumour, 35 had had their tumour removed prior to study.

Table W12, continued. Summary of studies of circulating IL-6 concentrations and breast cancer (BC)Study,(author, year)

Study design

N participants

Age of participants

N (%) female



Studies with IL-6 and cancer as a main aimBursa, Turkey

[Gonullu et al., 2005]

Case-control


Mean:

BC: 49.1Controls: 46.2

40 (100) Biological mechanismTo examine the role of TNF-α, IL-6 and insulin resistance in overweight or obese patients with early stage breast cancer.

Mean (SE) IL-6, pg/ml, by HOMA-IR score:

BC, IR<2.7: 5.16 (0.50) IR>2.7: 41.12 (7.07)Controls: IR<2.7: 7.11 (0.79) IR>2.7: 10.14 (2.12)BC low IR vs. control groups, p<0.05 and p<0.01 respectively.BC high IR vs. all other groups: p<0.01

Healthy controls selected from outpatients without breast disease at the same clinics where the cases were recruited. Controls were matched for BMI. All participants had BMI over 25.


Health study, Memphis, TN and Pittsburgh, PA, US


Cohort Cancer-free participants: 2169Incident cancers: 296Breast cancer: 30

Median (IQR):

Cases: 74 (71-76)Non-cases: 73 (71-76)

Cases: 113 (38)Non-cases: 1193 (55)


Multivariable-adjusted HR [95% CI] for breast cancer, per log unit IL-6, pg/ml:

0.95 [0.54, 1.65]


Participants recruited from Medicare beneficiaries.

Exclusion criteria were difficulty walking ¼ mile, climbing 10 steps or doing basic daily activities, life threatening illness or intent to leave area in the subsequent 3 years.




Study design

N participants

Age of participants

N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsReykjavik, Iceland

[Asgeirsson et al., 1998]

Case-control, with cell culture experiment


Mean (range):

BC: 57.5 (32-92)Controls: 53 (28-81)

109 (99.1)

Biological mechanismTo test the effect of IL-6 on four breast cancer cell lines and normal mammary epithelium cultured from milk and to investigate whether IL-6 concentrations are associated with survival in breast cancer patients

No. (%) of participants with IL-6 concentration >6 pg/ml:

BC: 16 (27)Controls: 1 (2)p=0.008




Baton Rouge, LA, US

[Jiang et al., 2000]

Case-control


BC: >50: 63≤ 50: 28

178 (100) Treatment and prognosisTo measure serum IL-5 and GM-CSF before and after vaccination with TAA to determine whether vaccination changed these concentrations.


Before vaccination:BC: 38.3 (138.6) (n=111)Controls: 0.7 (2.5) (n=36)p<0.01

After vaccination:BC: 8.1 (14.6) (n=85) p before vs. after <0.05

Healthy controls were cancer-free women attending breast cancer screening.



Different numbers of participants at different points of time during the study. Age of participants of controls not given.


Study design

N participants

Age of participants

N (%) female



Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsAntwerp, Belgium

[Benoy et al., 2002]

Case-control


Not cited. 130 (100)

PrognosisTo evaluate the clinical significance of VEFG, blood counts and IL-6 in people with locoregional and metastatic breast cancer.

Mean (SD) IL-6, pg/ml

Locoregional cancer: 1.4 (1.4) Metastatic cancer: 12.4 (55.5)Controls: 0.5 (0.4)BC vs. controls p<0.0001Metastatic BC vs. controls p=0.0014




Belgium

[Dirix et al., 2002]

Case-control


Mean (SD):

BC, stage I-II: 56 (14)Stage IV: 59 (18)Controls: not given.

137 (100)

Prognosis and survivalTo assess fibrin D-dimer in breast cancer progression and to examine whether markers of fibrin degradation relate to markers of angiogenesis.

Mean (SD) IL-6, pg/ml¹:

Stage IV cancer: 12.3 (21.6)Stage I-II cancer: 2.0 (1.1)Controls: 0.5 (0.4)Stage IV vs. stage I-II p<0.001



Duplicate publication of the data previously published by the same group of researchers (Benoy 2002).

Birmingham, UK


Case-control

Breast cancer: 30Healthy controls: 60

Mean (SD):

BC: 31 (12)Healthy female controls: 30 (11)



BC: 11 (5-15)Female controls: 5.5 (5-7.38), p=0.014





Table W13 Summary of studies of circulating IL-6 concentrations and kidney cancer (renal cell carcinoma, RCC)


Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimFrance

[Blay et al., 1992]

Case-control

RCC: 138Healthy controls: 73

Median (range):

RCC: 58 (24-77)

RCC: 39 (28)

PrognosisTo investigate IL-6 and CRP in renal cell carcinoma patients before and after IL-2 treatment.

No. (%) participant with IL-6 ≥ 76 pg/ml:

RCC: 66 (48)Controls: 8 (11)p<0.001




All cases had metastatic disease.Umeå, Sweden

[Ljungberg et al., 1997]

Case-control

RCC: 196Controls with benign kidney tumours: 24

Mean (range):

Renal cell carcinoma: 64.3 (25-86)Controls: not given.

77 (39.3) Prognosis and survivalTo compare serum concentrations of IL-6 with clinical outcome , survival, tumour stage, grade and size and acute phase reactants and erythrocyte sedimentation rate in renal cell carcinoma.

Mean (SD) IL-6, ng/L:

RCC: 28.1 (68.4)Controls: 1.7 (2.6)p<0.001

Selection of controls with benign disease not described.



Table W13, continued. Summary of studies of circulating IL-6 concentrations and kidney cancer (renal cell carcinoma, RCC)


Study design


N (%) female


Studies with IL-6 and cancer as a main aimTübingen, Germany

[Wechsel et al., 1999]

Case-control


Mean (range):

RCC: 54.4 (31-89)Controls: 32 (21-62)

Not cited.

Biological mechanismTo investigate whether indications of IL-6 control of dysproteinemia (associated with RCC) results from a correlation of IL-6 titres with changed hepatic parameters.

Mean (SD) IL-6 titre, ng/ml:

RCC: 10.7 (6.6)Controls: 1.2 (1.7)p=0.0001

At predetermined specificity of 95% (cut-off of 3 ng/ml) the sensitivity of IL-6 to differentiate between RCC and healthy participants was 90%.




Osaka, Japan

[Yoshida et al., 2002]

Case-control


Mean:

RCC: not given.Controls: 61.9

Not cited.

DiagnosisTo examine the roles of TNF-α, IL-1β and IL-6 in tumour biology and diagnosis of renal cell carcinoma.


RCC: 8.91 (13.12)Controls: 1.79 (2.03)p not given

Il-6 correlated with tumour size: r=0.42, p<0.0001

Area under ROC-curve for IL-6 (cut-off not given) ca. 0.70 (Data presented in a figure.)






Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimGlasgow, UK

[Ramsey et al., 2006]

Case-control

RCC: 64Benign renal disease: 12

Proportion of participants aged 60+:

RCC: 29 (45.3)Benign renal disease: 3 (25.0)

RCC: 22 (34.4)Benign renal disease: 8 (66.7)

PrognosisTo examine concentrations of CRP, IL-6 and IL-10 before and after curative resection of renal tumour.

Median (range)IL-6, pg/ml-1:

RCC: 4 (<2, 142)Benign renal disease: <2 (<2, 19)p=0.007

Controls were patients undergoing surgery for renal disease at the same hospital as the cases.

No adjustment for potential confounders but controls were similar to cases in terms of age, sex, clinical stage and performance status, haemoglobin, white blood cell count and albumin concentration.


Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsJapan

[Hayakawa et al., 1998]

Case-control

RCC: 26Controls with benign renal cysts: 18Healthy controls: 14

Not cited. Not cited. DiagnosisTo determine whether cytokines measured in cystic fluid are useful in diagnosing RCC in people with renal cysts.


RCC: 5 (2)Controls with benign cysts: 2 (1)p cited as not significant.

Range: RCC: 0.35-39.97Healthy controls: 0.35-15.22






Study design


N (%) female



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsBrno, Czech Republic

[Lauerova et al., 1999]

Case-control, with a follow-up


Mean (range):

RCC: 61 (39-79)Controls: not given.

RCC: 25 (36.2)Controls: not given.

PrognosisTo investigate immune status in RCC patients before and after surgery.

Geometric mean [95% CI] IL-6, pg/l:

RCC: 0.11 [0.00-0.23]Controls: 0.00p=0.042




Table W14 Summary of studies of circulating IL-6 concentrations and melanoma


Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimParis, France

[Mouawad et al., 1996]

Case-control

Melanoma: 41Healthy controls: 40

Median (range):

Melanoma: 44 (21-680

19 (47.5) PrognosisTo examine the potential role of IL-6 as a tumour marker in metastatic melanoma.

Mean (SD) IL-6, pg/ml, before treatment onset:

Melanoma: 8.07 (4.9)Controls: 2.65 (2.9)p=0.002

Selection of healthy controls not described. Controls reported to be similar to cases in terms of age and sex.



Melanoma patients’ IL-6 was measured before and during biochemotherapy, consisting of cisplatinum, IL-2 and IFN-α.

Houston, TX, US

[Porter et al., 2001]

Case-control


Median (range):

Melanoma: 49 (18-80)

Melanoma: 97 (44.45)

PrognosisTo examine whether various plasma biomarkers predict recurrence in melanoma patients with negative sentinel lymph nodes.


Melanoma: 27.(7.3)Controls: 5.92 (3.21)p=0.002

5-yr disease free survival in melanoma patients:IL-6≥15.6 pg/ml: 83IL-6<15.6pg/ml: 79p=0.64




Table W14, continued. Summary of studies of circulating IL-6 concentrations and melanoma


Study design




Comments

Studies with IL-6 and cancer as a main aimBrno,Czech Republic

[Lauerova et al., 2002]



Median (range):

Melanoma R: 48 (24-60)Melanoma NR: 35 (27-59)Controls: not given.

Melanoma (responders to immune therapy): 7 (41.2)Melanoma (non-responders): 4 (44.4)Controls: not given.

PrognosisTo examine immune alterations and potential prognostic markers associated with melanoma.

Geometric mean IL-6 [95% CI], pg/ml:

Melanoma: 1.75 [1.42-2.14]Controls: 0.83 [0.55-1.15]p<0.001




Istanbul, Turkey

[Tas et al., 2005b]



Median (range):

Melanoma: 51 (27-72)

Melanoma: 6 (37.5)

PrognosisTo evaluate the association between pre-treatment serum IL-6, TNF-α and erythropoietin (EPO) and metastatic distribution and survival in people with metastatic malignant melanoma.


Melanoma: 30.55 (19.8-201.0)Controls: 23.4 (18.9-(2.0)p=0.0009

Elevated IL-6 associated with shorter overall survival in metastatic melanoma.

Selection of healthy controls not described. No details of controls given. Cancer cases were consecutive patients at a cancer hospital and had metastatic disease.



Table W14, continued. Summary of studies of circulating IL-6 concentrations and melanomaStudy,(author, year)

Study design

N participants

Age of participants

N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsItaly

[Moretti et al., 2001]

Case-control


Mean:

localised melanomas: 49Metastatic melanomas: 34

32 (71.1) PrognosisTo evaluate serum cytokines in response against or progression of melanoma.

Mean IL-6 (pg/ml):

Melanoma: 19.4Controls: 1.7p=0.001

Localised melanoma: 14.4Metastatic melanoma: 21.09p=0.1


Controls matched for age and sex but no demographic details given.


Paris, France

[Mouawad et al., 2006]

Case-control


Melanoma:

N aged >47: 35≤47: 40Controls: Range- 25-55

Melanoma: 32 (42.7)Controls: 15 (50.0)

PrognosisTo evaluate concentrations of soluble epidermal growth factor receptor in melanoma patients and to assess the relationship between these and other blood biomarkers, including IL-6, and survival.


Melanoma: 19 (0-354.6)Controls: 2.65 (0-32)p<0.0001



All cancer patients had metastatic melanoma.


May have used some of the same controls as a previous study by Mouawad and colleagues, 1996.

Table W15 Summary of studies of circulating IL-6 concentrations and soft tissue sarcomas (STS)Study,(author, year)

Study design

N participants

Age of participants

N (%) female



Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsWarsaw, Poland

[Ruka et al., 2001]

Case-control

STS: 145Healthy controls: 50

Mean (SD):

STS: 49.9 (16.9)Controls: 38.9 (15.1)

STS: 70 (48.3)Controls: 24 (48.0)

Prognosis and survivalTo evaluate the relationship between pre-treatment routine blood markers and various cytokines and their association with tumour characteristics and survival.

Mean IL-6, pg/ml:

STS: 17.04Controls: 0.94p<0.001

IL-6 was not associated with survival in crude or adjusted analysis.

Selection of healthy controls not described. Controls had similar age and gender distribution as cases.

Contains the same data as the study by Rutkowski and colleagues, 2002.

Warsaw, Poland

[Rutkowski et al., 2002]

Case-control

STS: 156Healthy controls: 50

Median (range):

STS: 51 (17-81)Controls: 49 (19-71)

STS: 75 (48.1)Controls: 24 (48.0)

PrognosisTo examine the relationships between pro-inflammatory, hematopoietic and angiogenic cytokines and soluble cytokine receptors in soft tissue sarcoma patients.


STS: 3.7 (0.7-206.0)STS without metastasis: 4.3 (0.7-206)Controls: 0.8 (0.5-6.0)

STS vs. controls p<0.001STS without metastasis vs. controls p<0.001

IL-6 >2.4 pg/ml was associated with overall survival in crude analysis (p<0.0001) and multivariate analysis (p=0.02)..


No adjustment for potential confounders in comparative analysis. Survival analysis adjusted for various blood markers and cytokines.


32 patients had lung metastases.

Table W16 Summary of studies of circulating IL-6 concentrations and Kaposi’s sarcomaStudy,(author, year)

Study design


N (%) female


Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsAmsterdam, the Netherlands

[de Wit et al., 1991]


HIV+Kaposi’s sarcoma: 14HIV without cancer: 10Healthy controls: 10

Not cited. 0 (0) PrognosisTo test the hypothesis that serum IL-6 increases before IFN-α treatment and decreases in patients who respond to this treatment.

Mean (SD) IL-6, pg/ml-1:

Kaposi’s: 26.2 (13.5)HIV: 7.3 (2.4)Controls: 8.2 (2.8)

Kaposi’s vs. other groups: p<0.001HIV vs. healthy: p=0.49

Pre-treatment IL-6 was not different in patients who later responded to treatment and those who did not (p=0.45).

Selection of none of the controls described, but they were matched for age.

All cancer patients also had HIV and had received treatment for it.

Columbus, OH, US

[Bailer et al., 1995]

Case-control

HIV + Kaposi’s sarcoma: 9HIV without cancer: 10Healthy controls: 5


Biological mechanismTo assess cytokine release in AIDS-related and normal cell lines and to examine whether AIDS-Kaposi’s sarcoma is associated with a unique serum cytokine profile.

IL-6, pg/ml: HIV + Kaposi’s: 4.5HIV+: 6.5Controls: 4.5(Approximate values: data presented in a figure)p vs. controls: p=0.045

Selection of none of the controls described, but they were matched for age.

All cancer patients also have HIV and had received treatment for it.

Table W17 Summary of studies of circulating IL-6 concentrations and uterine cancerStudy,(author, year)

Study design


N (%) female


Comments

Studies with IL-6 and cancer as a main aimGalveston, TX, US


Case-control

Endometrial cancer: 39Healthy controls: 20

Range: 30-60

59 (100) PrognosisTo investigate the excess serum concentrations of growth factors and cytokines during stages of endometrial cancer and to identify cytokines that may act as regulators of progression and metastasis.

Mean IL-6, pg/nl, by cancer stage:

I: <10II: <10III: <10IV: <10Controls <10

Selection of healthy controls not described. Controls were age-matched and free of any benign uterine conditions, were not on medication or drugs and were non-smokers.



Serum IL-6 was undetectable in cases and controls.

Table W17, continued. Summary of studies of circulating IL-6 concentrations and uterine cancerStudy,(author, year)

Study design


N (%) female


Studies with IL-6 and cancer as a main aimLittle Rock, Arkansas, US

[Bellone et al., 2005]

Case-control

Endometrioid carcinoma: 19Uterine serous papillary carcinoma: 13Controls with benign abdominal diseases: 19Healthy controls: 20

Mean (SD):

EC: 62.9 (11.3)USPC: 98.2 (9.5)Benign disease: 46.2 (15.6)Healthy: 42.6 (10.9)

71 (100) Biological mechanismTo investigate IL-6 gene expression and protein secretion in different types of uterine cancer in vivo and in vitro.


USPC: 125.7 (44.2)EC: 20.43 (6.1)Benign disease: 13.07 (4.9)Healthy: 3.1 (1.1)

p-values:Healthy vs. cancer: <0.01Benign vs. EC: >0.05Benign vs. USPC: >0.02

Mean copy number of IL-6 gene, as measured in mRNA from tissue samples was 5.9 times higher in USPC than in EC, and higher in both cancer in comparison to healthy controls.




IL-6 gene expression also measured in a subset of primary endometrial cancers with single type differentiation (EC: 14 and USPC: 10).

Table W17, continued. Summary of studies of circulating IL-6 concentrations and uterine cancerStudy,(author, year)

Study design


N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsChoriocarcinomaCairo, Egypt

[Shaarawy et al., 1996]


Choriocarcinoma: 24Vesicular mole: 42Healthy controls: 24

Mean (range):

Choriocarcinoma and vesicular mole: 23.6 918-43)

89 (100) PrognosisTo investigate the clinical value of cytokine measurements in gestational trophoblastic disease by determining the circulating concentrations of IL-6, IL1-β and TNF-α in pregnant women.

Mean IL-6 (SE), pg/ml:

Progressive choriocarcinoma: 8790 (1118)Remissive choriocarcinoma: 3301 (767)Vesicular mole: 55.9 (9.38)Controls: 30.5 (1.31)

Controls recruited from outpatients in the same hospital as cases.

Controls “comparable” in terms of age and parity: unclear if the authors mean matched.


Table W18 Summary of studies of circulating IL-6 concentrations and bladder cancer


Study design


N (%) female


Studies with IL-6 and cancer as a main aimCairo, Egypt

[El-Salahy, 2002]

Case-control

Bladder cancer: 50Cystitis: 20

Mean (SD):

Bladder cancer: 57.48 (11.1)Cystitis: 48.07 (8.17)

Not cited.

Diagnosis and prognosisTo evaluate the expression of CK-9 and CK-20 in tissue samples and IL-6 in sea of bladder cancer patients and examine their associations with clinico-pathological parameters, bilharziasis and relapse.


Bladder cancer: 65.5 (14.8-329.6)Cystitis: 23.7 (12.4-59.1)p<0.0001

At cut-off of 49.2 pg/ml, sensitivity and specificity for detecting bladder cancer were 66% and 95%, respectively.

Controls selected form patients at the same hospital as the cases.No adjustment for potential confounders.


19/50 bladder cancer patients and 7/20 cystitis patients also had bilharziasis.


[Andrews et al., 2002]


Bladder cancer: 51Healthy controls: 44

Mean (SD):

Bladder cancer: 65.0 (8.5)

Bladder cancer: 4 (8.0)

Prognosis and survivalTo test the hypothesis that preoperative plasma IL-6 and sIL-6r concentrations predict cancer stage and prognosis in patients with transitional cell bladder carcinoma.


Bladder cancer: 4.51 (1.48)Controls: 1.51 (0.61)p<0.001

HR [95% CI] for prognostic outcomes per preoperative IL-6:Recurrence: 1.417 [.954-2.107] p=0.084Survival: 2.171 [1.288-3.659] p=0.05

Controls were consecutive patients attending bladder cancer screening at the same institute as cases and were matched for age.


2 cases had secondary cancer. Most participants were men.

Table W19 Summary of studies of circulating IL-6 concentrations and cervical cancerStudy,(author, year)

Study design


N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsGalveston, Texas, US


Case-control

Cervical cancer: 61Healthy controls: 20

Not cited. 81 (100) PrognosisTo investigate the role of various angiogenic factors in cervical cancer progression.

Mean IL-6, pg/ml:

Cancer stage 0: <10 Cancer stage I: 21.6 (9.8)Cancer stage II: 32.8 (8.9)Cancer stage III: 27.5 (5.7)Cancer stage IV: 42.4 (3.6)Controls: <10

IL-2, IL-7 and IL-8 showed similar patterns.

Selection of healthy controls not described, but they were not on any medication and were matched for age.

All participants were non-smokers and did not use intravenous drugs.



Cancer patients with immunological diseases, infections, diabetes or those on immune function altering medication were excluded.

Table W20 Summary of studies of circulating IL-6 concentrations and bone sarcomaStudy,(author, year)

Study design


N (%) female


Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsWarsaw, Poland

[Rutkowski et al., 2003]

Case-control

Malignant BS: 72Benign BS: 22Healthy controls: 50

Median (range):

BS: 35 (18-72)Controls: 49 (19-71)

BS: 42 (44.7)Controls: 24 (48.0)

Prognosis and survivalTo evaluate whether serum cytokines or their receptors involved in bone metabolism are associated with disease features or survival in bone sarcoma.


Malignant BS: 4.9 (0.7-161.0)Benign BS: 0.7 (0.7-7.0)Controls: 0.8 (0.5-6.0)Malignant vs. controls: p<0.001Malignant vs. benign: p<0.0001

IL-6 > 2.4 pg/ml was associated with overall survival in crude analysis (p<0.001), but not in multivariate analysis.


No adjustment for potential confounders in comparative analysis. Multivariate survival analysis adjusted for other cytokines. Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy.

Participants were free of infection.

Appears to have used the same controls as the study by Rutkowski and colleagues, 2002.

Table W21 Summary of studies of circulating IL-6 concentrations and multiple cancer typesStudy,(author, year)

Study design


N (%) female



Comments



Case-control

MM: 47MGUS: 24Non-Hodgkin’s lymphoma (NHL): 25 Myeloproliferative disorders: 8Healthy controls: 10



MM (progressive): 6 (2-33)MM (plateau): 3 (1-10)MGUS: 4 (1-7)MPD: 2 (1-2)NHL: 3 (2-10)Healthy controls: <5Advanced MM vs. plateau MM or MGUS: p<0.01

Selection of healthy controls not described.No adjustment for potential confounders.Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy.IL-6 measured in 101/104 participants. Participants with NHL had low-grade disease.

Table W21, continued. Summary of studies of circulating IL-6 concentrations and multiple cancer typesStudy,(author, year)

Study design


N (%) female



Comments



Case-control

MM: 55MGUS: 28Waldenström’s disease: 19Acute non-lymphoblastic leukaemia (ANLL): 13Acute lymphoblastic leukaemia (ALL): 5Hodgkin’s lymphoma (HL): 5Non-Hodgkin’s lymphoma (NHL): 8Castleman’s disease: 2Healthy controls: 66



Median (range) IL-6, pg/ml, p vs. controls:MM: 317 (153-947), p=0.05MGUS: 351 (142-668), p=0.05Waldenström’s disease: 356 (174-568), p=0.05ANLL: 625 (351-1774), p=0.005ALL: 544 (424-834), p=0.005HL: 548 (223-8271), p=0.005NHL: 401 (219-8887), p=0.01Controls: 287 (113-520)

Selection of healthy controls not described. No demographic detail of participants given. No adjustment for potential confounders.


IL-6 not measured in the 2 participants with Castleman’s disease.


Study design


N (%) female



Comments



Cross-sectional

MM: 66MGUS: 128Waldenström’s disease: 27non-Hodgkin’s lymphoma (NHL): 11Chronic lymphocytic leukaemia (CLL): 7

Mean (range):

MM: 68 (36-94)MGUS: 72 (36-96) Waldenström’s disease: 68 (44-92)NHL: 75 (57-90) CLL: 67 (52-90)



MM: 0.284 (0.053-0.734)MGUS: 0.200 (0.062-1.090)Waldenström’s disease: 0.212 (0.078-0.592)NHL: 0.201 (0.073-2.464) CLL: 0.207 (0.146-0.318)No p value cited.

IL-6 reported as having no positive predictive value for MM; negative predictive value was 0.71.


No adjustment for potential confounders.Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy.Of the participants with MGUS, 32 also had cancer, 13 autoimmune disease, 3 acute infection, 1 alcoholic hepatitis, 1 amylosis and 1 Gaucher’s disease.

Yokohama, Japan

[Makino et al., 1998]

Case-control

Cancer: 23Healthy controls: 6

Mean (range):Cancer: 62 (46-78)Controls: 57 (45-67)

Cancer: 8 (34.8)Controls: 4 (66.7)

Insulin resistance in cancer patientsTo evaluate the role of cytokines in inducing insulin-resistance in cancer patients.

No. (%) participants with detectable IL-6:

Cancer: 8 (34.8)Controls 0 (0)

Selection of healthy controls not described.No adjustment for potential confounders.Possible that cancer patients’ IL-6 influenced by previous treatment.

Cancer cases had oesophageal, lung, colon or gastric cancer.


Study design


N (%) female



Studies with IL-6 and cancer as a main aimCagliari, Italy

[Mantovani et al., 2000]

Case-control Cancer: 29Healthy controls: 29

Mean (range):

Cancer: 45 (20-80)Controls: 58 (41-77)

Cancer: 15 (51.7)Controls: 16 (55.2)

Prognosis and survivalTo examine the relationship between serum leptin and serum IL-6 and TNF-α in people with advanced cancer and their role in disease progression and survival.


Cancer: 29 (24)Controls: 1 (2.5)p<0.0001

Selection of healthy controls not described but they were matched for age and sex.Cancer patients’ IL-6 measured before any surgery and not during any chemo- or radiotherapy.Cancer patients had lymphomas and ovarian, breast, lung, colorectal, pancreatic and respiratory tract cancers.

Switzerland

[Kovacs, 2001]

Case-control, with intervention

Breast cancer: 26GI cancer: 21Uterine/ovarian cancer: 11Renal/bladder cancer: 9Melanoma/soft tissue//lung cancer: 9Healthy controls: 28

Range:

Cancer patients: 24-68Controls: 31-62.

Cancer: 48 (63.2)Controls: 11 (39.3)

Prognosis To examine the alterations in serum IL-6, sIL-6r and sgp130 in relation to tumour stage and therapy in various cancers.

Mean (SE) IL-6, ng/ml, p vs. controls:

Cancer:Stage I+II, pre-therapy: 7.2 (4.6), p>0.05Stage III+ IV, pre-therapy: 4.0 (1.2), p>0.05Stage I+II, post-therapy: 4.1 (1.7), p>0.05Stage III + IV, post-therapy: 8.1 (2.2), p>0.05 Controls: 2.6 (0.3)

Selection of healthy controls not described but they were matched for age.

Cancer patients’ IL-6 measured before the onset, or at least 4 weeks after, any treatment:


Study design


N (%) female



Studies with IL-6 and cancer as a main aimAtlanta, GA, US

[Musselman et al., 2001]

Case-control


Mean (SD):

Cancer with depression: 57.6 (13.0)Cancer without depression: 51.0 (11.4)Depressed controls: 53.3 (12.6)Healthy controls: 42.5 (9.8)

Not cited. DepressionTo examine whether cancer patients with major depression had higher IL-6 concentrations and whether these were related to cortisol concentrations.

Median [95% CI] IL-6, pg/ml:

Cancer with depression: 116.4 [86-512.5]Cancer without depression: 0 [0-0.0]Depressed controls: 50.0 [11.1-296.0]Healthy controls 0.1 [0-2.2]p=0.003:

Participants recruited from hospital in- and outpatients and by newspaper adverts or word of mouth.



Controls referred to as healthy, but some of them had depression. Cancer patients had oesophageal, pancreatic or breast cancer.

Marseilles, France

[Mokart et al., 2002]

Case-control

Digestive tract or gynaecological cancers: 30Healthy controls: 14

Mean:

Cancer: 55

Cancer: 14 (46.7)

Prognosis and treatmentTo investigate the association between changes in serum pro- and anti-inflammatory cytokine concentrations and postoperative septic complications.

Mean (SE) IL-6 pg/ml:

Cancer: 22.2 (6.4)Controls: 3 (0)p<0.05

Postoperative increase in IL-6 concentration was the greatest in cancer patients who developed sepsis or septic shock than in those without complications.

Selection of healthy controls not described and no demographic details reported.




Study design


N (%) female



Comments

Studies with IL-6 and cancer as a main aimHealth ABC study, Memphis, TN and Pittsburgh, PA, US


Cohort Cancer-free participants: 2169Incident cancers: 296

Colorectal cancer: 40Lung cancer: 42Breast cancer: 30Prostate cancer: 63

Median (IQR):

Cases: 74 (71-76)Non-cases: 73 (71-76)

Cases: 113 (38)Non-cases: 1193 (55)


HR [95% CI] for incident cancer events/ log IL-6, pg/ml:

Crude: 1.18 [0.98-1.41]Adjusted: 1.13 [0.94-1.37]Adjusted and NSAID users excluded: 1.10 [0.90-1.35]

Multivariable-adjusted HR [95% CI] for cancer events by type/log IL-6, pg/ml:CRC: 1.44 [0.90-2.31]Lung: 1.43 [0.91-2.26]Prostate: 0.88 [0.59, 1.30]Breast: 0.95 [0.54, 1.65]

Additional adjustment for smoking: Lung: 1.22 [0.75, 1.97]

HR [95% CI] for cancer death per log IL-6, pg/ml:Adjusted: 1.63 [1.19-2.23]


Adjustment for age, gender, race and site. Further adjustment for BMI, pack-years of cigarettes smoked, physical activity, education, baseline medical conditions and medication used did not change the effect estimates (data not shown).


Any incident cancer group also included participants with gastrointestinal cancers.


Study design


N (%) female


Studies with IL-6 and cancer as a main aimHeraklion, Greece

[Xirouchaki et al., 2002]

Cross-sectional

Transudates: 17

Exudates: Malignant: 20 Parapneumonic: 11 Tuberculous: 9

Median (range):

All participants: 61 (23-79)

Not cited.

DiagnosisTo measure IL-1α, IL-6 and TNF-α in pleural fluid and serum in order to assess their diagnostic usefulness in differentiating between malignant, parapneumonic and tuberculous effusions.


Malignant: 210 (110)Parapneumonic: 625 (499)Tuberculous: 134 (44)p>0.05

Transudates: 157 (45)All exudates: 308 (146)p<0.02

IL-6 reported higher in pleural fluid than serum in all participant groups (p<0.05), and pleural IL-6 was higher in tuberculous than malignant (p<0.007) or parapneumonic (p<0.04) effusions.

Participants were consecutive patients with pleural effusions for whom definite diagnosis could be made.



Effusions were diagnosed as malignant if cytologic examination found malignant cells in pleural fluid or biopsy specimens.


Study design

N participants

Age of participants



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsHelsinki, Finland


Case-control

Sjögren’s syndrome: 22Chronic lymphocytic leukaemia: 9 MGUS: 12MM: 16Healthy controls: 32

Mean (range):

SS: 51 (26-80)CLL: 66 (43-78)MM: 65 (41-85)MGUS: 62 (44-86)Controls: 35 (21-54)

SS: 21 (95.5)CLL: 5 (55.6)MM: 6 (37.5)MGUS: 8 (66.7)Controls: 7 (21.9)

Biological mechanismTo measure serum immunoreactive Il-6 in patients with various lymphoproliferative diseases.


SS: 299 (100)CLL: 120 (32)MM: 113 (58)MGUS: 337 (92)Controls: 92 (77)

SS vs. MM/CLL/controls p<0.001 MGUS vs. MM/CLL/controls p<0.001MM or CLL vs. controls: p cited as not significant.




Participants were free of infections.

Rome, Italy


Case-control

Acute myeloid leukaemia: 19Non-Hodgkin’s lymphoma 14Healthy controls: 174

Median (range):

AML: 48 (19-74)NHL: 35 (21-55)Controls: 41 (14-65)

AML: 7 (36.8)NHL: 9 (64.3)Controls: 92 (52.9)

Prognosis and response to treatmentTo investigate antiphospholipid antibodies and treatment-related change in these in newly diagnosed acute myeloid leukaemia and non-Hodgkin’s lymphoma patients.


AML: 38.4 (30.6)p vs. controls=0.003NHL: 13.8 (10.1)p vs. controls=0.043

No. (%) participants with IL>7pg/ml: AML: 17 (89.5)NHL: 10 (71.4)





Study design

N participants

Age of participants


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsRotterdam, the Netherlands

[Pruimboom et al., 1995]

Case-control

Peritoneal cancer: 26Liver cirrhosis: 53Bacterial peritonitis: 10Healthy controls: 17

Mean (range):

Peritoneal cancer: 61 (37-81)Cirrhosis: 58 (27-82)Peritonitis: 48 (22-59)Controls: 29 (23-40)

Peritoneal cancer: 8 (30.8)Cirrhosis: 20 (37.7)Peritonitis: 3 (30.0)Controls: 5 (29.4)

Diagnosis and prognosisTo assess the diagnostic and prognostic value of various biochemical markers in plasma and ascites of patients with abdominal diseases.


Peritoneal cancer: 420 (215)Cirrhosis: 1191 (358)Peritonitis: 1736 (394)Controls: <2 (17)Cases vs. controls p<0.05

All cancer cases’ mean (SE) IL-6, ng/ml:Ascites: 26 (4.4)Plasma: 1 (0.3)p<0.05




All participants with cancer had metastatic disease. Cancers included colon, pancreatic, liver, lung and gastric cancers, peritoneal mesothelioma and sarcoma.


Study design




Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsRotterdam, the Netherlands

[Bac et al., 1995]

Case-control

Hepatic ascites: 28Malignant ascites: 7Bacterial peritonitis: 5

Mean (SD):

Hepatic ascites: 54 (15)Malignant ascites: 58 (14)Bacterial peritonitis: 42 (17)

Hepatic ascites: 11 (39.3)Malignant ascites: 1 (14.3)Bacterial peritonitis: 3 (60.0)

Diagnosis and prognosisTo assess the diagnostic and prognostic value of various cytokines measured in plasma or ascitic fluid.


Hepatic ascites: 542 (719)Malignant ascites: 59 (604)Bacterial peritonitis: 1637 (907)

p not given.

Selection of controls described.


IL-6 measured 24 hrs after paracentesis.

IL-6 also measured in ascitic fluid, but only the serum IL-6 concentrations are cited here.

In malignant ascites group, all participants had metastatic disease. 2 had pancreatic cancer, 2 unknown primary cancers, 1 gastric cancer, 1 mesothelioma, 1 colon cancer and 1 leiomyosarcoma.

In hepatic ascites group 16 participants had alcoholic cirrhosis, 7 had hepatitis induces cirrhosis, 5 had primary biliary cirrhosis or sclerosing cholangitis and 4 had other liver diseases.


Study design


N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsMilan, Italy

[Lissoni et al., 1997]

Before-and-after

Lung cancer: 5Colon cancer: 3BC: 1Controls:Rheumatoid arthritis: 2Scleroderma: 2Primary biliary cirrhosis: 1

Median (range):


6 (42.9) Response to treatmentTo evaluate the effect of administration of melatonin on inflammatory markers in people with solid tumours or autoimmune diseases.


Solid cancers: 87 (7)Autoimmune diseases: 85 (6)

Participants were consecutive patients at the same clinic.



Yokohama, Japan

[Nomura et al., 1997]

Case-control

CRC: 12Gastric cancer: 7BC: 7Healthy controls: 5

Not cited. CRC: 3 (25.0)Gastric: 3 (42.9)Breast: 7 (100)Controls: 3 (60.0)

PrognosisTo clarify the changes in lipoprotein lipase activity, the effects of tumour removal on that activity and the role of IL-6 in advanced cancer.

Proportion of patients with detectable circulating Il-6:

All: 6/26CRC and gastric cancer: 4/19BC: 2/7

No relationship between lipoprotein activity and IL-6 was detected.



Cancer patients’ IL-6 measured before the onset of any treatment.

All patients had advanced cancer. From 10 patients whose tumours had been resected, blood samples were obtained 3-4 weeks after surgery when their CRP concentrations were normal.


Study design

N participants

Age of participants



Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsCagliari, Italy


Case-control


Median (range):

Cancer: 63 (47-70)

Not cited. Biological mechanismTo investigate the role of tumour-associated lymphocytes in neoplastic effusions and their role in host-tumour relationships.


Cancer with peritoneal effusions: 2 333 (164)Cancer with pleural effusions: 2 118 (193)Controls: 11 (9)All group comparisons p<0.001



Cancer patients had cancer so the ovary, breast, liver, bladder, pancreas, kidney and mesothelioma.

Heraklion, Greece

[Alexandrakis et al., 2000b]

Cross-sectional

Malignant ascites: 23Non-malignant ascites: 13Non-malignant transudates: 25

Median (range):


Malignant ascites: 19 (82.6)Non-malignant ascites: 5 (38.5)Non-malignant transudates: 10 (40.0)

Evaluating a diagnostic modelTo investigate the value of various proteins in serum and ascitic fluid in discriminating between malignant and non-malignant ascites in a diagnostic model.


Malignant ascites: 7.2 (4.58)Non-malignant ascites: 9.2 (6.55)Non-malignant transudates: 4.3 (3.20)

p for difference among groups = 0.0063

All participants were patients with ascites at the same hospital. Potential participants with sepsis were excluded.

No adjustment for potential confounders in the cited results. The final model tested adjusted for ascitic fluid concentrations of various inflammatory biomarkers.



Study design

N participants

Age of participants

N (%) female



Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsHeraklion, Greece


Case-control

Malignant effusions: 56Non-malignant effusions: 46Transudates: 43

Median (range):

Malignant: 62 (39-880Non-malignant: 57 (22-79)Transudates: 58 (45-86)

Malignant: 19 (34.0)Non-malignant: 14 (30.4)Transudates: 16 (37.2)

Diagnosis To investigate the diagnostic value of various biomarkers in differentiating benign and malignant serous effusions and their relationship with IL-6 concentrations in people with serous effusions.


Malignant: 9.29 (17.9)Non-malignant: 8.96 (6.2)Transudate: 4.05 (2.6)

p malignant vs. non-malignant <0.001p malignant vs. transudate <0.001

At cut-off of 72.1 fmol/ml, discriminating malignant effusions vs. transudates:Sensitivity: 89.3%Specificity: 88.4%Positive predictive value: 90.9%

Participants were consecutive hospital patients with various diseases.

Transudate = transudative effusion.

Possible partial duplicate publication of the study by the same group of investigators in 2000.

Cagliari, Italy


Case - control


Mean (range):

Cancer: 59.7 (35-80)Controls: 50.1 (27-75)

Cancer: 33 (40.2)Controls: 14 (38.9)

PrognosisTo investigate whether the antioxidant systems are dysregulated in cancer and whether this relates to disease progression.

Mean (SD) IL-6 pg/ml:

Cancer: 31.2 (30.2)Controls: 1 (2.5)p<0.001



Most common cancers were oral cavity, lung and kidney cancers.


Study design

N participants

Age of participants

N (%) female


Comments

Studies with other primary aims but containing IL-6 data on cancer patients and cancer-free individualsCagliari, Italy


Case-control


Mean (SD):

Cases: 61.0 (10.6)Controls: 55.0 (7.2)

Cases: 55 (45.8)Controls: 24 (40.0)

Metabolism To assess biological markers relevant to cancer cachexia in a population of advanced cancer patients.


Cancer: 27.2 (16.7)Controls: 4.1 (3.8)p<0.0001

Selection of healthy controls not described. Controls matched for age, sex and weight/height.


Participants had head and neck, ovarian, breast, lung or colorectal cancers.

Birmingham, UK


Case-control

Breast cancer: 30Prostate cancer: 30Healthy controls: 60

Mean (SD):

Breast cancer: 31 (12)Healthy female controls: 30 (11)Prostate cancer: 63.5 (7)Healthy male controls: 30 (14)



Breast cancer: 11 (5-15)Female controls: 5.5 (5-7.38)p=0.014

Prostate cancer: 8.25 (5-12.5)Male controls: 7.25 (5.75-7.88)p=0.405




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