Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Postma et al., 2012

Type of study: Cross-sectional follow-up study

Setting: 2 tertiary referral Hospitals in Groningen and Nijmegen (UMCG and UMCN)

Country: The Netherlands

Source of funding: not funded

Inclusion criteria:

-  Patients in UMCG or UMCN diagnosed with acromegaly

-  Aged between 20-75 years

-  Still actively followed at endocrine outpatient clinics

-  Last treatment and QoL assessment at least 12 months

-  Participation in UMCG in 2005 and UMCN in 2008 and 2009

-  Surgery between 1975 and 2008

N total at baseline: 164, 108 returned questionnaires

Intervention: SST+ 41

Control: SST- 67, of which 38 were cured after surgery

Important prognostic factors:

Age at diagnosis ± SD:

I= SST+: 40.6 ± 11.3

C=SST-:42.2 ±10.6

Age at study ± SD:

I= SST+: 54.8 ± 11.6

C=SST-:53.6 ±11.2

Sex:

I: M/F=24/15

C: M/F=23/44

RT I:17/41 and C: 29/43

Groups comparable at baseline? Gender significantly differed (0,014)

Trend toward more thyroid hormone substitution in the SST+ group

SST

No SST

Length of follow-up:

-          Last treatment and QoL assessment at least 12 months

RR: 66%

Outcome measures:

QoL- questionnaires RAND-36, MFI-20, HADS, AcroQoL scores

SST+ reported poorer scores on five out of eight subscales of the RAND-36 and on all subscales of MFI-20. Scores of the ACROQoL were worse in SST+ patients

Subgroup analysis in patients with an IGF-1 SDS between +1,5 and -1: SST+ n=26 and SST- N=44

SST+ subgroup analysis worse scores on physical functioning, physical fatigue,  reduces activity, vitality and general health perception across all HR-QoL questionnaires

Multivariate analysis: SST+ and female gender highly significantly associated with worse scores on the Acro-QoL

RT not associated with worse scores on Acro-QoL

Level of evidence C (effect of radiotherapy was not aim of the study)

Paisley et al, 2007

Type of study:

Longitudinal Follow-up study

Setting: re-evaluation of original study in UK

Country: UK

Source of funding: none declared

Inclusion criteria:

Patients treated for acromegaly that participated in previous study.

Exclusion criteria:

-

N total at baseline:

Baseline: n= 56, of which surgery + RT N=29

Re-evaluation: n = 56, of which surgery +RT N=30

Important prognostic factors:

Age:

baseline: 55.4 ±  4.8

re-evaluation: 53.8 ± 14.5

Sex:

M=33/F23

Groups comparable at baseline? Yes, except for IGF-I level

n.a.

n.a.

Length of follow-up: median time 608 days

Loss-to-follow-up:

Intervention: 56

N (%) 56/80

Reasons (describe) unknown

Outcome measures

AcroQOL, PGWB, SSS and EQ-5D at baseline and after median time interval of 608 days

difference in QOL between baseline and follow-up

Subgroup analysis: Prior RT did not influence the change in QOL associated with change in IGF-levels

95%CI and p-value for the effect of RT on QoL is lacking

Level of evidence C (effect of radiotherapy was not aim of the study)

Kauppinen-Makelin et al., 2006

Type of study:

Follow-up study

Setting: all 5 university hospitals in Finland

Country: Finland

Source of funding: none declared

Inclusion criteria:

Patients:

-  Patients with acromegaly    diagnosed from Jan         1980-dec 1999

-  Over 15 years of age

-  In live 2000-2001

Controls:

Representative sample (age, gender) of the general population in the Finnish national Health Survey (1995/1996)

Exclusion criteria:

-  Died before 2002

N total at baseline:

Patients: 333 patients

Of participating 231 patients 31,6% RT

Controls: 3759 patients

Important prognostic factors:

age: 57.3 ± 11,9

Years after initial treatment: 11.4 ± 5.7 years

Age at diagnosis: 45.8 ± 11,9 years

Sex:

Patients:  M 103/ F 128

Hypopit 24,2% (n=231)

More common among patients treated with RT (47.4 vs 12.6%, P<0.001)

Groups comparable at baseline? yes

n.a.

n.a.

Length of follow-up: 20 years

Loss-to-follow-up:

42/333 patients died before the end of 2000 and 14 in 2001 and 2002

- 46/277 patients did not participate.

Outcome measure:

HR-QoL by 15 D instrument

Clinically important difference in overall score 0,03 or greater

Total 15 HR-QoL score of participants was lower than in the age and gender matched general population (0,858 vs. 0,929, P<0,001 and clinically important.

Multivariate analysis, better HRQoL predicted by not having had RT (P<0.004, 95% CI 1,49-8,44; OR 0,44)

Conventional RT 2D

Level of evidence C (effect of radiotherapy was not aim of the study)

Biermasz et al., 2005

Type of study: cohort study

Setting: tertiary referral center (LUMC, Leiden)

Country: the Netherlands

Source of funding: none declared

Inclusion criteria:

-  All acromegaly patients    treated and currently    followed in the centre

-  In long term-remission or    strictly controlled

N total at baseline: N=118

Important prognostic factors:

age ± SD: 58,6 ± 12,9

Sex:

I: M/F= 61M/57F

Primary therapy:

TSS n=108

RT: n=2

Octreotide: n=7

Pituitary apoplexy: n=1

All 118 patients were considered in remission based on glucose-suppressed serum GH, random GH and IGF-1

Mean duration 12.0 ± 7.4 years

Pituitary insufficiency in 40% of  patients.

Irradiated patients had a higher frequency of hypopituitarism than irradiated patients: 76 vs. 23, P<0.001

n.a.

n.a.

Length of follow-up:

RR=90% 118/131

Loss-to-follow-up:

Intervention:

N (%) 7 refused participation, 6 no response

Overall RR 95%

Outcome measures:

Quality of life assessment including 4 general health questionnaires (HADS, SF-36, MFI-20and NHP as well as  the Acro-QoL questionnaire

Univariate linear regression analysis: RT was a significant independent factor for some quality of life parameters: reduced physical function (SF-36) p=0,045) general fatigue and  reduced motivation (MVI-20) P= respectively  0.025 and 0.007, as well as reduced anxiety (HADS) P=0.04

Only univariate regression analysis

Level of evidence C (non-comparative  study)

Biermasz, et al., 2004

Type of study:

Cohort study

Setting: tertiary referral center (LUMC, Leiden)

Country: the Netherlands

Source of funding: none declared

Inclusion criteria:

-  All patients with cured    acromegaly based on    recent biochemical    evaluation and currently    followed in LUMC

-  Primarily treated with    SSA and additionally    occasionally with RT or    SST-analogues

Exclusion criteria:

N total at baseline:

Intervention: 131 (RR 90%)à118

Control: provided by patients extended with literature ref data on healthy controls (RR53%)à N=83

Important prognostic factors:

age ± SD:

patients:58.6 ± 12.9 (29-89) years

controls:56.8 ± 13.5 years

Sex:

pts: 61M/57F

ctrls: 36M/47F

Primary therapy:

TSS n=108

RT: n=2

Octreotide: n=7

Pituitary apoplexy: n=1

All 118 patients were considered in remission based on glucose-suppressed serum GH, random GH and IGF-1

Mean duration 12.0 +/- 7,4 years.

Pituitary insufficiency in 40% of  patients.

Irradiated patients had a higher frequency of hypopituitarism than irradiated patients: 76 vs. 23, P<0.001

Groups comparable at baseline?

Age  and sex not different

n.a.

n.a.

Length of follow-up:

RR=95%--> n=118

Loss-to-follow-up:

Intervention:

N (%) 7

Reasons (describe) refused to participate

Control:

N (%) RR 53%

Reasons (describe) none described

Outcome measures: Quality of life assessment including 4 general health

questionnaires (HADS, SF-36, MFI-20and NHP as well as  the Acro-QoL questionnaire

rradiated patients performed significantly worse than non-irradiated patients on general fatigue and reduced motivation scales (P=0.043 and P=0.011 respectively).

Linear regression analysis: irradiated patients had a worse score on the  SF-36 the general fatigue and reduced motivation scale (MFI-20) and energy and physical mobility scales of the NHP.

RT is associated with a reduced quality of life: RT affects quality of life , especially in general fatigue and performance scales

Conventional 2D RT

Level of evidence C (effect of radiotherapy was not aim of the study)

Rowles et al., 2005

Type of study:

Cohort study

Setting: Christie hospital

Country: UK

Source of funding: none declared

Inclusion criteria

English speaking patients

Attending for routine care at Christie hospital

Exclusion criteria:

?

N total at baseline:

Patients: N=80

Controls; population based normative data

 Important prognostic factors:

Age: 54.2 (range 20-84)

Sex:  M 43/F 37

Years from diagnosis mean 9.5 (range 20-84)

Previous  treatment of acromegaly:

Surgery n=10 (12,5%)

RT n=11 (13,8%)

Surgery +RT n 46 (53,8%)

Neither n=16 (20%)

n.a.

n.a.

Outcome measures:

Quality of life assessment including 4 questionnaires (PGWB, SSS, EoroQoL and Acro-QoL questionnaire)

Comparison with population based normative data patients with acromegaly score significantly worse on general health, vitality and total QoL (p=0.05)

Stepwise linear regression identified a history of prior RT to be associated with worse QoL (P<0.05)

RR unknown

Level of evidence C

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Van Aken et al., 2005

Type of study: Cohort study

Setting:  tertiary referral Hospital in Leiden (LUMC)

Country: The Netherlands

Source of funding: not funded

Inclusion criteria:

-  Living patients diagnosed with Cushing disease between 1978 and 2002

-  Treated in LUMC by TSS and occasionally additional therapy

-  Considered cured

N total at baseline:

Patients: n= 81 of whom 63 were considered cured

Controls: same sex and age distribution and from same geographical area recruited by participating patients (n=98)

As well as age-adjusted mean reference values collected from the literature for the used questionnaires.

Important prognostic factors:

Age ± SD:

I= 51.7 ± 15.2years

C=52.5 ± 13.3 years

Sex:

I : M/F=10/48

C: M/F=23/75

All participating patients underwent TSS (N=58)

Additional RT N=11 (19%)

Bilateral adrenelectomy N=3

Hypopit N=30 (52%)

Mean duration of remission 13.4 ± 6.7 years

Groups comparable at baseline?

Age and  sex were not different between patients and controls

n.a.

n.a.

RR: 95% (n=59)

Length of follow-up: 13.4 +/-6.7 years

Loss-to-follow-up: one patient refused to participate in the study

Intervention:

Patients n=58/ Controls n=98

Outcome measures:

QoL- questionnaires: SF-36, MFI-20, NHP and HADS.

All Cushing patients had a reduced QoL judged by all questionnaires and all assessed items compared to reference values from the literature

Patients who underwent RT did not report worse QoL than patients that were not irradiated.

Univariate Linear regression analysis: RT was not a significant independent predictor in any of the items of the QoL questionnaires.

Conventional RT unspecified

Level of evidence C

Tiemensma et al., 2011

Type of study:

Cross-sectional study

Setting:  tertiary referral Hospital in Leiden (LUMC)

Country: The Netherlands

Source of funding: no specific funding received

Inclusion criteria:

-  Patients with Cushing disease

-  > 18 years

-  remission defined by strict biochemical criteria for at least 1 year

Exclusion criteria:

-

N total at baseline:

Patients: n= 52

Control: reference population of other studies: N=349

Important prognostic factors:

All in remission for at least one year

age ± SD:

P: 55.4 ± 4.8;

Sex:

P: 7M 45F;

Groups comparable at baseline?

Yes, except for IGF-I level

n.a.

n.a.

RR= 68%

Length of follow-up:

Loss-to-follow-up:

Intervention: N=25 (32%)

Reasons (describe) refused participation

RT=27%

Outcome measures:

IPQ-R, QoL-questionnaires; physical symptom checklist, EuroQoL-5D, Cushing QoL

no differences between patients treated by different modalities including RT

Level of evidence C (effect of radiotherapy was not aim of the study)

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Nielsen et al., 2007

Type of study: cohort study

Setting:

Country: Denmark

Source of funding: supported by grants from the Aarhus University hospital research initiative and the Obel family Foundation, Aalborg, Denmark.

Inclusion criteria:

-  Pituitary surgery for clinically non-functioning pituitary adenoma from 1 January 1985 to December 31, 1996.

-  Radiologically present suprasellar tumor

Exclusion criteria:

-  Pituitary surgery or radiotherapy before 1985

-  Cushing disease, Acromegaly and prolactinoma.

N total at baseline: 192

Important prognostic factors:

Sex and age:

M: n= 116 (mean age 55.8, range 16,3-83,4)

F: n= 76 (mean age 52.4, range 17.8-81.1)

Transsphenoidal approach: n=160 (83,3%)

Craniotomy: n=31 (17%)

RT: N=42 (22%)

146 (76%) underwent one operation

Controls: Danisch reference population

Groups comparable at baseline? NA

n.a.

n.a.

Length of follow-up:

-  Median for surviving patients 13,1 years (range 8-20 years)

-  Median follow-up for patients who had died 4,6 years (range 0-18,6 years)

Loss-to-follow-up:

53 patients had died (34 men, 19 women)

4 patients refused to participate

RR 81% (N=109)

2 patients only completed the SF-36

Outcome measures:

QoL- questionnaires SF-36, MDI-10

Patients who had undergone craniotomy scored significantly worse on metal health (P=0,007) and mental component score (P=0,02) as well as had a significantly higher MDI-score than patients who had been operated transsphenoidally

Multivariate regression analysis: Radiotherapy was not an independent risk factor for reduced physical function

Conventional RT (45Gy) in 42 patients (22%) of which two for cancer unrelated to the pituitary adenoma

Level of evidence C (effect of radiotherapy was not aim of the study)

Van Beek et al, 2007

Type of study:

Cohort-study

Setting: large tertiary referral centre (UMCG, Groningen)

Country: the Netherlands

Source of funding: none declared

Inclusion criteria:

-  Histologically proven NFA

-  Between 20 and 70 years of age

-  Interval between last treatment and the quality of life assessment was at least 12 months

-  Still actively followed at the endocrine outpatient clinic

-  Patients who received primary surgical treatment in UMCG between Jan 1963 and Jan 2005

N total at baseline:

Intervention: 90, RR90%--> 81

Important prognostic factors²:

age ± SD: 55 ± 10 years

Intervention RT+:

Age:  58 (32-70) years

Age at prim treatment: 43 (13-67) years

Control RT-:

Age: 56 (34-70) years

Age at prim treatment: 50 (16-17) years

Sex:

M=49/F=23;

Transsphenoidally: n=62

Craniotomy: n=19

Second surgical intervention: n=14

46/81 received RT

Average time between surgery and RT was 8 months

Groups comparable at baseline? Patients who underwent RT more frequently had a craniotomy (n=16 vs. 3), were younger at the time of surgery (p=0.000) and their duration of follow-up was younger (p=0,008). They also used more hormonal substitution, significantly more in the case of thyroid hormone (P 0,049).

Current age, social status, level of education, type of employment (part-time or fulltime), social security benefit and comorbidity were similar.

RT+ group

RT- group

Length of follow-up:

RT+= 12 (1-43) years

RT-=  4 (1-30) years

RR: 90%

Loss-to-follow-up:

10% not responded

Outcome measure

RAND-36, MFI-20, HADS, Cognitive failure questionnaire

Most HR-QoL domains showed a similar score in the RT= and RT- groups.

Physical functioning (ES 0,44, vitality ( ES 0,47), mood (HADS-depression) (ES 0.56) and physical and mental fatigue (MFI-20) (both ES 0,54) were reported to be significantly worse in RT- patients.

No differences in cognitive function were observed.

In Rt- group

-  social functioning, vitality and general health perception (domains from RAND 36) significantly lower than in reference population.

In RT+ group

- general health perception was worse than in the  age-matched control population

- physical functioning and pain (RAND 36) and anxiety (HADS) were better

No differences in QoL were observed related to age (at primary treatment), prim surgical operation route, or second surgical intervention. Hormonal substitution had also no effect on HR-QoL

Multivariate analysis:

RT, sex, cortisol substitution, IGF-1 z-score <-2 and a second pituitary operation were independent determinants of quality of live (RAND 36).

Improved RAND-scores were seen in patients that received RT (physical functioning and vitality) ES 0,4-06

+

Conventional RT Mode of RT unspecified

Level of evidence B

Dekkers et al., 2006

Type of study:

Case-control-study

Setting: University hospital, Leiden, LUMC

Country: the Netherlands

Source of funding: none declared

Inclusion criteria P:

-  Patients with NFMA diagnosed between Jan 1985 and 2004

Inclusion criteria C:

-  Controls provided by patients from the same geographical area of comparable age, sex and socioeconomic status

N total at baseline:

I: 116/128

C: 66 provided patients, extended by controls to total of 125 patients

Important prognostic factors:

age ± SD:

I: 61.9, range 24-86 years

Age at diagnosis 50,7 ± 11.7

C: 61.5, range 26-86 years

Sex:

I:  M/F= 54/ 45

C:  M/F= 66/59

Groups comparable at baseline? Yes, for age and gender

n.a.

n.a.

RR= 91%

Loss-to-follow-up:

17 patients refused to participate

12 patients did not respond

Outcome measures:

HADS, MFI-20, NHP, SF-36

RT, visual field defects and GH deficiency were not found to be independent predictors for reduced QoL in any of the questionnaires.

Small subgroup analysis by means of linear regression

Conventional RT, Mode of RT unspecified

Level of evidence C (effect of radiotherapy was not aim of the study)