A randomised controlled trial of post-operative radiotherapy following breast-conserving surgery in a minimum-risk population. Quality of life at 5 years in the PRIME trial

Inclusions

1. Age of ≥ 65 years, receiving adjuvant endocrine therapy.

2. Medically suitable to attend for all treatments and follow-up.

3. Histologically confirmed unilateral breast cancer of TNM stages T0–2, N0 and M0.

4. No axillary node involvement on histological assessment.

5. Had breast-conserving surgery with complete excision on histological assessment.

6. Able and willing to give informed consent.

Exclusions

1. Past history of pure in situ carcinoma of either breast or previous or concurrent malignancy within the past 5 years other than non-melanomatous skin cancer or carcinoma in situ of cervix.

2. Grade III cancer with lymphovascular invasion (LVI) (because of a higher risk of local recurrence).

Questionnaire-based measures

The questionnaires, sent to the patients after 3 and 5 years, were a shortened version of the questionnaire that had been completed with the research nurses. Both the EORTC scales (QLQ-C30 and QLQ-BR23)24,25 were retained, as were the Hospital Anxiety and Depression Scale (HADS)26 and the European Quality of Life-5 Dimensions (EQ-5D). 27 These measures are discussed in depth in the previous report. 21 The open questions ‘Could we again ask you to say in your own words how breast cancer is affecting you now?’ and ‘Apart from breast cancer, have there been any events since the last visit/questionnaire which have had a major impact on your life?’ remained, as did the opportunity to give any further information that patients felt was important.

It was decided to omit the Clackmannan Scale because of its complexity and the Barthel Index because of its known ceiling effects, which would become more extreme as patients hopefully returned to their normal living. In addition, several patients had commented that these functional indices needed updating to take into account changes in lifestyles, such as use of a washing machine and shopping home delivery services. As neither of these scales had been informative during the first 15 months following surgery, it was decided to exclude them.

The questions in the Philadelphia Geriatric Center Morale Scale were considered to be too vague by many patients, with the word ‘things’ (e.g. ‘Do things keep getting worse as you get older?’) highlighted by many patients as being too non-specific to be able to reply to the question meaningfully. As there had been no evidence to suggest that there was any difference between the treatment groups in this scale, we reasoned that it could be removed.

Clinical measures

No changes were made to the clinical measures of morbidity [Radiation Therapy Oncology Group (RTOG) scales] since the previous report. However, although data on lung and bone problems were requested, very few problems were recorded, and the data were considered to be unreliable, as few of the clinical tests required (e.g. chest X-ray to detect rib fractures) were performed. Therefore, these results will not be reported. It should be noted that the observers were clinicians and were not blinded to the randomisation.

Functioning

For the functioning scales, a higher score indicates a higher level of functioning. Mean differences have been calculated by taking the mean of the patients who received RT from the mean of the patients who did not receive RT (i.e. no RT – RT). Thus, a positive mean indicates that those patients who did not receive RT had, on average, higher levels of functionality, and vice versa. ‘Adjusted’ refers to the p-values following adjustment due to the Bonferroni correction. All CIs were calculated following adjustment.

Functionality (mean of physical, role, emotional, cognitive and social functioning)

Whereas at 15 months there was no evidence of a difference over time, by 5 years this difference is significant (p = 0.002, adjusted p = 0.22), and follows the downwards trend evidenced by many of the individual items that constitute this summary statistic (Figure 2). The fall in means was 4.7 units for those patients without RT and 2.6 units for those who received RT. There is still no evidence of a statistically significant difference between the treatments, however. The mean difference was –0.90 and the adjusted 95% CI was –5.97 to 4.17.

FIGURE 2.

Mean scores of functionality by questionnaire. SE, standard error.

Symptoms (mean of fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties)

An increase in score indicates an increase in symptoms. There was no evidence of a time or treatment effect (Figure 3). This did not differ from the results at 15 months. The mean difference was 0.80 and the 95% CI was –2.39 to 3.99.

FIGURE 3.

Mean scores of symptoms by questionnaire. SE, standard error.

Physical functioning

• Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase?

• Do you have any trouble taking a long walk?

• Do you have any trouble taking a short walk outside of the house?

• Do you have to stay in a bed or a chair during the day?

• Do you need help with eating, dressing, washing yourself or using the toilet?

There was a significant change over time (p < 0.0001, adjusted p < 0.0001), but no evidence of a treatment effect, in accord with what was seen in the previous report (Figure 4). The mean difference was –0.45 and the 95% CI was –5.63 to 4.74.

FIGURE 4.

Mean scores of physical functioning by questionnaire.

Role functioning

• Were you limited in doing either your work or other daily activities?

• Were you limited in pursuing your hobbies or other leisure-time activities?

As in the previous report,21 there was no evidence of a time or treatment effect. The overall mean score was 77.6, with a standard error (SE) of 0.8. The mean difference was –1.47, with a 95% CI of –10.89 to 7.95.

Emotional functioning

• Did you feel tense?

• Did you worry?

• Did you feel irritable?

• Did you feel depressed?

There was slight evidence to suggest a time (p = 0.04, adjusted p = 1.0) and treatment (p = 0.06, adjusted p = 1.0) effect (Figure 5). At 15 months, these were p = 0.07 and p = 0.12, respectively (adjusted p = 1.0 for both). However, this difference in treatment effect was still only of the order of approximately 4 units at 5 years, which is not large. Mean difference was –2.96 and the 95% CI was –8.57 to 2.64.

FIGURE 5.

Mean scores of emotional functioning by questionnaire.

Cognitive functioning

• Have you had difficulty concentrating on things like reading a newspaper or watching television?

• Have you had difficulty remembering things?

There was no evidence of a treatment effect, in accord with the previous report (Figure 6). 21 There was some slight evidence that cognitive functioning is declining over time, with a mean fall of 0.6 units per questionnaire (p = 0.04, adjusted p = 1.0), adjusted for baseline. Mean difference was –0.87 and the 95% CI was –6.48 to 4.73.

FIGURE 6.

Mean scores of cognitive functioning by questionnaire.

Social functioning

• Has your physical condition or medical treatment interfered with your family life?

• Has your physical condition or medical treatment interfered with your social life?

There were significant differences between the questionnaires (p = 0.0009, adjusted p = 0.10), but no evidence of a treatment effect (Figure 7). This was no different to the results at 15 months, although the suggestion is that the RT group may be one time point behind the no RT group. Mean difference was 0.018 and the 95% CI was –6.34 to 6.38.

FIGURE 7.

Mean scores of social functioning by questionnaire.

Quality of life

• How would you rate your health during the past week?

• How would you rate your overall quality of life during the past week?

There was no evidence of a time or treatment effect in overall quality of life, which was unchanged from the previous report (Figure 8). 21 The overall mean score was 70.4 with an SE of 0.5. Mean difference was 0.36 and the 95% CI was –5.09 to 5.81.

FIGURE 8.

Mean scores for quality of life by questionnaire.

For the following symptom scales, a higher score indicates a higher level of problems. As above, mean differences were calculated by subtracting the mean of the patients who received RT from the mean of the patients who did not receive RT (i.e. no RT – RT). Thus, a positive mean indicates that those patients who did not receive RT had, on average, higher levels of problems, and vice versa. ‘Adjusted’ refers to the p-values following adjustment due to the Bonferroni correction. All CIs were calculated following adjustment.

Fatigue

• Did you need to rest?

• Have you felt weak?

• Were you tired?

There were significant differences between the questionnaires (p = 0.01, adjusted p = 1.0), a feature that was not present at 15 months. Apart from the spike in fatigue immediately following RT, the irradiated group had consistently lower (but not significantly lower) levels of fatigue (Figure 9). Mean difference was 1.08 and the 95% CI was –5.57 to 7.72.

FIGURE 9.

Mean scores of fatigue by questionnaire.

Nausea and vomiting

• Have you felt nauseated?

• Have you vomited?

As before, there was no evidence of a time or treatment effect. The overall mean score was 3.6, with an SE of 0.3. Mean difference was –0.25 and the 95% CI was –2.72 to 2.23.

Pain

• Have you had pain?

• Did pain interfere with your daily activities?

There were significant differences between the time points (p = 0.002, adjusted p = 0.22), which have become more pronounced since the results at 15 months (p = 0.09, adjusted p = 1.0). There was still no evidence of a treatment difference and the pattern of change in the pain scores was very similar between treatment groups (Figure 10). Mean difference was 2.08 and the 95% CI was –5.74 to 9.90.

FIGURE 10.

Mean scores of pain by questionnaire.

Dyspnoea

• Were you short of breath?

There were significant differences over time (p < 0.0001, adjusted p < 0.0001), which have become more marked from 15 months (p = 0.07, adjusted p = 1.0). As before, there was no evidence of a difference between treatment groups (Figure 11). Mean difference was 2.77 and the 95% CI was –4.05 to 9.60.

FIGURE 11.

Mean scores of dyspnoea by questionnaire.

Insomnia

• Have you had trouble sleeping?

Differences between the treatment groups remained significant (p = 0.03, adjusted p = 1.0), although by 5 years the significance was lower than that at 15 months (p = 0.01, adjusted p = 1.0). This was most likely due to the lessening of the difference at 5 years, which was only 1.7 units at that point (Figure 12). Mean difference was 5.30 and the 95% CI was –3.56 to 14.16.

FIGURE 12.

Mean scores of insomnia by questionnaire.

Appetite loss

• Have you lacked appetite?

As before, there was no evidence of a time or treatment effect. The overall mean score was 9.5, with an SE of 0.5. Mean difference was 0.74 and the 95% CI was –4.64 to 6.13.

Constipation

• Have you been constipated?

Although there was no evidence of a time effect at 15 months, there was a significant difference at 5 years (p = 0.003, adjusted p = 0.29). There was a linear relationship between mean score and questionnaire, with an increase of 1.1 units per questionnaire. As at 15 months, there was no evidence of a treatment effect (Figure 13). Mean difference was –0.20 and the 95% CI was –7.88 to 7.48.

FIGURE 13.

Mean scores of constipation by questionnaire.

Diarrhoea

• Did you have diarrhoea?

As with constipation, there was no evidence of a time effect at 15 months, but there was a significant effect at 5 years (p = 0.01, adjusted p = 1.0). Unlike constipation, however, there was no evidence of a trend in any direction, and we suggest that it was an entirely spurious effect owing to the small number of patients reporting diarrhoea at any point. There was no evidence of a treatment effect, as before (Figure 14). Mean difference was –0.54 and the 95% CI was –3.82 to 2.73.

FIGURE 14.

Mean scores of diarrhoea by questionnaire.

Financial difficulties

• Has your physical condition or medical treatment caused you financial difficulties?

The difference between time points was significant at 5 years (p = 0.04, adjusted p = 1.0), having been not significant at 15 months (p = 0.09). This factor may have been demonstrating the same time-shift behaviour seen in social functioning, although the scores remained very low. There remained no evidence of a difference between treatments (Figure 15). Mean difference was 0.48 and the 95% CI was –2.20 to 3.16.

FIGURE 15.

Mean scores of financial difficulties by questionnaire.

Body image

• Have you felt physically less attractive as a result of your disease or treatment?

• Have you been feeling less feminine as a result of your disease or treatment?

• Did you find it difficult to look at yourself naked?

• Have you been dissatisfied with your body?

As with the results at 15 months, there was no evidence of a time or treatment effect. The overall mean score was 92.9, with an SE of 0.4. Mean difference was 0.01 and the 95% CI was –4.10 to 4.11.

Sexual functioning

• To what extent were you interested in sex over the last month?

• To what extent were you sexually active (with or without intercourse) over the last month?

As before, this question was optional, with patients given the choice on whether to answer any part of it. There was some slight evidence that there was a treatment difference (15 months p = 0.05, 5 years p = 0.07, adjusted p = 1.0 for both), but it must be remembered that not all patients answered this question, and interpretation of the result should be cautious (Figure 16). On average, per questionnaire, 118 patients who gave an answer at baseline answered these questions. The number of degrees of freedom used in the calculation of the 95% CI was 151. Mean difference was 2.93 and the 95% CI was –2.78 to 8.64.

FIGURE 16.

Mean scores of sexual functioning by questionnaire.

Sexual enjoyment

• To what extent was sex enjoyable for you?

This question was completed only if the patient had indicated that he or she had been sexually active. Of the patients who had answered this question at baseline, on average 14 answered this question per subsequent questionnaire. Only 17 degrees of freedom were available for this analysis. As with the results at 15 months, there was no evidence of a time or treatment effect. The overall mean score was 57.8, with an SE of 1.9. Mean difference was 3.93 and the 95% CI was –19.42 to 27.29.

Future perspective

• Were you worried about your health in the future?

In accordance with the results at 15 months, there was no evidence of a time or treatment effect. The overall mean score was 21.4, with an SE of 0.6. Mean difference was 1.54, and the 95% CI was –5.33 to 8.41.

Arm symptoms

• Did you have any pain in your arm or shoulder?

• Did you have a swollen arm or hand?

• Was it difficult to raise your arm or move it sideways?

Despite no significant differences over time at 15 months (p = 0.73), by 5 years a significant difference appeared (p = 0.01, adjusted p = 1.0; Figure 17). There was no evidence to suggest a difference in treatments (p = 0.22, adjusted p = 1.0). Mean difference was –1.69 and the 95% CI was –6.60 to 3.22.

FIGURE 17.

Mean scores of arm symptoms by questionnaire.

Breast symptoms

• Have you had any pain in the area of your affected breast?

• Was the area of your affected breast swollen?

• Was the area of your affected breast oversensitive?

• Have you had skin problems on or in the area of your affected breast

Although time and treatment remained significantly different (both p < 0.0001, adjusted treatment p = 0.003, adjusted time p < 0.0001), by 3 years the levels of breast symptoms were similar in both treatment groups, and they remained similar at 5 years (Figure 18). Mean difference was –5.27 and the 95% CI was –9.07 to –1.46.

FIGURE 18.

Mean scores of breast symptoms by questionnaire.

Systemic therapy side effects

• Did you have a dry mouth?

• Did food and drink taste different from usual?

• Were your eyes painful, irritated or watery?

• Have you lost any hair?

• Did you feel ill or unwell?

• Did you have hot flushes?

• Did you have headaches?

The differences between treatments have become less significant over time (up to 15 months p = 0.03, up to 5 years p = 0.07, both adjusted p = 1.0), most likely owing to the large difference at 15 months being mitigated by the smaller differences at later time points (Figure 19). There was no evidence of a time effect, however (p = 0.80). Mean difference was 2.00 and the 95% CI was –1.86 to 5.86.

FIGURE 19.

Mean systemic therapy side effect scores by questionnaire.

Hair loss

• Were you upset by the loss of your hair?

As with the sexual questions, very few patients answered this question. The mean scores were based only on those patients who acknowledged that they had encountered hair loss (Figure 20). Only 28 degrees of freedom were available for this analysis. Mean difference was –3.47 and the 95% CI was –24.52 to 17.59.

FIGURE 20.

Mean upset by hair loss scores by questionnaire.

If we include those patients who did not respond with any hair loss as being not upset by hair loss, then the mean difference was 0.06 and the 95% CI was –5.51 to 5.64. No variables were significant.

Cough

• Did you have a cough?

• (If yes) How much has it affected you?

As with hair loss and sexual enjoyment, only patients who answered ‘yes’ to the question ‘Did you have a cough?’ were included, so the degrees of freedom were 62. In accordance with the results at 15 months, there was no evidence of a time or treatment effect. The overall mean score was 37.1, with an SE of 1.2. Mean difference was 4.74 and the 95% CI was –15.53 to 25.02.

Anxiety

There was no evidence of a time (p = 0.09) or treatment (p = 0.16) effect (adjusted p = 1.0 for both). This did not differ from the results at 15 months. There was a suggestion that anxiety levels were lower in the RT group (Figure 21), but the difference was still not significant. Mean difference was 0.35 and the 95% CI was –0.55 to 1.26.

FIGURE 21.

Mean scores of anxiety by questionnaire.

It must be remembered that in order for anxiety to be considered a clinical issue, it must equal or exceed a score of 10. As can be seen in Table 6, there was no evidence of a difference over time (p = 0.37), and once we take into account the correlation due to the fact that the patients at each point were not independent, there was no evidence to suggest that there was a significant difference between treatments (p = 0.17).

Depression

As before, there was a significant change over time (p < 0.0001, adjusted p = 0.005). However, these differences are small (approximately 1 unit over 5 years), and are unlikely to be of clinical interest (Figure 22). There was no evidence of a difference between treatment groups (p = 0.78). Mean difference was –0.06 and the 95% CI was –0.88 to 0.75.

FIGURE 22.

Mean scores of depression by questionnaire.

As with anxiety, depression becomes clinically important only if the score is ≥ 10. As can be seen from Table 7, there were very few patients with significant depression. There was no evidence to suggest that there was a difference between treatments (p = 0.84), with only a weak suggestion that there was a difference over time (p = 0.07, adjusted p = 1.0).

Breast oedema

An abnormal collection of fluid in the tissues, causing a puffy swelling (Figure 24).

FIGURE 24.

Percentage of patients with oedema score > 0.

1. 0: None

2. 1: Asymptomatic

3. 2: Symptomatic

4. 3: Secondary dysfunction.

Only one patient recorded a score of 3, which was reported at 8 months and from a patient treated with RT. Across all time points, patients who received RT had < 5% of scores > 1 (other than at 8 months, 6.3%), with only 1% of scores > 1 for those patients who did not receive RT.

It is not unexpected to see continued evidence of breast oedema as late as 4 and 5 years after surgery.

Telangiectasia

The formation of a lesion in the breast consisting of a number of dilated capillaries which have a web-like appearance. The categories are based on the size of area affected (Figure 25).

FIGURE 25.

Percentage of patients with telangiectasia score > 0.

1. 0: None

2. 1: < 1 cm²

3. 2: 1–4 cm²

4. 3: > 4 cm².

As would be expected, only patients who received RT had any scores of 3, ranging from 0% to 3.5% (at 24 months). There were two scores of 2 in the no RT group, at 48 and 60 months. Telangiectasia is a morbidity that would be expected to increase over time, although it is odd that there was evidence of the lesion in the no RT group.

Fibrosis

A measure of the formation of fibrous connective tissue in the breast (Figure 26).

FIGURE 26.

Percentage of patients with fibrosis score > 0.

1. 0: None

2. 1: Barely palpable increased density

3. 2: Definite increased density and firmness

4. 3: Very marked density, retraction and fixation.

There were two patients with a score of 3, both in the RT group, at 24 months and 36 months. There were also comparatively few scores of 2 in the no RT group (mean of 1.3% vs 12%). Although fibrosis is generally due to RT, there may be a surgical component. Despite the high levels of fibrosis still evident at 5 years, it appeared to be diminishing.

Retraction/Atrophy

A wasting of the tissues, pulling back from the wound. Again, the categories are based on the proportion of the breast affected (Figure 27).

FIGURE 27.

Percentage of patients with retraction/atrophy score > 0.

1. 0: None

2. 1: 10%–25%

3. 2: > 25%–40%

4. 3: > 40%–75%

5. 4: Whole breast.

Only one score of 3 was recorded for retraction/atrophy, at 24 months for an RT patient. The number of patients with scores of ≥ 2 was similar between the treatment groups (0.8% with no RT vs 1.2% with RT). As above, it is possible that some of the retraction was due to surgical procedures.

Ulcer

A region where there is a breach in the continuity of the epithelium.

1. 0: None

2. 1: Epidermal only, ≤ 1 cm²

3. 2: Dermal, > 1 cm²

4. 3: Subcutaneous

5. 4: Bone exposed, necrosis.

Very few patients were reported to have developed an ulcer. Of those treated with no RT, there was a record of one patient with an ulcer at 24 months, and another at 36 months. Of those treated with RT, there was one ulcer at 8 months and another at 48 months. These were all singular and were for four different patients.

Pain management

Records the actions taken to resort to control any breast pain that the patients may have experienced (Figure 28).

FIGURE 28.

Percentage of patients with pain management score > 0.

1. 0: None

2. 1: Occasional non-narcotic

3. 2: Regular non-narcotic

4. 3: Regular narcotic

5. 4: Surgical intervention.

The sole record of a score of 3 was from a patient who was not treated with RT and occurred at 48 months.

Causes of death (up to 5 years)

• Radiotherapy (n = 13):

  1. – breast cancer: 3

  2. – other cancer: 1 (second primary, believed related to breast cancer)

  3. – intercurrent disease: 9.

• No RT (n = 16):

  1. – breast cancer: 5

  2. – other cancer: 3

  3. – intercurrent disease: 8.

Endocrine therapy effects

Figure 33 illustrates the finding of no significant difference between groups at the 3- and 5-year questionnaires. This is in contrast to our earlier findings where the RT group offered considerably fewer comments about endocrine side effects. In general, the number of comments diminished as time progressed, although a significant proportion (approximately 40%) of patients would have very recently discontinued tamoxifen or other endocrine therapy by the 5-year questionnaire completion time.

FIGURE 33.

Percentage of patients reporting negative physical effects due to endocrine therapy by questionnaire.

At 3 years, 2% of patients reported some emotionally negative effect as a consequence of hormone therapy, which had reduced to 1% by 5 years. No differences between the groups were evident.

In addition, at 3 years 7% of the RT and 1% of the no RT group commented on complications from therapy such as abnormal liver function or allergy which had resulted in the treatment being terminated or replaced by an alternative. By 5 years, 2% in the RT and none in the control group remarked on treatment complications.

Radiotherapy

No specific comments about ongoing effects of RT were made in either the 3- or 5-year postal questionnaires.

Fatigue

At 3 years none of the responses in either group were about fatigue or tiredness, while at 5 years 3% in the RT group and 4% in the no RT group mentioned this symptom (Figure 34). This does not tally with the results of the fatigue score in the EORTC QLQ-C30 scale.

FIGURE 34.

Percentage of patients reporting fatigue by questionnaire.

Concern about cancer recurrence

Gradually fewer patients voluntarily expressed such concerns at 3 and 5 years (Figure 35). No significant difference between the groups was found.

FIGURE 35.

Percentage of patients expressing concerns about recurrence by questionnaire.

Anxiety about the process of clinical follow-up

As time progressed, the difference between groups was not as marked as in the earlier questionnaires (Figure 36). As before, this trend reflects the proportions expressing concerns about cancer recurrence.

FIGURE 36.

Percentage of patients expressing anxiety about clinical follow-up.

Other breast cancer effects

Other topics that occurred only up to 3 years and in < 5% of patients in either group were:

• the negative impact that the media had on the women

• a change in life perspective as a result of breast cancer

• experiencing discomfort from wearing a bra.

Functionality

In the first report we observed no difference between treatment groups in the mean values of overall functionality (physical, role, emotional, cognitive and social functioning) at 15 months. 21 However, between 3 and 5 years there was a decline in the mean global scores of functioning. This is likely to reflect the impact of ageing on the older population under study. Given that no difference was seen at 15 months, and that there is no statistically significant difference in score between groups, we think it highly unlikely that the decline was in any way related to RT treatment.

Physical functioning

The decline from baseline continued beyond 15 months. Again we believe that this was due to the ageing process and was broadly in line with what would be expected over a period of 5 years in this age group. 34 There was no evidence of a treatment effect.

Emotional functioning

There was a small change in emotional functioning between 15 months and 5 years. However, the treatment effect was extremely small and we did not consider it to be clinically significant.

Cognitive functioning

Between 15 months and 5 years there was further decline in cognitive functioning. There was no evidence of a treatment effect and we believe that the pattern was related to the ageing process, again broadly similar to the reference data. 34

Fatigue

Fatigue is a well-recognised feature of post-operative WBRT. Its severity and intensity are highly variable. Some patients experience no fatigue after RT, while others experience prolonged fatigue over months and sometimes years. Its pathogenesis is unclear. For the first 15 months we found no evidence of a time, treatment or time by treatment effect. Beyond 15 months we observed significant differences in fatigue between questionnaires, although once adjusted for multiple testing these differences were no longer significant. The irradiated group had consistently, but not statistically significantly lower levels of fatigue. However, there was still no evidence of a treatment effect. The upwards trend in fatigue is again probably related to ageing and progressive acquisition of new comorbidities or exacerbation of existing ones.

Dyspnoea

Greater levels of dyspnoea were observed between 15 months and 5 years than before 15 months. Again there was no evidence of a treatment effect. Any late radiation-induced lung toxicity would have manifested itself by 15 months. This trend was likely to be due to new or existing comorbidities such as anaemia or cardiac or pulmonary disease.

Insomnia

One of the most intriguing findings in our original report was the higher level of insomnia in the non-irradiated group. This was statistically significant. It is noteworthy that this difference persists to 5 years even though the difference is less than at 15 months, although following adjustment with Bonferroni’s correction, this is no longer statistically significant. We speculated in our initial report that this might have been due to greater concern among non-irradiated patients that breast cancer might recur. As this difference disappears following adjustment, it is possible that this result is merely an artefact of multiple testing.

Financial difficulties

In our first report21 we observed no time-related difference in the reporting of financial difficulties. However, with longer-term follow-up, there was slight evidence of a time effect, although the size of the differences was very small, and not significant following adjustment. There remained no evidence of a treatment effect. The increase in financial difficulties might be related to greater costs of personal care as a result of acquisition of more comorbidities and the erosion of older patients’ financial resources with the passage of time. The findings are relevant to cancer support services such as Macmillan Cancer Support in estimating the additional financial support these older patients with breast cancer may require.

Arm symptoms

Despite no difference between the trial arms at 15 months, there is a suggestion of a time, but not treatment effect by 5 years (unadjusted only). We think that this is likely to be related to the acquisition of musculoskeletal comorbidities such as osteoarthritis or rheumatoid arthritis with age (see Table 11).

Breast symptoms

The decline in breast symptoms in both arms of the trial seen at 15 months continues up to 5 years. This probably reflects the settling of breast symptoms seen after surgery. Sharp pains in the breast known to be related to surgery usually settle by 2 years after surgery. RT-related pain is also likely to have settled by 5 years in the majority of patients. A significant difference between the treatment options is still evident following adjustment for multiple testing.

Systemic therapy side effects

In our initial report21 we observed a significantly higher level of side effects of endocrine systemic therapy in the no RT group, although by 5 years this difference is no longer statistically significant. By the final questionnaire, 40% of patients had recently discontinued endocrine therapy, as per protocol. We speculated in the previous report that this might have been due to the greater attention given to irradiated patients in addressing these toxicities during review during RT, but this is not a reasonable explanation in the long term.

Most patients had been receiving adjuvant endocrine therapy for 5 years from the time of surgery. Some of the patients had changed endocrine therapy during the follow-up period, most commonly owing to intolerance of the first endocrine agent, which may be the reason for the lessening of the side effects over time.

Anxiety

We did not observe any time or treatment effect in relation to anxiety up to 15 months. The same is true up to 5 years. There was a slightly lower level of anxiety among irradiated patients, although this was not statistically significant. We might speculate that this difference was due to higher degrees of anxiety about recurrence in non-irradiated patients. However, the population under study was at low risk of recurrence and this would have been explained to patients at entry to the trial. Levels of anxiety about recurrence even in the non-irradiated group may persist over time, but are likely to be modest. There was, however, no statistical evidence of a treatment effect.

Depression

At 15 months we observed a small time-related increase in depression in both arms of the trial. This trend continued up to 5 years, and was significant even following adjustment for multiple testing. There remained no evidence of a treatment effect. Other life events such as the acquisition of comorbidities and bereavement become increasingly common with advancing age and may in large part explain this continuing trend.

Breast oedema

There was a progressive decline in clinical reports of breast oedema in both irradiated and non-irradiated patients. At 5 years, < 5% of irradiated patients reported oedema scores > 1. These findings are compatible with the expected resolution of these symptoms between 3 and 5 years.

Breast fibrosis

Levels of breast fibrosis were predictably higher in the irradiated group up to 15 months. It is well recognised that breast fibrosis plateaus around 3 years after RT. 35 Our results show that between 15 months and 5 years, clinical reporting of breast fibrosis declined. This may reflect the stabilisation of this clinical feature.

Impact of local recurrence

In the first 5 years after randomisation, six patients (2.4% of the trial accrual of 255 patients) developed a local recurrence, all in the non-irradiated arm of the trial. Recurrence is likely to have an adverse affect on the quality of life of patients, particularly if they were randomised to RT, as a further course of RT is not possible and the surgical option is then mastectomy. However, the numbers of patients with local recurrence were very small and have not had any impact on the difference in quality of life of patients at 3 and 5 years after surgery.

In the low-risk group of patients included in the PRIME trial, it is likely that the annual risk of ipsilateral breast tumour recurrence will be about 0.5%, similar to that reported in the British Association of Surgical Oncology (BASO) trial. 36

Survival

At the time of the most recent analysis (2010) there had been 16 deaths in the no RT group and 13 in the RT group by 5 years. The majority of these were from causes unrelated to breast cancer (20/29), with deaths considered to be related to breast cancer split equally between the group who were randomised to receive RT (4/13) and those who were not to receive RT (5/16). This emphasises, as observed in the Cancer and Leukemia Group B (CALBG) trial evaluating the omission of breast RT in low-risk older patients receiving adjuvant tamoxifen,19 that competing risks of non-breast cancer mortality are significant in the older age group.

Patient view of longer-term effects of breast cancer

It is noteworthy that the proportion of open comments confirming that patients were no longer affected by concerns about breast cancer had increased to > 70% by 5 years, and was similar in both groups.

Endocrine therapy

At 3 years, endocrine therapy side effects were the most frequently volunteered comments. By 5 years, the proportion of women reporting side effects was smaller, but had still not disappeared completely. This may have been due to recent discontinuation of endocrine therapy, or was possibly the result of patients changing treatment to a hormone with fewer side effects.

Radiotherapy

No spontaneous comments about persisting side effects of RT were mentioned by any of the irradiated patients at 3 or 5 years. This is in keeping with the resolution of RT-related symptoms reported earlier in the discussion.

Other major impacting events

Comorbidity was the most commonly cited life-impacting event at 3 and 5 years after surgery. This was mentioned by nearly 30% of patients in both arms of the trial. These observations are consistent with the increased comorbidities on which we commented earlier.

Comorbidity

Women with breast cancer and three or more comorbid conditions have a 20-fold higher rate of mortality from causes other than breast cancer, and a fourfold higher rate of all-cause mortality than patients who have no comorbid conditions. 37

In our previous report,21 we documented comorbidities at baseline and categorised them according to the Charlson list. We did not attempt to assess the severity of comorbidities at baseline or those subsequently acquired. We did, however, add some new categories of comorbidities (for example, visual difficulties, urinary incontinence). For the purpose of this analysis, we have recategorised the baseline and subsequent comorbidities to identify categories most likely to affect quality of life.

An important general finding was that patients with longer follow-up expressed more concerns about comorbidities than about breast cancer. This probably reflects adjustment to breast cancer on longer-term follow-up and the reality of experiencing more comorbidities with advancing age.

Primary recommendation for further research

1. Further economic modelling on the longer-term costs and consequences of omitting RT.

Secondary recommendations

1. There are clear indications that there is a short-term economic benefit from the omission of RT in this group of patients. However, the evidence for the longer-term benefit requires longer follow-up to determine local recurrence rates with and without post-operative WBRT.

2. Investigate the application of novel methodologies (such as touch-screen technology) for capturing and grading comorbidity and quality of life at baseline and at clinical follow-up.

3. Investigate the influence of specific types and degrees of comorbid disease on quality of life.

4. Refine methodologies and develop software to integrate the prediction of recurrence rates from breast cancer with the competing effects of mortality from other diseases to improve clinical decision-making.

5. Develop a validated questionnaire/scale to assess the impact of access to health-care services for older patients.

Prioritisation Group

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Professor Imti Choonara, Professor in Child Health, Academic Division of Child Health, University of Nottingham

   Chair – Pharmaceuticals Panel

3. Dr Bob Coates, Consultant Advisor – Disease Prevention Panel

4. Dr Andrew Cook, Consultant Advisor – Intervention Procedures Panel

5. Dr Peter Davidson, Director of NETSCC, Health Technology Assessment

6. Dr Nick Hicks, Consultant Adviser – Diagnostic Technologies and Screening Panel, Consultant Advisor–Psychological and Community Therapies Panel

7. Ms Susan Hird, Consultant Advisor, External Devices and Physical Therapies Panel

8. Professor Sallie Lamb, Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick

   Chair – HTA Clinical Evaluation and Trials Board

9. Professor Jonathan Michaels, Professor of Vascular Surgery, Sheffield Vascular Institute, University of Sheffield

   Chair – Interventional Procedures Panel

10. Professor Ruairidh Milne, Director – External Relations

11. Dr John Pounsford, Consultant Physician, Directorate of Medical Services, North Bristol NHS Trust

    Chair – External Devices and Physical Therapies Panel

12. Dr Vaughan Thomas, Consultant Advisor – Pharmaceuticals Panel, Clinical

    Lead – Clinical Evaluation Trials Prioritisation Group

13. Professor Margaret Thorogood, Professor of Epidemiology, Health Sciences Research Institute, University of Warwick

    Chair – Disease Prevention Panel

14. Professor Lindsay Turnbull, Professor of Radiology, Centre for the MR Investigations, University of Hull

    Chair – Diagnostic Technologies and Screening Panel

15. Professor Scott Weich, Professor of Psychiatry, Health Sciences Research Institute, University of Warwick

    Chair – Psychological and Community Therapies Panel

16. Professor Hywel Williams, Director of Nottingham Clinical Trials Unit, Centre of Evidence-Based Dermatology, University of Nottingham

    Chair – HTA Commissioning Board

    Deputy HTA Programme Director

HTA Commissioning Board

1. Professor of Dermato-Epidemiology, Centre of Evidence-Based Dermatology, University of Nottingham

2. Professor of General Practice, Department of Primary Health Care, University of Oxford Programme Director,

3. Professor of Clinical Pharmacology, Director, NIHR HTA programme, University of Liverpool

1. Professor Ann Ashburn, Professor of Rehabilitation and Head of Research, Southampton General Hospital

2. Professor Deborah Ashby, Professor of Medical Statistics and Clinical Trials, Queen Mary, Department of Epidemiology and Public Health, Imperial College London

3. Professor Peter Brocklehurst, Director, National Perinatal Epidemiology Unit, University of Oxford

4. Professor John Cairns, Professor of Health Economics, London School of Hygiene and Tropical Medicine

5. Professor Peter Croft, Director of Primary Care Sciences Research Centre, Keele University

6. Professor Jenny Donovan, Professor of Social Medicine, University of Bristol

7. Professor Jonathan Green, Professor and Acting Head of Department, Child and Adolescent Psychiatry, University of Manchester Medical School

8. Professor John W Gregory, Professor in Paediatric Endocrinology, Department of Child Health, Wales School of Medicine, Cardiff University

9. Professor Steve Halligan, Professor of Gastrointestinal Radiology, University College Hospital, London

10. Professor Freddie Hamdy, Professor of Urology, Head of Nuffield Department of Surgery, University of Oxford

11. Professor Allan House, Professor of Liaison Psychiatry, University of Leeds

12. Dr Martin J Landray, Reader in Epidemiology, Honorary Consultant Physician, Clinical Trial Service Unit, University of Oxford

13. Professor Stephen Morris, Professor of Health Economics, University College London, Research Department of Epidemiology and Public Health, University College London

14. Professor E Andrea Nelson, Professor of Wound Healing and Director of Research, School of Healthcare, University of Leeds

15. Professor John David Norris, Chair in Clinical Trials and Biostatistics, Robertson Centre for Biostatistics, University of Glasgow

16. Dr Rafael Perera, Lecturer in Medical Statisitics, Department of Primary Health Care, University of Oxford

17. Professor James Raftery, Chair of NETSCC and Director of the Wessex Institute, University of Southampton

18. Professor Barney Reeves, Professorial Research Fellow in Health Services Research, Department of Clinical Science, University of Bristol

19. Professor Martin Underwood, Warwick Medical School, University of Warwick

20. Professor Marion Walker, Professor in Stroke Rehabilitation, Associate Director UK Stroke Research Network, University of Nottingham

21. Dr Duncan Young, Senior Clinical Lecturer and Consultant, Nuffield Department of Anaesthetics, University of Oxford

22. Professor Stephen Morris, Professor of Health Economics, University College London, Research Department of Epidemiology and Public Health, University College London

23. Professor E Andrea Nelson, Professor of Wound Healing and Director of Research, School of Healthcare, University of Leeds

24. Professor John David Norris Chair in Clinical Trials and Biostatistics, Robertson Centre for Biostatistics, University of Glasgow

25. Dr Rafael Perera, Lecturer in Medical Statisitics, Department of Primary Health Care, University of Oxford

26. Professor James Raftery, Chair of NETSCC and Director of the Wessex Institute, University of Southampton

27. Professor Barney Reeves, Professorial Research Fellow in Health Services Research, Department of Clinical Science, University of Bristol

28. Professor Martin Underwood, Warwick Medical School, University of Warwick

29. Professor Marion Walker, Professor in Stroke Rehabilitation, Associate Director UK Stroke Research Network, University of Nottingham

30. Dr Duncan Young, Senior Clinical Lecturer and Consultant, Nuffield Department of Anaesthetics, University of Oxford

1. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

HTA Clinical Evaluation and Trials Board

1. Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick and Professor of Rehabilitation, Nuffield Department of Orthopaedic, Rheumatology and Musculoskeletal Sciences, University of Oxford

2. Professor of the Psychology of Health Care, Leeds Institute of Health Sciences, University of Leeds

3. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

1. Professor Keith Abrams, Professor of Medical Statistics, Department of Health Sciences, University of Leicester

2. Professor Martin Bland, Professor of Health Statistics, Department of Health Sciences, University of York

3. Professor Jane Blazeby, Professor of Surgery and Consultant Upper GI Surgeon, Department of Social Medicine, University of Bristol

4. Professor Julia M Brown, Director, Clinical Trials Research Unit, University of Leeds

5. Professor Alistair Burns, Professor of Old Age Psychiatry, Psychiatry Research Group, School of Community-Based Medicine, The University of Manchester & National Clinical Director for Dementia, Department of Health

6. Dr Jennifer Burr, Director, Centre for Healthcare Randomised trials (CHART), University of Aberdeen

7. Professor Linda Davies, Professor of Health Economics, Health Sciences Research Group, University of Manchester

8. Professor Simon Gilbody, Prof of Psych Medicine and Health Services Research, Department of Health Sciences, University of York

9. Professor Steven Goodacre, Professor and Consultant in Emergency Medicine, School of Health and Related Research, University of Sheffield

10. Professor Dyfrig Hughes, Professor of Pharmacoeconomics, Centre for Economics and Policy in Health, Institute of Medical and Social Care Research, Bangor University

11. Professor Paul Jones, Professor of Respiratory Medicine, Department of Cardiac and Vascular Science, St George‘s Hospital Medical School, University of London

12. Professor Khalid Khan, Professor of Women’s Health and Clinical Epidemiology, Barts and the London School of Medicine, Queen Mary, University of London

13. Professor Richard J McManus, Professor of Primary Care Cardiovascular Research, Primary Care Clinical Sciences Building, University of Birmingham

14. Professor Helen Rodgers, Professor of Stroke Care, Institute for Ageing and Health, Newcastle University

15. Professor Ken Stein, Professor of Public Health, Peninsula Technology Assessment Group, Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth

16. Professor Jonathan Sterne, Professor of Medical Statistics and Epidemiology, Department of Social Medicine, University of Bristol

17. Mr Andy Vail, Senior Lecturer, Health Sciences Research Group, University of Manchester

18. Professor Clare Wilkinson, Professor of General Practice and Director of Research North Wales Clinical School, Department of Primary Care and Public Health, Cardiff University

19. Dr Ian B Wilkinson, Senior Lecturer and Honorary Consultant, Clinical Pharmacology Unit, Department of Medicine, University of Cambridge

1. Ms Kate Law, Director of Clinical Trials, Cancer Research UK

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

Diagnostic Technologies and Screening Panel

1. Scientific Director of the Centre for Magnetic Resonance Investigations and YCR Professor of Radiology, Hull Royal Infirmary

2. Professor Judith E Adams, Consultant Radiologist, Manchester Royal Infirmary, Central Manchester & Manchester Children’s University Hospitals NHS Trust, and Professor of Diagnostic Radiology, University of Manchester

3. Mr Angus S Arunkalaivanan, Honorary Senior Lecturer, University of Birmingham and Consultant Urogynaecologist and Obstetrician, City Hospital, Birmingham

4. Dr Stephanie Dancer, Consultant Microbiologist, Hairmyres Hospital, East Kilbride

5. Dr Diane Eccles, Professor of Cancer Genetics, Wessex Clinical Genetics Service, Princess Anne Hospital

6. Dr Trevor Friedman, Consultant Liason Psychiatrist, Brandon Unit, Leicester General Hospital

7. Dr Ron Gray, Consultant, National Perinatal Epidemiology Unit, Institute of Health Sciences, University of Oxford

8. Professor Paul D Griffiths, Professor of Radiology, Academic Unit of Radiology, University of Sheffield

9. Mr Martin Hooper, Public contributor

10. Professor Anthony Robert Kendrick, Associate Dean for Clinical Research and Professor of Primary Medical Care, University of Southampton

11. Dr Anne Mackie, Director of Programmes, UK National Screening Committee, London

12. Mr David Mathew, Public contributor

13. Dr Michael Millar, Consultant Senior Lecturer in Microbiology, Department of Pathology & Microbiology, Barts and The London NHS Trust, Royal London Hospital

14. Mrs Una Rennard, Public contributor

15. Dr Stuart Smellie, Consultant in Clinical Pathology, Bishop Auckland General Hospital

16. Ms Jane Smith, Consultant Ultrasound Practitioner, Leeds Teaching Hospital NHS Trust, Leeds

17. Dr Allison Streetly, Programme Director, NHS Sickle Cell and Thalassaemia Screening Programme, King’s College School of Medicine

18. Dr Alan J Williams, Consultant Physician, General and Respiratory Medicine, The Royal Bournemouth Hospital

1. Dr Tim Elliott, Team Leader, Cancer Screening, Department of Health

2. Dr Catherine Moody, Programme Manager, Medical Research Council

3. Professor Julietta Patrick, Director, NHS Cancer Screening Programme, Sheffield

4. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

5. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

6. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Disease Prevention Panel

1. Professor of Epidemiology, University of Warwick Medical School, Coventry

2. Dr Robert Cook, Clinical Programmes Director, Bazian Ltd, London

3. Dr Colin Greaves, Senior Research Fellow, Peninsula Medical School (Primary Care)

4. Mr Michael Head, Public contributor

5. Professor Cathy Jackson, Professor of Primary Care Medicine, Bute Medical School, University of St Andrews

6. Dr Russell Jago, Senior Lecturer in Exercise, Nutrition and Health, Centre for Sport, Exercise and Health, University of Bristol

7. Dr Julie Mytton, Consultant in Child Public Health, NHS Bristol

8. Professor Irwin Nazareth, Professor of Primary Care and Director, Department of Primary Care and Population Sciences, University College London

9. Dr Richard Richards, Assistant Director of Public Health, Derbyshire Country Primary Care Trust

10. Professor Ian Roberts, Professor of Epidemiology and Public Health, London School of Hygiene & Tropical Medicine

11. Dr Kenneth Robertson, Consultant Paediatrician, Royal Hospital for Sick Children, Glasgow

12. Dr Catherine Swann, Associate Director, Centre for Public Health Excellence, NICE

13. Professor Carol Tannahill, Glasgow Centre for Population Health

14. Mrs Jean Thurston, Public contributor

15. Professor David Weller, Head, School of Clinical Science and Community Health, University of Edinburgh

1. Ms Christine McGuire, Research & Development, Department of Health

2. Dr Kay Pattison Senior NIHR Programme Manager, Department of Health

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

External Devices and Physical Therapies Panel

1. Consultant Physician North Bristol NHS Trust

2. Reader in Wound Healing and Director of Research, University of Leeds

3. Professor Bipin Bhakta, Charterhouse Professor in Rehabilitation Medicine, University of Leeds

4. Mrs Penny Calder, Public contributor

5. Dr Dawn Carnes, Senior Research Fellow, Barts and the London School of Medicine and Dentistry

6. Dr Emma Clark, Clinician Scientist Fellow & Cons. Rheumatologist, University of Bristol

7. Mrs Anthea De Barton-Watson, Public contributor

8. Professor Nadine Foster, Professor of Musculoskeletal Health in Primary Care Arthritis Research, Keele University

9. Dr Shaheen Hamdy, Clinical Senior Lecturer and Consultant Physician, University of Manchester

10. Professor Christine Norton, Professor of Clinical Nursing Innovation, Bucks New University and Imperial College Healthcare NHS Trust

11. Dr Lorraine Pinnigton, Associate Professor in Rehabilitation, University of Nottingham

12. Dr Kate Radford, Senior Lecturer (Research), University of Central Lancashire

13. Mr Jim Reece, Public contributor

14. Professor Maria Stokes, Professor of Neuromusculoskeletal Rehabilitation, University of Southampton

15. Dr Pippa Tyrrell, Senior Lecturer/Consultant, Salford Royal Foundation Hospitals’ Trust and University of Manchester

16. Dr Sarah Tyson, Senior Research Fellow & Associate Head of School, University of Salford

17. Dr Nefyn Williams, Clinical Senior Lecturer, Cardiff University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

3. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Interventional Procedures Panel

1. Professor of Vascular Surgery, University of Sheffield

2. Consultant Colorectal Surgeon, Bristol Royal Infirmary

3. Mrs Isabel Boyer, Public contributor

4. Mr David P Britt, Public contributor

5. Mr Sankaran ChandraSekharan, Consultant Surgeon, Breast Surgery, Colchester Hospital University NHS Foundation Trust

6. Professor Nicholas Clarke, Consultant Orthopaedic Surgeon, Southampton University Hospitals NHS Trust

7. Ms Leonie Cooke, Public contributor

8. Mr Seamus Eckford, Consultant in Obstetrics & Gynaecology, North Devon District Hospital

9. Professor David Taggart, Consultant Cardiothoracic Surgeon, John Radcliffe Hospital

10. Professor Sam Eljamel, Consultant Neurosurgeon, Ninewells Hospital and Medical School, Dundee

11. Dr Adele Fielding, Senior Lecturer and Honorary Consultant in Haematology, University College London Medical School

12. Dr Matthew Hatton, Consultant in Clinical Oncology, Sheffield Teaching Hospital Foundation Trust

13. Dr John Holden, General Practitioner, Garswood Surgery, Wigan

14. Professor Nicholas James, Professor of Clinical Oncology, School of Cancer Sciences, University of Birmingham

15. Dr Fiona Lecky, Senior Lecturer/Honorary Consultant in Emergency Medicine, University of Manchester/Salford Royal Hospitals NHS Foundation Trust

16. Dr Nadim Malik, Consultant Cardiologist/ Honorary Lecturer, University of Manchester

17. Mr Hisham Mehanna, Consultant & Honorary Associate Professor, University Hospitals Coventry & Warwickshire NHS Trust

18. Dr Jane Montgomery, Consultant in Anaesthetics and Critical Care, South Devon Healthcare NHS Foundation Trust

19. Professor Jon Moss, Consultant Interventional Radiologist, North Glasgow Hospitals University NHS Trust

20. Dr Simon Padley, Consultant Radiologist, Chelsea & Westminster Hospital

21. Dr Ashish Paul, Medical Director, Bedfordshire PCT

22. Dr Sarah Purdy, Consultant Senior Lecturer, University of Bristol

23. Professor Yit Chiun Yang, Consultant Ophthalmologist, Royal Wolverhampton Hospitals NHS Trust

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Pharmaceuticals Panel

1. Professor in Child Health, University of Nottingham

2. Senior Lecturer in Clinical Pharmacology, University of East Anglia

3. Dr Martin Ashton-Key, Medical Advisor, National Commissioning Group, NHS London

4. Mr John Chapman, Public contributor

5. Dr Peter Elton, Director of Public Health, Bury Primary Care Trust

6. Dr Peter Elton, Director of Public Health, Bury Primary Care Trust

7. Dr Ben Goldacre, Research Fellow, Division of Psychological Medicine and Psychiatry, King’s College London

8. Dr James Gray, Consultant Microbiologist, Department of Microbiology, Birmingham Children’s Hospital NHS Foundation Trust

9. Ms Kylie Gyertson, Oncology and Haematology Clinical Trials Manager, Guy’s and St Thomas’ NHS Foundation Trust London

10. Dr Jurjees Hasan, Consultant in Medical Oncology, The Christie, Manchester

11. Dr Carl Heneghan Deputy Director Centre for Evidence-Based Medicine and Clinical Lecturer, Department of Primary Health Care, University of Oxford

12. Dr Dyfrig Hughes, Reader in Pharmacoeconomics and Deputy Director, Centre for Economics and Policy in Health, IMSCaR, Bangor University

13. Dr Maria Kouimtzi, Pharmacy and Informatics Director, Global Clinical Solutions, Wiley-Blackwell

14. Professor Femi Oyebode, Consultant Psychiatrist and Head of Department, University of Birmingham

15. Dr Andrew Prentice, Senior Lecturer and Consultant Obstetrician and Gynaecologist, The Rosie Hospital, University of Cambridge

16. Ms Amanda Roberts, Public contributor

17. Dr Martin Shelly, General Practitioner, Silver Lane Surgery, Leeds

18. Dr Gillian Shepherd, Director, Health and Clinical Excellence, Merck Serono Ltd

19. Mrs Katrina Simister, Assistant Director New Medicines, National Prescribing Centre, Liverpool

20. Professor Donald Singer Professor of Clinical Pharmacology and Therapeutics, Clinical Sciences Research Institute, CSB, University of Warwick Medical School

21. Mr David Symes, Public contributor

22. Dr Arnold Zermansky, General Practitioner, Senior Research Fellow, Pharmacy Practice and Medicines Management Group, Leeds University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Mr Simon Reeve, Head of Clinical and Cost-Effectiveness, Medicines, Pharmacy and Industry Group, Department of Health

3. Dr Heike Weber, Programme Manager, Medical Research Council

4. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

5. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Psychological and Community Therapies Panel

1. Professor of Psychiatry, University of Warwick, Coventry

2. Consultant & University Lecturer in Psychiatry, University of Cambridge

3. Professor Jane Barlow, Professor of Public Health in the Early Years, Health Sciences Research Institute, Warwick Medical School

4. Dr Sabyasachi Bhaumik, Consultant Psychiatrist, Leicestershire Partnership NHS Trust

5. Mrs Val Carlill, Public contributor

6. Dr Steve Cunningham, Consultant Respiratory Paediatrician, Lothian Health Board

7. Dr Anne Hesketh, Senior Clinical Lecturer in Speech and Language Therapy, University of Manchester

8. Dr Peter Langdon, Senior Clinical Lecturer, School of Medicine, Health Policy and Practice, University of East Anglia

9. Dr Yann Lefeuvre, GP Partner, Burrage Road Surgery, London

10. Dr Jeremy J Murphy, Consultant Physician and Cardiologist, County Durham and Darlington Foundation Trust

11. Dr Richard Neal, Clinical Senior Lecturer in General Practice, Cardiff University

12. Mr John Needham, Public contributor

13. Ms Mary Nettle, Mental Health User Consultant

14. Professor John Potter, Professor of Ageing and Stroke Medicine, University of East Anglia

15. Dr Greta Rait, Senior Clinical Lecturer and General Practitioner, University College London

16. Dr Paul Ramchandani, Senior Research Fellow/Cons. Child Psychiatrist, University of Oxford

17. Dr Karen Roberts, Nurse/Consultant, Dunston Hill Hospital, Tyne and Wear

18. Dr Karim Saad, Consultant in Old Age Psychiatry, Coventry and Warwickshire Partnership Trust

19. Dr Lesley Stockton, Lecturer, School of Health Sciences, University of Liverpool

20. Dr Simon Wright, GP Partner, Walkden Medical Centre, Manchester

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Expert Advisory Network

1. Professor Douglas Altman, Professor of Statistics in Medicine, Centre for Statistics in Medicine, University of Oxford

2. Professor John Bond, Professor of Social Gerontology & Health Services Research, University of Newcastle upon Tyne

3. Professor Andrew Bradbury, Professor of Vascular Surgery, Solihull Hospital, Birmingham

4. Mr Shaun Brogan, Chief Executive, Ridgeway Primary Care Group, Aylesbury

5. Mrs Stella Burnside OBE, Chief Executive, Regulation and Improvement Authority, Belfast

6. Ms Tracy Bury, Project Manager, World Confederation of Physical Therapy, London

7. Professor Iain T Cameron, Professor of Obstetrics and Gynaecology and Head of the School of Medicine, University of Southampton

8. Professor Bruce Campbell, Consultant Vascular & General Surgeon, Royal Devon & Exeter Hospital, Wonford

9. Dr Christine Clark, Medical Writer and Consultant Pharmacist, Rossendale

10. Professor Collette Clifford, Professor of Nursing and Head of Research, The Medical School, University of Birmingham

11. Professor Barry Cookson, Director, Laboratory of Hospital Infection, Public Health Laboratory Service, London

12. Dr Carl Counsell, Clinical Senior Lecturer in Neurology, University of Aberdeen

13. Professor Howard Cuckle, Professor of Reproductive Epidemiology, Department of Paediatrics, Obstetrics & Gynaecology, University of Leeds

14. Professor Carol Dezateux, Professor of Paediatric Epidemiology, Institute of Child Health, London

15. Mr John Dunning, Consultant Cardiothoracic Surgeon, Papworth Hospital NHS Trust, Cambridge

16. Mr Jonothan Earnshaw, Consultant Vascular Surgeon, Gloucestershire Royal Hospital, Gloucester

17. Professor Martin Eccles, Professor of Clinical Effectiveness, Centre for Health Services Research, University of Newcastle upon Tyne

18. Professor Pam Enderby, Dean of Faculty of Medicine, Institute of General Practice and Primary Care, University of Sheffield

19. Professor Gene Feder, Professor of Primary Care Research & Development, Centre for Health Sciences, Barts and The London School of Medicine and Dentistry

20. Mr Leonard R Fenwick, Chief Executive, Freeman Hospital, Newcastle upon Tyne

21. Mrs Gillian Fletcher, Antenatal Teacher and Tutor and President, National Childbirth Trust, Henfield

22. Professor Jayne Franklyn, Professor of Medicine, University of Birmingham

23. Mr Tam Fry, Honorary Chairman, Child Growth Foundation, London

24. Professor Fiona Gilbert, Consultant Radiologist and NCRN Member, University of Aberdeen

25. Professor Paul Gregg, Professor of Orthopaedic Surgical Science, South Tees Hospital NHS Trust

26. Bec Hanley, Co-director, TwoCan Associates, West Sussex

27. Dr Maryann L Hardy, Senior Lecturer, University of Bradford

28. Mrs Sharon Hart, Healthcare Management Consultant, Reading

29. Professor Robert E Hawkins, CRC Professor and Director of Medical Oncology, Christie CRC Research Centre, Christie Hospital NHS Trust, Manchester

30. Professor Richard Hobbs, Head of Department of Primary Care & General Practice, University of Birmingham

31. Professor Alan Horwich, Dean and Section Chairman, The Institute of Cancer Research, London

32. Professor Allen Hutchinson, Director of Public Health and Deputy Dean of ScHARR, University of Sheffield

33. Professor Peter Jones, Professor of Psychiatry, University of Cambridge, Cambridge

34. Professor Stan Kaye, Cancer Research UK Professor of Medical Oncology, Royal Marsden Hospital and Institute of Cancer Research, Surrey

35. Dr Duncan Keeley, General Practitioner (Dr Burch & Ptnrs), The Health Centre, Thame

36. Dr Donna Lamping, Research Degrees Programme Director and Reader in Psychology, Health Services Research Unit, London School of Hygiene and Tropical Medicine, London

37. Professor James Lindesay, Professor of Psychiatry for the Elderly, University of Leicester

38. Professor Julian Little, Professor of Human Genome Epidemiology, University of Ottawa

39. Professor Alistaire McGuire, Professor of Health Economics, London School of Economics

40. Professor Neill McIntosh, Edward Clark Professor of Child Life and Health, University of Edinburgh

41. Professor Rajan Madhok, Consultant in Public Health, South Manchester Primary Care Trust

42. Professor Sir Alexander Markham, Director, Molecular Medicine Unit, St James’s University Hospital, Leeds

43. Dr Peter Moore, Freelance Science Writer, Ashtead

44. Dr Andrew Mortimore, Public Health Director, Southampton City Primary Care Trust

45. Dr Sue Moss, Associate Director, Cancer Screening Evaluation Unit, Institute of Cancer Research, Sutton

46. Professor Miranda Mugford, Professor of Health Economics and Group Co-ordinator, University of East Anglia

47. Professor Jim Neilson, Head of School of Reproductive & Developmental Medicine and Professor of Obstetrics and Gynaecology, University of Liverpool

48. Mrs Julietta Patnick, Director, NHS Cancer Screening Programmes, Sheffield

49. Professor Robert Peveler, Professor of Liaison Psychiatry, Royal South Hants Hospital, Southampton

50. Professor Chris Price, Director of Clinical Research, Bayer Diagnostics Europe, Stoke Poges

51. Professor William Rosenberg, Professor of Hepatology and Consultant Physician, University of Southampton

52. Professor Peter Sandercock, Professor of Medical Neurology, Department of Clinical Neurosciences, University of Edinburgh

53. Dr Philip Shackley, Senior Lecturer in Health Economics, Sheffield Vascular Institute, University of Sheffield

54. Dr Eamonn Sheridan, Consultant in Clinical Genetics, St James’s University Hospital, Leeds

55. Dr Margaret Somerville, Director of Public Health Learning, Peninsula Medical School, University of Plymouth

56. Professor Sarah Stewart-Brown, Professor of Public Health, Division of Health in the Community, University of Warwick, Coventry

57. Dr Nick Summerton, GP Appraiser and Codirector, Research Network, Yorkshire Clinical Consultant, Primary Care and Public Health, University of Oxford

58. Professor Ala Szczepura, Professor of Health Service Research, Centre for Health Services Studies, University of Warwick, Coventry

59. Dr Ross Taylor, Senior Lecturer, University of Aberdeen

60. Dr Richard Tiner, Medical Director, Medical Department, Association of the British Pharmaceutical Industry

61. Mrs Joan Webster, Consumer Member, Southern Derbyshire Community Health Council

62. Professor Martin Whittle, Clinical Co-director, National Co-ordinating Centre for Women’s and Children’s Health, Lymington