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Background Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. Aims In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. Methods We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Results Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42); p = 0.0004). Conclusion Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Data access statement Anonymized summary data may be requested from the corresponding author.

The Nottingham Prognostic Index Plus (NPI+) is a clinical decision making tool in breast cancer (BC) that aims to provide improved patient outcome stratification superior to the traditional NPI. This study aimed to validate the NPI+ in an independent series of BC. Eight hundred and eighty five primary early stage BC cases from Edinburgh were semi-quantitatively assessed for 10 biomarkers [Estrogen Receptor (ER), Progesterone Receptor (PgR), cytokeratin (CK) 5/6, CK7/8, epidermal growth factor receptor (EGFR), HER2, HER3, HER4, p53, and Mucin 1] using immunohistochemistry and classified into biological classes by fuzzy logic-derived algorithms previously developed in the Nottingham series. Subsequently, NPI+ Prognostic Groups (PGs) were assigned for each class using bespoke NPI-like formulae, previously developed in each NPI+ biological class of the Nottingham series, utilising clinicopathological parameters: number of positive nodes, pathological tumour size, stage, tubule formation, nuclear pleomorphism and mitotic counts. Biological classes and PGs were compared between the Edinburgh and Nottingham series using Cramer's V and their role in patient outcome prediction using Kaplan-Meier curves and tested using Log Rank. The NPI+ biomarker panel classified the Edinburgh series into seven biological classes similar to the Nottingham series (p > 0.01). The biological classes were significantly associated with patient outcome (p 0.01). The good PGs were similarly validated in Luminal B, Basal p53 normal, HER2+/ER- tumours and the poor PG in the Luminal N class (p > 0.01). Due to small patient numbers assigned to the remaining PGs, Luminal N, Luminal B, Basal p53 normal and HER2+/ER- classes could not be validated. This study demonstrates the reproducibility of NPI+ and confirmed its prognostic value in an independent cohort of primary BC. Further validation in large randomised controlled trial material is warranted.

Background and Purpose— The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the incidence, characteristics, and outcome of lobar and nonlobar ICH. Methods— In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335. Results— There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.8 [95% confidence interval, 7.7–12.4] versus 8.6 [95% confidence interval, 6.7–11.1] per 100 000 adults/y). At baseline, adults with lobar ICH were more likely to have preceding dementia (21% versus 5%; P =0.01), lower Glasgow Coma Scale scores (median, 13 versus 14; P =0.03), larger ICHs (median, 38 versus 11 mL; P P P =0.02) than those with nonlobar ICH. One-year case fatality was lower after lobar ICH than after nonlobar ICH (adjusted odds ratio for death at 1 year: lobar versus nonlobar ICH 0.21; 95% confidence interval, 0.07–0.63; P =0.006, after adjustment for known predictors of outcome). There were 4 recurrent ICHs, which occurred exclusively in survivors of lobar ICH (annual risk of recurrent ICH after lobar ICH, 11.8%; 95% confidence interval, 4.6%–28.5% versus 0% after nonlobar ICH; log-rank P =0.04). Conclusions— The baseline characteristics and outcome of lobar ICH differ from other locations.

Purpose To investigate conventional prognostic factors for ipsilateral breast tumor recurrence (IBTR), distant metastasis (DM), and survival after breast-conserving therapy (BCT) in screen-detected and symptomatic cases on surveillance up to 25 years. Patients and Methods A total of 1812 consecutive patients in three cohorts (1981–1989, 1990–1992, and 1993–1998) with T12N01M0 invasive breast cancer were treated with BCT (median follow-up, 14 years). Tumor type and grade were reviewed by a single pathologist. Hormone receptor status was measured by immunohistochemistry on tissue microarrays. A Cox proportional hazards model was used to assess independent prognostic variables for relapse and survival. Results A total of 205 IBTR occurred, with 5-, 10-, 15-, and 20-year actuarial relapse rates of 4.5% (95% confidence interval [CI] 3.35–5.5%), 8.4% (95% CI 7.1–9.8%), 14.1% (95% CI 12.0–16%), and 17.4% (95% CI 14.5–20.2%). Number of nodes, young age, pathologic tumor size, and multifocality were significant factors for IBTR. Three hundred seventy-eight patients developed DM. The actuarial metastatic rate was 12% at 5 years and 17.9% at 10 years. Young age, number of positive nodes, pathologic tumor size, and tumor grade were significant factors for DM relapse. When conventional prognostic indices were taken into account screen-detected cancers showed no improvement in overall relapse or survival rate compared with symptomatic cases but did show a reduced risk of DM after IBTR. After 10 years IBTR relapse continued at a constant rate of 0.87% per annum. Conclusions The Edinburgh BCT series has shown that screen-detected invasive breast cancers do not have significantly different clinical outcomes compared with symptomatic cases when pathologic risk factors are taken into account. This suggests that these patients be managed in a similar way.

We present a review of 111 patients who were treated over an initial 3-year period with erlotinib. The median treatment time was 68 days and 59% of patients had stopped treatment within the first 3 months. However, 20 patients were on erlotinib for more than 12 months. Performance status and smoking history were the significant prognostic factors. The overall 3-year survival in patients who had never smoked was 26%.

Aims: To assess the validity of grading in the Edinburgh Breast Conservation Series; a consecutive cohort of 1812 early breast cancer patients treated by breast conservation and radiotherapy between 1981 and 1998 in a single specialist centre with ≥9 years’ follow-up and full staging data. Methods and results: A single pathologist (J.St.J.T) graded 1650 cases using the Elston and Ellis method (EE) with particular reference to the component data: acinar differentiation, nuclear pleomorphism and mitotic counts. The original method was then compared with binary scoring of the same components and the relationship to prognosis reassessed. EE grades and individual grade components were prognostic (P

Purpose The aim of this study was to investigate the potential benefits of prolonged treatment with neoadjuvant letrozole. Patients and Methods About 182 consecutive patients have been treated in Edinburgh with neoadjuvant letrozole for 3 months or longer and 63 patients have continued on letrozole beyond 3 months. Outcomes are reported. Results Of the 63 patients who continued on letrozole, 38 patients took letrozole for more than 1 year and 23 took letrozole for more than 24 months. The median reduction in clinical volume in the first 3 months in these 63 patients was 52%. Similar reductions in median clinical volume were seen between three to 6 months (50%), 6–12 months and 12–24 months (medians 37 and 33%, respectively). At 3 months 69.8% of the 182 patients had a partial or complete response. The response rate increased to 83.5% with prolonged letrozole treatment. Continuing letrozole beyond 3 months increased the number of women who initially required mastectomy or had locally advanced breast cancer who were subsequently suitable for breast conserving surgery from 60% (81/134) at 3 months to 72% (96/134). Thirty-three women remain on letrozole alone (man age at diagnosis 83 years) and at 3 years the median time to treatment failure has not been reached. Conclusion Continuing letrozole in responding patients beyond 3–4 months achieves further clinical reduction in tumour size. For elderly women with a short life expectancy letrozole alone may provide long-term disease control.

Purpose: Neoadjuvant androgen deprivation and radical radiotherapy is an established treatment for localized prostate carcinoma. This study sought to analyze the outcomes of patients treated with relatively low-dose hypofractionated radiotherapy. Methods and Materials: Three hundred patients with T1–T3 prostate cancer were treated between 1996 and 2001. Patients were prescribed 3 months of neoadjuvant androgen deprivation before receiving 5250 cGy in 20 fractions. Patients’ case notes and the oncology database were used to retrospectively assess outcomes. Median follow-up was 58 months. Results: Patients presented with prostate cancer with poorer prognostic indicators than that reported in other series. At 5 years, the actuarial cause-specific survival rate was 83.2% and the prostate-specific antigen (PSA) relapse rate was 57.3%. Metastatic disease had developed in 23.4% of patients. PSA relapse continued to occur 5 years from treatment in all prognostic groups. Independent prognostic factors for relapse included treatment near the start of the study period, neoadjuvant oral anti-androgen monotherapy rather than neoadjuvant luteinizing hormone releasing hormone therapy, and diagnosis through transurethral resection of the prostate rather than transrectal ultrasound. Conclusion: This is the largest reported series of patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy in the United Kingdom. Neoadjuvant hormonal therapy did not appear to adequately compensate for the relatively low effective radiation dose used.

Aims The aim of this retrospective analysis was to review the outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre over the past 15 years, and to see whether there had been any changes over three 5-year cohorts. Materials and methods Patients referred with gonadal and extra-gonadal primary germ-cell tumours, between 1988 and 2002, were identified from the departmental database, and survival by stage and prognostic group was analysed. Results and conclusions The proportion of patients with stage I seminoma has significantly increased. The good prognosis of patients with early stage disease is confirmed, with the outcome for some groups of patients being better than expected. There is a non-significant trend to improved results over the three 5-year cohorts. The outcome for patients with stage IV seminoma is worse than would be expected, but numbers are small. The poor prognosis of patients with non-seminomatous germ-cell tumours who fall into the International Germ Cell Consensus Classification (IGCCC) poor-prognostic group is confirmed. Failure of patients with metastatic non-seminomatous germ-cell tumours to achieve a complete response to initial therapy is shown to be a poor prognostic indicator.

Aims Sex cord–stromal tumours of the testis are uncommon tumours, accounting for around 5% of testicular neoplasms. Treatment is primarily surgical, with no adjuvant therapy of proven benefit. We present a single-centre experience over a period of 15 years. Materials and methods From 1988 to 2002, 18 patients with a diagnosis of sex cord–stromal tumour were referred to our centre. A retrospective analysis of their case notes was made and a pathological review undertaken. Results Sixteen were Leydig-cell tumours and two were Sertoli cell. For the Leydig-cell tumours, the median age at presentation was 42 years, 50% presented with a testicular mass and 31% with gynaecomastia. Two patients followed a malignant course: one revealing disease dissemination at initial staging, and a second 12 months after potentially curative orchidectomy. Salvage retroperitoneal lymphadenectomy in the latter patient proved unsuccessful. Clinical outcome correlated strongly with the presence of adverse pathological features described previously in the literature. After a median follow-up of 46 months, two patients have developed progressive disease, and two patients have died, one of metastatic Leydig-cell tumour. No patient defined as being of low malignant potential on pathological examination has relapsed outside our review period of 2 years. Conclusion We confirm the overall excellent prognosis for most of the patients with sex cord–stromal tumours of the testis. Compared with most previous reports, pathological features seem to predict with reasonable accuracy the risk of malignant behaviour, and can adequately inform the subsequent review policy.

To determine whether palliation of chest symptoms from a 10 Gy single fraction (regimen 1) was equivalent to that from 30 Gy in 10 fractions (regimen 2).Patients with cytologically proven, symptomatic lung cancer not amenable to curative therapy, with performance status 0-3, were randomised to receive either 30 Gy in 10 fractions or a 10 Gy single fraction. Local symptoms were scored on a physician-assessed, five-point categorical scale and summed to produce a total symptom score (TSS). This, performance status, Hospital Anxiety and Depression (HAD) score and Spitzer's quality-of-life index were noted before treatment, at 1 month after treatment and every 2 months thereafter. Palliation was defined as an improvement of one point or more in the categorical scale. Equivalence was defined as less than 20% difference in the number achieving an improvement in the TSS.We randomised 149 patients and analysed 74 in each arm. According to the design criteria, palliation was equivalent between the two arms. TSS improved in 49 patients (77%) on regimen 1, and in 57 (92%) patients on regimen 2, a difference of 15% (95% confidence interval [CI] 3-28) in the proportion improving between the two regimens. A complete resolution of all symptoms was achieved in three (5%) on regimen 1, and in 14 (23%) patients on regimen 2 (P0.001), a difference in the proportion between the two regimens of 21% (95% CI 10-33). A significantly higher proportion of patients experienced palliation and complete resolution of chest pain and dyspnoea with regimen 2. No differences were observed in toxicity. The median survival was 22.7 weeks for regimen 1 and 28.3 weeks for regimen 2 (P = 0.197).Although this trial met the pre-determined criteria for equivalence between the two palliative regimens, significantly more patients achieved complete resolution of symptoms and palliation of chest pain and dyspnoea with the fractionated regimen.

ABSTRACT: The objective of this study was to review the results of our policy of primary radiotherapy (RT) and salvage cystectomy for transitional carcinoma (TCC) of the bladder in the light of changes in our radiotherapy planning procedure, in particular the introduction of CT planning. The case notes of 163 patients treated with radical radiotherapy using a CT planning technique were examined. The main endpoint for assessment was response at the time of the check cystoscopy 6 months after the completion of treatment. In addition survival was estimated by stage of disease and by response at the time of first cystoscopy. Patterns of relapse and time to relapse were analysed. All percentages quoted in the text use the initial 163 patients as the denominator. One hundred patients (61%) achieved a complete response. The complete response rate was significantly related to T stage at presentation being 90% for TI, 75% for T2, and 53% for T3 disease respectively. Of these patients 78 remain disease free in the bladder (47%). Twenty-two have relapsed in the bladder, of whom 5 have also relapsed at metastatic sites. Fifteen patients have relapsed outside the bladder whilst remaining disease free within the bladder. At the time of last follow up or death from other causes 63 of the 100 patients who had a complete response remained disease free with an intact bladder. There were 18 (11%) partial responders. Seven of these patients went on to have a cystectomy. Ten remain alive, 7 disease free, 4 with intact bladders. In 24 patients (15%) there was no response and these patients have all died, the median survival being 10 months. In 21 patients (13%) a postradiotherapy cystoscopy was not performed. In all but one patient, who was lost to follow up, this was because of progressive disease. The median survival of these 20 patients was 6 months. Of the 163 patients 35% are alive and well with an intact bladder. If patients dying from other causes are included then 42% were rendered disease free. Cause specific survival was significantly related to stage of disease at presentation with 5 year actuarial survival being 87%, 48% and 26%, for T1, T2 and T3 disease respectively. Survival was also related to response to treatment at 6 months with 5 year survival being 64%, and 52% for complete and partial responders respectively. Survival was extremely poor for non-responders with only 37.5% surviving 1 year and none 5 years. There was a highly significant relationship between response and the development of, and the time to developing metastatic disease. Of those who exhibited a response 21% developed metastatic disease compared to 78% of non-responders. Salvage cystectomy offers the possibility of cure in those who achieve a complete or partial response with 42% of such patients being rendered disease free. Results however are poor in those who did not respond with all patients dying of their disease. Response rates for all stages, and survival for stages T1 and T2 are much improved from those previously reported from this centre and compare favourably with other published series. These results confirm the place of radiotherapy and salvage cystectomy in the management of TCC of the bladder in selected patients. In about one-third of patients the desired outcome of curing the patient of their cancer with organ preservation is achieved. The prognostic significance of cystoscopic response at 6 months and stage at presentation is confirmed. The outcome for patients with early stage disease is excellent. The relationship between response and the development of metastatic disease would suggest that even if these patients had had a primary cystectomy they may have fared badly, a conclusion supported by the fact that these results are comparable with surgical series. This series supports the role of radiotherapy in the management of this disease and suggests that modern RT techniques including CT planning have had a beneficial effect on the results of radical radiotherapy.

Aims To analyse our 5 and 10 year prostate brachytherapy outcome data and to assess the impact of PSA nadir on relapse free survival and whether an alternative definition of PSA relapse could detect men destined to fail by the Phoenix definition at an earlier time point. Materials and methods 474 men were treated over a 10 year period between 20012 and 2011and divided into 2 five year cohorts for the purpose of the analysis. Results The risk of relapse is strongly predicted by post treat prostate-specific antigen (PSA) nadir. After 3 years post-treatment, PSA nadir plus 0.4 ng/ml identified men at risk of relapse 17 months earlier than the Phoenix definition. Conclusion The Phoenix definition of nadir plus 2.0 ng/ml does not allow the early identification of men destined to relapse. The initiation of salavage therapy at the earliest opportunity could potentially affect subsequent survival and an outline randomised controlled trial proposal is presented.

The aim of palliative thoracic radiotherapy in patients with advanced non-small cell lung cancer (NSCLC) is to alleviate symptoms. This study was designed to determine whether any patients achieved long-term survival after this treatment. In Edinburgh, between 1974 and 1993, 4531 patients were treated with palliative radiotherapy for NSCLC, receiving ten fractions or fewer. We reviewed the case notes of the long-term survivors. Sixty-one (1.3%; 95% confidence interval (CI) 1.0-1.6) patients survived for more than 5 years; 43 (70%) had histological confirmation of cancer; 28 (46%) had stage Stage I or II, 28 (46%) Stage III and one Stage IV disease; 53 (87%) patients were treated with doses of 30-35 Gy in ten daily fractions, seven (12%) received 20 Gy in five daily fractions and one received a 10 Gy single fraction. Forty-two (69%) patients had a radiological complete response, 16 (26%) a partial response and the remainder stable disease. Clinically significant radiation pneumonitis occurred in one (2%) patient, radiation myelopathy in two (3%) and multiple rib fractures in one (2%). There did not appear to be an association between long-term survival and a radiosensitive phenotype. On univariate analysis, long-term survival was more frequent in patients receiving ten-fraction regimens than in those who underwent a shorter course of radiotherapy (chi 2 = 19.5, P < 0.001). Thirty-four (0.8%; 95% CI 0.6-1.0) patients were disease free at death or at last review (median 10 years; range 5-17). We conclude that palliative thoracic radiotherapy produces long-term survival in 1.3% and personal cure in up to 1% of patients with advanced NSCLC.

Background : The optimum dose and fractionation schedule for the palliative irradiation of painful bone metastases is controversial. Purpose : To compare the efficacy, side-effects and effect on quality of life of two commonly used radiotherapy schedules in the management of painful bone metastases. Materials and methods : In a prospective trial, 280 patients were randomised to receive either a single 10 Gy treatment or a course of 22.5 Gy in five daily fractions for the relief of localised metastatic bone pain. Results : Response rates have been calculated from 240 assessable treated sites of pain. The overall response rates were 83.7% (single treatment) and 89.2% (five fractions). The complete response rates were 38.8% (single treatment) and 42.3% (five fractions). The median duration of pain control was 13.5 weeks (single treatment) and 14.0 weeks (five fractions). None of these differences was statistically significant. There were no differences between the groups in the effect of treatment on a variety of quality of life parameters. Conclusions : It is concluded that a single 10 Gy treatment is as effective as a course of 22.5 Gy in five fractions in the management of painful bone metastases.

The purpose of this study was for us to identify factors associated with survival and laryngeal function in a contemporary, population-based study of stage III laryngeal carcinoma.Patients presenting to a tertiary center with stage III laryngeal carcinoma between 1999 and 2010 were included in the study. Kaplan-Meier and Cox proportional hazards analyses were utilized.Of 137 patients receiving either surgery ± adjuvant therapy (SURG±Adj = 24.1%), chemoradiotherapy (CRT = 32.8%), or radiotherapy alone (RT = 36.5%), 5-year cause-specific survival (5-year CSS) was 81.0% and 2-year local relapse rate was 27.5%. RT had higher recurrence (p.01), lower 5-year CSS (90.8% vs 87.8% vs 68.9%/SURG±Adj vs CRT vs RT/p = .0026) and lower overall survival (p = .001). Adjusting for excess of severe comorbidity in the RT group, there was no difference in 5-year CSS between treatment modality.SURG±Adj and CRT had similar survival. Severe comorbidity was associated with selection bias to RT and reduced 5-year CSS. Comorbidity is a key prognostic variable and should be considered in the interpretation of treatment outcomes.

Objective To assess the Results of radiotherapy in the treatment of localized prostate cancer. End points for assessment were survival, local control, development of metastases, and the toxicity of therapy. Materials and methods The case notes of 191 patients who were treated with radical radiotherapy between 1982 and 1992 were reviewed. The pathology of 130 patients was reviewed by a single pathologist. A multivariate analysis was performed to identify significant prognostic factors with regard to survival and relapse. Results One-hundred and eighty-two patients were assessable. The minimum length of follow-up was one year (median = 40 months). The actuarial cause-specific 5 and 10 year survival rates were 63% and 35% respectively. Local progression occurred in 41% of patients with 37% developing metastases. Multivariate statistical analysis demonstrated that T stage and Gleason Score were significant predictors for survival. Late complications were usually mild, with only 4% developing serious bladder toxicity. Conclusion Radical radiotherapy has a role in the curative treatment of prostate cancer. Survival is significantly related to T stage at the time of presentation, and to the Gleason Score of the tumour. Survival in this series was not as good as the best surgical series, but it is still not clear which patients should receive radiotherapy and which surgery as their primary management.

Glycogen synthase kinase 3β (GSK3β) is phosphorylated and inactivated by the phosphoinositide 3 kinase PI3K/Akt pathway. Activation of Akt phosphorylates GSK3β preventing phosphorylation of cyclin D1 which leads to accumulation and nuclear localisation of cyclin D1, activation of CDK4/6 and cell cycle progression. The CCND1 gene found at chromosome 11q13 has been shown to be amplified in approximately 15 % of breast cancers. Cyclin D1, the product of the CCND1 gene, is one of the most commonly overexpressed proteins in breast cancer. Protein expression for GSK3β, phosphorylated-GSK3β (p-GSK3β), cyclin D1 and gene expression of CCND1 were examined in tissue microarrays of 1,686 patients from the Edinburgh Breast Conservation Series. High GSK3β expression was associated with reduced distant relapse-free survival (DRFS), while no association between p-GSK3β and breast cancer-specific survival was seen. CCND1 amplification is also associated with poor DRFS. On the contrary, cyclin D1 overexpression is associated with an increase in DRFS. Multivariate analysis was performed. We suggest that analysis of both GSK3β and cyclin D1 expressions can be considered as a marker of good prognosis in early breast cancer.

Overexpression of EGFR, HER2 and HER3 are known to be associated with poor outcome in breast cancer. Few studies have examined the clinical impact of activation of these proteins. In the present study, we evaluated EGFR, HER2 and HER3 and the activated (phosphorylated) forms of these proteins in patients with early breast cancer. EGFR, HER2, HER3, pEGFR, pHER2 and pHER3 expression was determined by immunohistochemical analysis of tissue microarrays constructed from tumours within the Edinburgh Breast Conservation Series (BCS). The BCS represents a fully-documented consecutive cohort of 1,812 patients treated by breast conservation surgery in a single institution. Our results demonstrate overexpression of HER2 and pHER2 to be associated with a significant reduction in overall survival (OS) (HR: 1.66, 95 % CI 1.22-2.26, p = 0.001 and HR: 1.57, 95 % CI 1.22-2.03, p = 0.001, respectively) and distant relapse-free survival (DRFS) (HR: 1.63, 95 % CI 1.23-2.18, p = 0.001 and HR: 1.55, 95 % CI 1.23-1.97, p = 0.0002, respectively). Paradoxically, expression of pEGFR was associated with a significantly improved OS (HR: 0.67 95 % CI 0.50-0.91, p = 0.01) and DRFS (HR: 0.73, 95 % CI 0.56-0.96, p = 0.025). Expression of activated EGFR/HER2 provides additional information on ER positive breast cancer patients and suggests alternative treatment for those in this subgroup.

Four staging systems for breast cancer have been introduced in turn and have been in general use in the United Kingdom since 1948. Each of these systems has been applied to a cohort of nearly 4000 patients treated in the Radiotherapy Department in Edinburgh between 1954 and 1964 to determine the effect of such changes on prognosis and, presumably, also on management for the various stage groupings. The changes in staging systems over the years have highlighted the importance of some factors, e.g. tumour size and extent of nodal involvement. However, the overall effect on survival of these changes is minimal and the value of frequent changes in staging systems at less than 10-year intervals is questionable. Even the most recent changes in the UICC staging system make assumptions which are not validated by this review.

Aims The optimal management of axillary lymph node metastases from occult breast cancer (TXN1-2M0) is uncertain and practice varies in the use of primary breast radiotherapy. We conducted a retrospective review to examine clinical outcomes for patients managed with or without primary breast radiotherapy. Materials and methods Case records from the clinical oncology database were reviewed to identify patients presenting with axillary nodal metastases but no detectable primary tumour between 1974 and 2003. Fifty-three patients with TXN1-2M0 breast cancer were identified, representing 0.4% of patients managed for breast cancer during this period. Of those tested, 59% had oestrogen receptor-positive tumours. Seventy-seven per cent received ipsilateral breast radiotherapy. Results There was a trend towards reduced ipsilateral breast tumour recurrence in patients who received radiotherapy (16% at 5 years, 23% at 10 years) compared with those who did not (36% at 5 years, 52% at 10 years). Similarly, the locoregional recurrence rate was 28% at 5 years for patients who received radiotherapy compared with 53.7% at 5 years for non-irradiated patients. Breast cancer-specific survival was higher ( P =0.0073; Log-rank test) in patients who received ipsilateral breast radiotherapy (72% at 5 years, 66% at 10 years) compared with those who did not (58% at 5 years, 15% at 10 years). Conclusion Primary breast radiotherapy may reduce ipsilateral breast tumour recurrence and may increase survival in patients presenting with axillary lymph node metastases and occult breast primary (TXN1-2M0). Larger studies or prospective registration studies are needed to validate these findings.

This retrospective audit was conducted to examine the changes in patient characteristics, referral, treatment and outcome over a 20-year period in a large regional neuro-oncology centre, focusing on the impact of the changes in pathological classification of gliomas. Using the Edinburgh Cancer Centre (ECC) database all cases of glioma were identified and patient, tumour and treatment characteristics noted. Survival was calculated from date of surgery or, if no operation was performed, the date of referral. Comparison was made between four periods 1988–1992 (c1), 1993–1997(c2), 1998–2002(c3) and 2003–2007 (c4). During the 20 years, 1175 patients with a glioma were referred to ECC. The median age increased from 53 years to 57 years (p < 0.001) but the proportion without pathology remained unchanged (10%). The distribution of pathological grades changed over time Grade I–II: 24, 6, 6, and 6%, Grade III: 42, 27, 17, and 13% and Grade IV: 24, 61, 68, and 68% in c1, c2, c3 and c4, respectively (p < 0.001). Immediate RT was given to 68% (c1), 70% (c2), 78% (c3) and 79% (c4). Median interval from resection to RT reduced from 43 days (c1) to 36 days (c4) (p < 0.001). 5-year overall survival for patients with Grade III lesions increased: 21% (c1), 35% (c2), 37% (c3), 33% (c4) as did 1-year overall survival for Grade IV lesions: 18% (c1), 26% (c2), 29% (c3), 27% (c4)). This improvement probably reflects the change in pathological classification rather than a change in management. Proportional hazards analysis of grade IV 1993–2007 only (to reduce pathological variation) showed that younger age, frontal lesions, excision, higher RT dose had reduced hazard of death. Interval from surgery to RT had no impact on survival in this series.

All patients with FIGO Stage IB cervical cancer registered with the Department of Clinical Oncology at the Western General Hospital, Edinburgh, during the 6 years from 1979 to 1984 have been reviewed, as part of a continuing programme of clinical audit. Of the 140 patients with Stage IB disease, 68 (49%) were treated by primary surgery of whom 44 (31%) also received adjuvant radiotherapy. Radical radiotherapy was the definitive treatment for 69 patients (49%). Three patients (2%) were not treated with curative intent. The crude 5-year survival rate for all cases was 72% and the cause-specific 5-year survival rate was 78%. Local tumour control at 5 years was 72%. There was no significant difference in outcome between the surgically treated and irradiated groups of patients. Age, histology and nodal status did not influence outcome. Irradiated patients with bulky tumours fared significantly worse than the other patients who received radical radiotherapy. Multivariate analysis of all patients revealed no significant independent prognostic variables. Primary surgery appears to confer no benefit over radical radiotherapy in terms of either survival or local control. Treatment-related late bladder and bowel morbidity was, however, significantly worse in irradiated patients.

An anonymous questionnaire study was designed to assess sexual function after orchidectomy and radiotherapy for testicular cancer. Questionnaires were sent to: (1) 237 patients treated with orchidectomy and abdominal radiotherapy in Edinburgh from 1974 to 1988; (2) 32 patients under “surveillance” following orchidectomy alone; (3) 402 “normal” age-matched controls. All were asked questions concerning sexual function over the preceding 6 months. All the patients were also asked the same questions with reference to the first 6 months after completion of treatment. Completed questionnaires were returned from 137 (62%) radiotherapy patients, 18 (56%) surveillance patients and 121 (35%) controls. There was a significant difference between the radiotherapy patients and the controls in almost all the parameters looked at including erection, ejaculation and libido with the treated group performing less well. In addition, almost 24% of the radiotherapy patients felt disabled or disfigured by the treatment, most commonly because of the presence of only one testicle. A deterioration in sexual function was observed with increasing age. In the radiotherapy group of patients there was no difference in response between the two time periods or in any of the treatment variables. The clinical significance of these observations are unclear but together with the increasing information on other toxicities emerging following this therapy the role of radiation for early stage seminoma is being brought into question. This study also confirms the morbidity of orchidectomy. We suggest that testicular implants should be offered more widely.

Fifty-four consecutive patients underwent 61 orthopaedic operations for metastatic bone disease affecting the upper and lower limbs. These patients were subsequently managed using a consistent postoperative radiotherapy (RT) policy. There were 27 prophylactic internal fixations and 34 internal fixations of pathological fractures. There was a marked difference in survival between these groups. The median postoperative survival of the prophylactic (P) group was 15 months whereas that of the fracture (F) group was 2 months (P less than 0.0001). Ninety-three per cent of the P group and 59% of the F group were able to be discharged home following treatment. Subsequent local fracture requiring further surgical intervention occurred in 11% of the P group and in none of the F group. Seventy-eight per cent of the P group and 62% of the F group did not suffer any further sequelae at the operation site until the time of death or last follow-up. Patient mobility following surgery and RT for metastatic lesions occurring in the lower limb was significantly improved in both the P group (P less than 0.05) and in the F group (P less than 0.0001) such that 91% and 58%, respectively, of these patients were subsequently able to walk.

Radiotherapy for pituitary adenomas is an effective treatment but remains controversial due to toxicity concerns.A retrospective audit of patients referred for radiotherapy during 1974-2003 was conducted, the case records were examined and data linkage to cancer registry and hospital discharge records was performed to assess the overall survival (OS), progression-free survival (PFS) and late effects (hormone deficiency, reduced vision, second cancer and stroke).Three hundred and eighty-five patients had radiotherapy (median 45 Gy). The OS was 74% and 49%, PFS was 97% and 96%, at 10 and 20 years, respectively. No specific factors influenced local control. Additional hormone deficiencies occurred in 19% (ACTH) and 26% (TSH). Actuarial rate optic neuropathy at 10 years was 0.8%. Seventy-eight patients had a stroke, a RR for a matched Scottish population of 1.45 (CI 1.05-1.18, p=0.03) men and 2.22 (1.56-3.08, p0.01) women. Four intra-cranial tumours were identified; 20-year actuarial risk 1.9% (CI 0-2.6%), a RR of 5.65 (0.53-20.77, p=0.10) men and 9.94 (0.94-36.56, p=0.04) women.This treatment is effective with good local control rates at 20 years. A significant proportion developed hypo-pituitarism. The risk of optic neuropathy was low but risk of stroke increased, particularly in women who had slight increased risk of intra-cranial tumours.

A retrospective analysis of malignant melanoma of the upper aerodigestive tract treated in Scotland between 1976 and 1988 has been performed to define the incidence clinical features and response to treatment. Using the Scottish Melanoma Group database and pathology and oncology department registers 32 patients, 20 female, 12 male, were identified, representing a population incidence of approximately 0.5 per million per year. The median age was 69 years, range 38–86. Tumour arose in the nose or sinuses in 23 cases and the oral cavity or pharynx in eight cases. Metastases were present at presentation in four cases. Radical treatment was attempted in 27 patients: radiotherapy alone in 13, surgery alone in 10 and combined modality treatment in four. Complete regression, which was sustained in five cases occurred in eight of the 13 radically irradiated patients; whereas sustained local control was achieved by radical surgery in only four of ten patients. The median survival is 14 months, none lived more than 63 months. Only one patient is alive and disease free, three more survive with disease. Of the 28 who have died, nine had local tumour only, nine metastases only and ten both local and distant disease. Outcome was not affected by age, sex, primary site or nodal spread.

Prior to 1982 the standard radiation tissue absorbed dose administered to the chest wall following mastectomy was 40.0-42.5 Gy in 10 alternate day fractions over 4 weeks. From 1982 the standard maximum dose was 45.0 Gy administered in 20 daily fractions over 4 weeks. On review of the records of the 770 patients treated between 1979 and 1984, 19 (2.5%) had symptoms of acute radiation pneumonitis, 7/484 (1.4%) treated by the earlier technique and 12/286 (4.2%) by the later technique (X2 = 4.56, P less than 0.05). The mean 4 cm depth doses on the chest wall were 33.98 Gy and 36.84 Gy respectively in the earlier and later populations (t = 5.06, P less than 0.001) and 33.62 Gy and 38.30 Gy in those developing acute pneumonitis. Comparison of these two schedules gives an alpha/beta ratio of 8.5 Gy. It is suggested that the sparing of symptomatic acute reactions in human lung by smaller doses per fraction may be less than currently believed.

To determine whether the introduction of early concomitant chemoradiotherapy for patients with limited stage small cell lung cancer (LS-SCLC) has resulted in acceptable outcomes and toxicity in a UK practice.The case records of all patients with LS-SCLC treated with chemoradiotherapy from July 2001 to 2004 were reviewed, and subjected to descriptive statistics and proportional hazards analysis.Concomitant chemoradiotherapy was delivered to 30 patients and sequential chemoradiotherapy was delivered to 36 patients. The former patients tended to be younger (mean 58.9 vs 64.1 years, P=0.01); the latter patients tended to have bulkier disease. There was no difference in performance status, but cisplatin was given more often in the former group (90% vs 44%, P0.0001). Grade 3 acute oesophagitis occurred in less than 10% of either group and there were no cases of grade 3 or greater pneumonitis. Two-year actuarial survival for the concomitant group was 53% (95% confidence interval 36-71%) and 36% (95% confidence interval 20-52%) for the sequential group (P=0.018). Proportional hazards analysis showed an increased hazard of death with increasing performance status and age, sequential therapy and the use of cisplatin with sequential therapy.Concomitant chemoradiotherapy can be safely given in a UK population with outcomes comparable with those reported in North American series.

Purpose: The aim of this study is to report the incidence of soft tissue sarcoma in a large group of patients treated with fast neutrons. Methods: A systematic review was conducted of long-term follow-up after trials of fast neutron therapy for cancers at various sites. The study took place at Edinburgh Cancer Centre, Western General Hospital, Edinburgh, Scotland, United Kingdom. From 1977 to 1984, 620 patients were treated using fast neutrons in the MRC cyclotron unit in Edinburgh. Most of these were treated within randomized controlled trials. Follow-up was maintained in all except 2 patients, who left the area to return abroad. The main outcome measure was the incidence of new soft-tissue sarcomas during long-term follow-up. Results: Three cases of sarcoma, developing within the treatment volume, were observed in a small group of patients treated some years earlier using fast neutrons. This incidence was 111 times what would have been expected in the normal population and 15 times the incidence in a comparable photon-treated group of patients. Conclusion: The long-term incidence of sarcomas in patients previously treated with fast neutrons is significant.

Background and purpose : Overall treatment time is an important factor in the outcome of radical radiotherapy in head and neck, bladder and lung cancer and in cervix cancer treated over more than 7 weeks. This study analysed the effect of prolongation of overall treatment time on survival and late morbidity for patients receiving radical radiotherapy for cervical cancer treated with a 4-week regimen. Materials and methods : Using the departmental SAS data-base we identified all patients with cervix cancer treated between 1974 and 1988 and investigated the 647 patients who received 20 fractions of external beam radiotherapy plus intracavitary therapy with a total dose to point A of at least 60Gy. A retrospective case-note review identified tumour and treatment-related variables. Results : Four hundred and twenty-five (66%) patients had at least one gap in treatment. Seventy-nine gaps (11%) were due to unavoidable patient or treatment-related causes. We could not find an effect of a treatment gap ( P =0.43) or an increased overall treatment time ( P =0.79) on the cause specific survival of patients. There was significantly more grade 4 morbidity in those patients treated over a short period (29–32 days) compared to the rest ( P =0.005), possibly related to the loss of radiotherapy-free days to weekend intracavitary insertions. Conclusions : We could not demonstrate a significant effect of overall treatment time in this series of patients, almost all of whom were treated in less than 7 weeks. Those patients treated over the shortest period had an increased incidence of late morbidity.

Purpose: Data on patients with cancer of the larynx are analyzed using statistical models to estimate the effect of gaps in the treatment time on the local control of the tumor. Methods and Materials: Patients from four centers, Edinburgh, Glasgow, Manchester, and Toronto, with carcinoma of the larynx and treated by radiotherapy were followed up and the disease-free period recorded. In all centers the end point was control of the primary tumor after irradiation alone. The local control rates at

Background and purpose : Cholangiocarcinoma is rare but carries a poor prognosis. Radiotherapy has been used either as an adjuvant treatment following surgical resection of tumour or for palliation. The purpose of this study was to assess the feasibility and morbidity of accelerated external beam radiotherapy with or without intraluminal radiotherapy in the treatment of locally advanced bile duct cancer. Materials and methods : Thirty eight patients were treated. Surgical procedures performed prior to radiotherapy were extended hepatectomy (3), hepaticojejunostomy with tumour resection (6), palliative biliary-enteric bypass (6), biopsy (4), Whipple's procedure (1), gastrojejunostomy (1) and cholecystectomy (1). Twenty patients received external beam radiotherapy (ERT). Six patients received one Phase of ERT and 12 received two Phases, separated by a 2-week gap. Dose per Phase was 22.5 Gy in 10 twice daily fractions. After 1989, dose per Phase was increased to 27.5 Gy. One patient received Phase I ERT (30.0 Gy) using conventional fractionation and one patient received an uninterrupted, conventionally fractionated course of treatment (50.0 Gy). Fourteen patients received both ERT and intraluminal radiotherapy (IRT) using iridium-192 ( 192 Ir) wire passed through a percutaneous, transhepatic catheter (median dose, ERT 23.8 Gy + IRT 40.0 Gy). In addition, four patients received IRT alone (median dose 45.0 Gy at 1 cm radius). Patients were followed for at least 42 months. Results : Median overall survival was 15 months. Overall survival for the whole group at 1, 2 and 3 years was 59.6%, 32.5% and 16.2%. Thirty four patients died of disease. Radiotherapy caused acute toxicity in seven patients. According to RTOG/EORTC criteria toxicity was Grade 1 in four cases, Grade 2 in two cases and Grade 3 in one case. Two patients developed gastrointestinal bleeding as a late complication of radiotherapy. Conclusions : Accelerated external beam radiotherapy with or without intraluminal radiotherapy is feasible and associated with acceptable toxicity when used in the management of advanced cholangiocarcinoma.

We have undertaken a retrospective analysis of 238 patients with Stages I and II seminoma of the testis treated with radiotherapy in Edinburgh between 1974 and 1989. There were five deaths from seminoma. Cause-specific survival for the whole group at 2 and 5 years was 99.2% and 98.1%, respectively. Cause-specific survival at 2 and 5 years by stage (Royal Marsden staging classification) was: Stage I, 99.5% and 98.7% and Stage II, 98.1% and 96.1%. Fourteen (5.9%) patients relapsed (one after treatment for his second testicular seminoma). Eight were given successful salvage treatment, five died of seminoma and one died of intercurrent disease. 13 (5.5%) patients developed World Health Organisation (WHO) grade 3 gastrointestinal or haematological toxicity and two developed grade 4 gastrointestinal toxicity as a result of abdominal radiotherapy. 22 patients (9.2%) developed problems ascribed to late morbidity of abdominal radiotherapy including 18 with peptic ulcer disease. Contralateral testicular tumours occurred in seven (2.9%) patients and five (2.1%) patients developed malignancies at other sites.

Two hundred and ninety-six patients irradiated for pituitary adenoma in Edinburgh between 1962 and 1990 were reviewed. The number of subsequent tumours was noted. The expected incidence of tumours was estimated, based on data from the Scottish Cancer Registry, for an age and sex matched population. One malignant brain tumour was found; the expected incidence was 0.3 (95% CI 0–12). One meningioma was reported. Thirty non-CNS tumours were found, compared with an expected incidence of 17.5 (95% CI 12–26). We see no reason at present to alter our practice as a result of radiation induced neoplasia in this group, although close follow-up continues.

Mehanna and colleagues highlight the increasing incidence of oral and oropharyngeal cancer in the United Kingdom and its likely association with sexually transmitted human papilloma virus (HPV).1 However, by reporting oropharyngeal cancer along with oral cancer the true rate of increase in oropharyngeal cancer is probably being masked. Using data from the Scottish Cancer Registry, we found that oropharyngeal cancer now has the …

In Edinburgh in 1982, radiotherapy for patients with T 4 breast cancer was modified by an increase in tumour absorbed dose from 42.5–45.0 Gy to 60–75 Gy by using tumour boosts and changing from alternate day to daily fractions. To assess whether this improved local control or survival, the records of all females with T 4 -N 0 - 3 M 0 breast cancer referred between January 1978 and December 1985, who received radiotherapy without initial mastectomy or adjuvant chemotherapy, were reviewed. There were 193 patients in the study. Minimum follow-up was 36 months. Actuarial survival at 5 years was 27.1% and median survival 29 months. Local control was achieved by 25.9%. On multivariate analysis, the probability of survival fell with increasing tumour size, advanced clinical node status and the presence of inflammatory change. Radiotherapy technique also affected prognosis. Four-field techniques were associated with a better chance of survival than the breast and axillary jig or other treatment methods. The probability of local control increased with reduced tumour size and showed the same relationship to radiotherapy technique as did survival. Dose was not a significant variable for either survival or local control. No improvement in survival or local control was apparent in comparison with a previous study. It is concluded that radiotherapy alone at a dose of 60 Gy is insufficient to produce durable local control for the majority of women with T 4 breast cancer.

The optimal frequency of clinic follow-up after radical radiotherapy to early cervical cancer is not well established. A retrospective analysis was carried out of 392 patients with FIGO Stage IIA and IIB carcinoma of the cervix treated by radical radiotherapy who attended a radiotherapy clinic for follow-up. A total of 38 (43%) of the 87 loco-regional and 25 (38%) of the 66 metastatic relapses were detected at routine clinic visits. There were 72 clinic visits per relapse detected. The majority of locoregional and metastatic relapses whether detected at routine or interval visits were symptomatic of the locoregional recurrences 78% (42/54) occurred in the first two years following treatment. The majority were advanced. 7% (4/54) of locoregional relapses occurred after 5 years. Only 17% (9/54) of patients with locoregional relapse underwent salvage surgery. More intensive follow-up in the first two years is recommended.

A series of 88 cases of male breast cancer was compared with 241 cases of female breast cancer randomly selected from Departmental records. Cases of male breast cancer differed significantly from control female cases with regard to stage of the disease, age of onset and liability to the development of a second carcinoma. In 11 of the 88 cases (12.5%) of male breast cancer another primary malignant tumour developed. In seven instances the large bowel or rectum was the site of the other carcinoma. When correction was made for age and for the stage of the disease the prognosis of breast cancer in men and women was found to be similar. Only minor histological differences were found between male and female cases. Two of 54 cases examined for X-chromatin proved to be Barr-positive.

The results of treatment of 838 patients who were irradiated for germ cell tumours of the testis between 1950 and 1969 are presented. The overall 10-year survival rate was 61.8%. For seminomas alone it was 75.3% and for teratomas 37.7%. No increase in survival was found which could be attributed to the introduction of megavoltage beams.

A series of 243 patients with adenocarcinoma of the rectum treated with radiotherapy is presented. In the early part of the study radiotherapy was combined with 5-fluorouracil (5FU). Later, radiotherapy was given alone. Seventy-four patients were treated with radical external beam radiotherapy for recurrent or inoperable rectal adenocarcinoma. One hundred and forty-five patients with advanced pelvic tumours or with metastases were treated with palliative pelvic radiotherapy. Twenty-four patients who had small-volume residual pelvic tumour or who were felt to be at high risk of pelvic recurrence following radical resection received postoperative radiotherapy. Complete tumour regression was seen in 38 per cent of radically treated patients, and 24 per cent of palliatively treated patients. Partial regression was observed in 56 per cent of radically treated patients, and 58 per cent of palliatively treated patients. Long-term local tumour control was more commonly observed for small tumours (

Sixty-four patients (37 stage I and 27 stage II) with low grade non-Hodgkin's lymphoma were treated by surgical excision alone (two patients) or with radiotherapy (53 patients), chemotherapy (five patients) or both (four patients). Actuarial survival was 80.7% at 5 years and 77.9% at 10 years. Actuarial recurrence-free survival at 10 years was 49.4% for stage I and 38.0% for stage II patients. Local control was achieved in 52 out of 56 (93%) patients treated with a radiation dose of 30 Gy or greater. There was no advantage for extended compared with involved, field irradiation. A multivariate analysis identified age, sex, stage and disease site as independent prognostic variables for survival.

A retrospective analysis has been made of a consecutive series of 3924 cases of breast carcinoma in women seen in one centre subject to a consistent management policy between 1954 and 1964. Survival was studied in relation to the clinical stages of the disease as defined by three different staging systems, Manchester, International TNM and that of the International Union Against Cancer and the American Joint Committee on Cancer Staging and End Results Reporting (UICC/AJC). In spite of considerable differences in the distribution of cases between stages according to the system applied there was markedly little difference in survival rates up to 20 years when each stage was compared with the other two. The most important prognostic factor used in staging is the size of the primary tumour. Although the frequency of clinical evidence of spread outside the breast is related to tumour size, significantly higher 20-year survival rates were found for patients in whom the tumour appeared to be confined to the breast on clinical examination when compared with patients in whom there was clinical evidence of spread beyond the breast only for tumours less than 5 cm maximum diameter. These results suggest that staging systems relying wholly on restricted clinical criteria are of limited value in terms of prognosis and their overfrequent modification is not justified.

The case records of 116 patients treated with radical megavoltage X-ray therapy for carcinoma of the prostate have been reviewed. The age-corrected actuarial 5-year survival rate was 60.0% and the 10-year rate was 31.5%. Multivariate analysis demonstrated that T classification was the strongest prognostic variable but a long delay between diagnosis and radiotherapy also had a detrimental effect on prognosis. The incidence of severe acute and late radiation morbidity was low. Radical radiotherapy has been shown to be a safe and effective form of management for localised carcinoma of the prostate.