Effect of physical exercise on the hippocampus and global grey matter volume in breast cancer patients: A randomized controlled trial (PAM study).

BACKGROUND: Physical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory. METHODS: Chemotherapy-exposed breast cancer patients (stage I-III, 2-4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale 'fatigue' of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients. RESULTS: Multiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm3, 95 % CI = 3.0 - 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = -52.3 mm3, 95 % CI = -100.3 - -4.4)), which was related to improved memory functioning (HVLT-R total recall: B = -0.022, 95 % CI = -0.039 - -0.005; ACS Wordlist Learning: B = -0.039, 95 % CI = -0.062 - -0.015). CONCLUSIONS: No exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding.

Microcystic elongated and fragmented (MELF) pattern of invasion: Molecular features and prognostic significance in the PORTEC-1 and -2 trials.

OBJECTIVE: Microcystic, elongated fragmented (MELF) pattern of myometrial invasion is a distinct histologic feature occasionally seen in low-grade endometrial carcinomas (EC). The prognostic relevance of MELF invasion was uncertain due to conflicting data, and it had not yet appropriately been studied in the context of the molecular EC classification. We aimed to determine the relation of MELF invasion with clinicopathological and molecular characteristics, and define its prognostic relevance in early-stage low/intermediate risk EC. METHODS: Single whole tumor slides of 979 (85.8%) out of 1141 (high)intermediate-risk EC of women who participated in the PORTEC-1/-2 trials were available for review. Clinicopathological and molecular features were compared between MELF invasion positive and negative cases. Time-to-event analyses were done by Kaplan-Meier method, log-rank tests and Cox' proportional hazards models. RESULTS: MELF invasion was found in 128 (13.1%) cases, and associated with grade 1-2 histology, deep myometrial invasion and substantial lymph-vascular space invasion (LVSI). 85.6% of MELF invasion positive tumors were no-specific-molecular-profile (NSMP) EC. NSMP EC with MELF invasion were CTNNB1 wild type in 92.2% and KRAS mutated in 24.4% of cases. Risk of recurrence was lower for MELF invasion positive as compared to MELF invasion negative cases (4.9% vs. 12.7%, p = 0.026). However, MELF invasion had no independent impact on risk of recurrence (HR 0.65, p = 0.30) after correction for clinicopathological and molecular factors. CONCLUSIONS: MELF invasion has no independent impact on risk of recurrence in early-stage EC, and is frequently observed in low-grade NSMP tumors. Routine assessment of MELF invasion has no clinical implications and is not recommended.

Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: a randomized controlled trial (PAM study).

BACKGROUND: Up to 60% of breast cancer patients treated with chemotherapy is confronted with cognitive problems, which can have a significant impact on daily activities and quality of life (QoL). We investigated whether exercise training improves cognition in chemotherapy-exposed breast cancer patients 2-4 years after diagnosis. METHODS: Chemotherapy-exposed breast cancer patients, with both self-reported cognitive problems and lower than expected performance on neuropsychological tests, were randomized to an exercise or control group. The 6-month exercise intervention consisted of supervised aerobic and strength training (2 h/week), and Nordic/power walking (2 h/week). Our primary outcome was memory functioning (Hopkins Verbal Learning Test-Revised; HVLT-R). Secondary outcomes included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognition (MD Anderson Symptom Inventory for multiple myeloma; MDASI-MM), physical fitness (relative maximum oxygen uptake; VO2peak), fatigue (Multidimensional Fatigue Inventory), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ C-30), depression (Patient Health Questionnaire-9, Hospital Anxiety and Depression Scale; HADS), and anxiety (HADS). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement (≥ 5 words). Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors. RESULTS: We randomized 181 patients to the exercise (n = 91) or control group (n = 90). Two-third of the patients attended ≥ 80% of the exercise sessions, and physical fitness significantly improved compared to control patients (B VO2peak 1.4 ml/min/kg, 95%CI:0.6;2.2). No difference in favor of the intervention group was seen on the primary outcome. Significant beneficial intervention effects were found for self-reported cognitive functioning [MDASI-MM severity (B-0.7, 95% CI - 1.2; - 0.1)], fatigue, QoL, and depression. A hypothesis-driven analysis in highly fatigued patients showed positive exercise effects on tested cognitive functioning [ACS Reaction Time (B-26.8, 95% CI - 52.9; - 0.6) and ACS Wordlist Learning (B4.4, 95% CI 0.5; 8.3)]. CONCLUSIONS: A 6-month exercise intervention improved self-reported cognitive functioning, physical fitness, fatigue, QoL, and depression in chemotherapy-exposed breast cancer patients with cognitive problems. Tested cognitive functioning was not affected. However, subgroup analysis indicated a positive effect of exercise on tested cognitive functioning in highly fatigued patients. Trial Registration Netherlands Trial Registry: Trial NL5924 (NTR6104). Registered 24 October 2016, https://www.trialregister.nl/trial/5924 .

Limited Impact of Breast Cancer and Non-breast Malignancies on Survival in Older Patients with Early-Stage Breast Cancer: Results of a Large, Single-Centre, Population-Based Study.

AIMS: To analyse the disease-free survival and overall survival in older adults with breast cancer after breast-conserving therapy, focusing on the relevance of non-breast malignancy (NBM) with respect to survival rates. MATERIALS AND METHODS: Analyses were based on 1205 women aged 65 years and older with breast cancer treated with breast-conserving therapy between 1999 and 2015. Patients were divided into three age categories: 65-70, 71-75 and >75 years. Multivariate survival analysis was carried out using Cox regression analysis. RESULTS: The two youngest age categories showed excellent results, with a 12-year disease-free survival of 84.6 and 86.3%, respectively. We noted a 17.2% incidence of NBM, particularly for colon cancer and lung cancer. Most (72.9%) occurred after a diagnosis of breast cancer. Of those 72.9%, about 50% died as a result of NBM within 2 years of the diagnosis of NBM. The overall 12-year NBM-specific survival was 92.0%. The 12-year overall survival was 60.0% for all and for the three abovementioned age categories was 73.3, 54.4 and 28.4%, respectively. The cause of death for all was predominantly non-malignancy-related morbidity. CONCLUSION: The impact of breast cancer on life expectancy was limited, in particularly for women aged 65-75 years. The relevance of NBM on survival was limited.

Impaired Geriatric 8 Score is Associated with Worse Survival after Radiotherapy in Older Patients with Cancer.

AIMS: To investigate whether the Geriatric 8 (G8) score and the Timed Get Up and Go Test (TGUGT), together with clinical and demographic patient characteristics, are associated with survival and late toxicity after (chemo)radiation therapy, administered with curative intent in older patients with cancer. MATERIALS AND METHODS: Four hundred and two patients aged ≥65 years (median age 72 years, range 65-96 years), diagnosed with either breast, non-small cell lung, prostate, head and neck, rectal or oesophageal cancer, and referred for curative (chemo)radiation therapy, took part in a multicentre prospective cohort study in eight radiotherapy centres in the Netherlands. The G8 and TGUGT scores were assessed before starting treatment. Other potential predictors and late toxicity were also recorded. Survival status and date of death, if applicable, were ascertained at the Dutch national death registry. RESULTS: After 2.5 years, the overall survival was 83%. Survival was 87% for patients with high G8 scores and 55% for patients with low G8 scores (Log-rank P value < 0.0001). Survival was 77% for patients with good TGUGT results and 50% for patients with poor TGUGT results (Log-rank P value < 0.001). In multivariable analysis, in addition to age and type of primary tumour, the association of the G8 score with overall survival remained, with a hazard ratio of 2.1 (95% confidence interval 1.2-3.8) for low versus high scores. CONCLUSIONS: G8 was associated with overall survival in older patients with cancer irradiated with curative intent. This association was independent of the predictive value of age and primary tumour.

Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy.

BACKGROUND: PORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis. METHODS: 427 women with HIR endometrial cancer were randomised between 2002-2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis. RESULTS: Median follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors. CONCLUSION: Long-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.

Breast-conserving therapy versus mastectomy in T1-2N2 stage breast cancer: a population-based study on 10-year overall, relative, and distant metastasis-free survival in 3071 patients.

PURPOSE: Our previous study demonstrated breast-conserving surgery with radiation therapy (BCT) to be at least equivalent to mastectomy in T1-2N0-1 breast cancer. Yet, 10-year survival rates after BCT and mastectomy with radiation therapy (MAST) in T1-2N2 breast cancer specifically have not been examined. Our study aimed to determine 10-year overall (OS), relative (RS), and distant metastasis-free survival (DMFS) in T1-2N2 breast cancer after BCT and MAST, stratified for T category. METHODS: All women diagnosed with primary invasive T1-2N2 breast cancer in 2000-2004, treated with BCT or MAST, both with axillary dissection and RT, were selected from the Netherlands Cancer Registry. Ten-year OS and DMFS were estimated using multivariable Cox regression. Excess mortality ratios (EMR) were calculated to estimate RS, using life tables of the general population. OS and RS were determined on the whole cohort, and DMFS on the 2003 cohort with completed follow-up. Missing data were imputed. RESULTS: Of 3071 patients, 1055 (34.4 %) received BCT and 2016 (65.7 %) MAST. BCT and MAST showed equal 10-year OS and RS. After stratification, BCT was significantly associated with improved 10-year OS [HRadjusted 0.82 (95 % CI 0.71-0.96)] and RS (EMRadjusted 0.81 (95 % CI 0.67-0.97]) in T2N2, but not in T1N2. Ten-year DMFS was equal for both treatments [HRadjusted 0.87 (95 % CI 0.64-1.18)] in the 2003 cohort (n = 594), which was representative for the full cohort. CONCLUSION: BCT showed at least equal 10-year OS, RS, and DMFS compared to MAST. These results confirm that BCT is a good treatment option in T1-2N2 breast cancer.

Bilateral breast cancer, synchronous and metachronous; differences and outcome.

The aims of this study were twofold: to analyze the incidence of patients having synchronous or metachronous bilateral invasive breast cancer (SBBC and MBBC) and to assess the characteristics and outcome compared to those having unilateral breast cancer (UBC). The used data were obtained from our prospective population-based cohort study which had been started in 1983. Bilateral breast cancer (BBC) was categorized as SBBC (≤3 months of the first primary) or MBBC (>3 months after the first primary). The incidence of SBBC was 1% and that of MBBC 7.0 %. Patients with UBC showed more ductal carcinoma compared to patients with BBC. MBBC status was an independent significant predictor of local failure (HR 1.9; 95% CI 1.3-2.7). SBBC status was an independent predictor of distant metastases (HR 2.6; 95% CI 1.4-4.5). Overall survival (OS) was better for MBBC (HR 0.6; 95% CI 0.4-0.8) and worse for SBBC (HR 2.3; 95% CI 1.5-3.6) compared to UBC. We noted: (1) MBBC showed a significant higher local failure compared to UBC, (2) SBBC, compared to MBBC and UBC had a significant higher distant metastases rate, (3) disease-specific survival and OS were significantly worse for SBBC compared to UBC and MBBC, and (4) that the OS for MBBC compared to UBC, was significantly better.

Factors influencing time between surgery and radiotherapy: A population based study of breast cancer patients.

This study describes variation in the time interval between surgery and radiotherapy in breast cancer (BC) patients and assesses factors at patient, hospital and radiotherapy centre (RTC) level influencing this variation. To do so, the factors were investigated in BC patients using multilevel logistic regression. The study sample consisted of 15,961 patients from the Netherlands Cancer Registry at 79 hospitals and 19 (RTCs) with breast-conserving surgery or mastectomy directly followed by radiotherapy. The percentage of patients starting radiotherapy ≤42 days varied from 14% to 94%. Early year of incidence, higher age, higher stage, mastectomy, higher ASA category and no availability of radiotherapy facilities were significantly associated with a longer time interval between radiotherapy and surgery. More patients received radiotherapy ≤42 days in hospitals with on-site radiotherapy facilities (OR 1.36, p = 0.024). Among the remainder, significant variation was found at the RTC level (11.1%, σ(2) = 0.254, SE 0.054), and at the hospital level (6.4% σ2 = 0.443, SE 0.163) (ICC 0.064). The significant delay and unexplained variance remaining at the RCT and hospital level suggests delays caused by the patient referral pathway from hospital to RCT, and indicates potential for improvement at both levels.

L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: pooled PORTEC trial results.

BACKGROUND: L1 cell adhesion molecule (L1CAM) expression has been implicated as risk factor for disease recurrence in endometrial cancer (EC), most likely due to its role in promoting tumour cell motility. We tested the performance of L1CAM expression in predicting the risk of recurrence in the randomised post operative radiation therapy in endometrial carcinoma (PORTEC)-1 and -2 trials. METHODS: In the PORTEC trials, stage I EC patients were randomised to external beam radiotherapy (EBRT) versus no additional treatment (PORTEC-1, n=714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n=427). Tumour samples of 865 (75.8%) patients were available for L1CAM expression analysis by immunohistochemistry. An established scoring system for EC was used, with >10% L1CAM staining defined as positive. RESULTS: Positive L1CAM expression was significantly correlated with risk of distant recurrence, with a hazard ratio (HR) of 5.1 (95% confidence interval (CI) 3.1-8.7) but not with vaginal relapse, while a trend for pelvic nodal relapse was found. Tumours with the highest expression levels (>50% positive) had the strongest risk of distant recurrence (HR 5.3, CI 2.7-10.4). In multivariate Cox analysis with the risk factors age, depth of invasion, grade, lympho-vascular space invasion (LVSI) and treatment, L1CAM expression remained an independent prognostic factor for distant recurrence (HR 3.5, CI 1.92-6.30) and overall survival (HR 2.1, CI 1.41-2.98). CONCLUSION: L1CAM expression is a strong independent predictor for distant recurrence and overall survival in stage I endometrial cancer. These results warrant prospective validation of L1CAM as marker for selecting patients who could benefit from more extensive diagnostic and/or therapeutic procedures.

Timing of radiotherapy in breast-conserving therapy: a large prospective cohort study of node-negative breast cancer patients without adjuvant systemic therapy.

BACKGROUND: To investigate the issue of timing of radiation therapy (RT) after lumpectomy in relation to recurrences and outcome. METHODS: Analysis was done on 1107 breast-conserving therapies (BCT) with 1070 women, all without lymph node metastasis and without any adjuvant systemic therapy. Timing was defined as time from lumpectomy till RT. Patients were categorised into tertiles: <45 days, 45-56 days, and 57-112 days. RESULTS: Local control did not show a difference between the tertiles. The distant metastasis-free survival as well as the disease-specific survival showed a decreased outcome starting the RT to early after the lumpectomy. CONCLUSION: The results of this cohort study further refines the hypothesis that timing of RT in BCT might have an impact on outcome. It suggests that a randomised trial in timing of RT in BCT seems necessary to give a definite answer.

Increased risks of third primary cancers of non-breast origin among women with bilateral breast cancer.

BACKGROUND: This study examined the risk of third cancer of non-breast origin (TNBC) among women with bilateral breast cancer (BBC; either synchronous or metachronous), focussing on the relation with breast cancer treatment. METHODS: Risk was assessed, among 8752 Dutch women diagnosed with BBC between 1989 and 2008, using standardised incidence ratios (SIR) and Cox regression analyses to estimate the hazard ratio (HR) of TNBC for different treatment modalities. RESULTS: Significant increased SIRs were observed for all TNBCs combined, haematological malignancies, stomach, colorectal, non-melanoma skin, lung, head and neck, endometrial, and ovarian cancer. A 10-fold increased risk was found for ovarian cancer among women younger than 50 years (SIR=10.0, 95% confidence interval (CI)=5.3-17.4). Radiotherapy was associated with increased risks of all TNBCs combined (HR=1.3; 95%CI=1.1-1.6, respectively). Endocrine therapy was associated with increased risks of all TNBCs combined (HR=1.2; 95%CI=1.0-1.5), haematological malignancies (HR=2.0; 95%CI=1.1-3.9), and head and neck cancer (HR=3.3; 95%CI=1.1-10.4). After chemotherapy decreased risks were found for all TNBCs combined (HR=0.63; 95%CI=0.5-0.87). CONCLUSION: Increased risk of TNBC could be influenced by genetic factors (ovarian cancer) or an effect of treatment (radiotherapy and endocrine therapy). More insight in the TNBC risk should further optimise and individualise treatment and surveillance protocols in (young) women with BBC.

Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors.

BACKGROUND: Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS: Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). RESULTS: At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS: EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.

Mapping use of radiotherapy for patients with non-small cell lung cancer in the Netherlands between 1997 and 2008.

AIM: After the publication of several reports that the utilisation rate of radiotherapy for patients with non-small cell lung cancer (NSCLC) varies for both medical and non-medical reasons, the utilisation of radiotherapy was studied in four regions in the Netherlands. MATERIALS AND METHODS: Data from 1997-2008 were collected from the population-based cancer registries of four comprehensive cancer centres ('regions'), which represent about half of the Dutch population, resulting in 24 185 non-metastatic patients with NSCLC. Treatment had to be started or planned within 6 months of diagnosis. We evaluated the utilisation of radiotherapy according to age, gender and period for each region. RESULTS: The utilisation of radiotherapy alone decreased over time (from 35 to 19%), whereas the utilisation of radiotherapy in combination with chemotherapy increased (from 5 to 19%). The total utilisation rate remained rather stable at about 40%. The differences between the four regions remained in general no more than 15%. Elderly patients with stage I and II disease had increased odds of receiving radiotherapy (≥75 versus <50 years: odds ratio 2.6, 95% confidence interval 2.0-3.3, whereas this was the opposite for patients with stage III disease: odds ratio 0.5, 95% confidence interval 0.4-0.6). For 17-24% of all patients, especially the elderly, best supportive care was applied. CONCLUSIONS: In the Netherlands, with good accessibility to medical care and well-implemented national guidelines, variation between the four regions is limited for the treatment of non-metastatic NSCLC with radiotherapy.

Use of primary radiotherapy for rectal cancer in the Netherlands between 1997 and 2008: a population-based study.

AIMS: To describe variation in the utilisation rates of primary radiotherapy for patients with rectal cancer in the Netherlands, focusing on time trends and age effects. MATERIALS AND METHODS: Data on primary non-metastatic rectal cancer were derived from the population-based cancer registries of four comprehensive cancer centres (regions) in the Netherlands (1997-2008, n=13,055). RESULTS: An increase in the utilisation rate was noted for the four regions, from 37-46% in 1997 to 66-76% in 2008, for both genders. This increase was found predominately for preoperative radiotherapy (from 13-31% to 58-67%) and (unsurprisingly) was most pronounced for stage T2-3 patients (from 9-27% to 68-80%). The probability of receiving radiotherapy decreased with age: the odds of receiving preoperative radiotherapy was reduced in patients aged 65 years and older, as well as the odds of receiving postoperative radiotherapy in those aged 75 years and older, which remained significant after adjustment for stage, gender and region. Regional differences persisted in multivariable analyses, i.e. the odds of receiving preoperative radiotherapy was reduced in two regions: odds ratio: 0.4 (95% confidence interval: 0.4-0.5) and 0.7 (0.6-0.8). The odds of receiving postoperative radiotherapy was significantly increased in these regions [odds ratio: 2.6 (2.2-3.2) and 1.6 (1.3-1.9), respectively] and reduced in another [odds ratio 0.8 (0.6-0.96)]. CONCLUSIONS: The utilisation rate of radiotherapy for rectal cancer increased significantly over time, particularly for preoperative radiotherapy and was most pronounced for T2-3 patients. Due to national multidisciplinary treatment guidelines, regional differences became limited in recent years after adjustment for age and stage of the disease. A low utilisation rate of radiotherapy was seen in women and elderly patients.

A population-based study on the utilisation rate of primary radiotherapy for prostate cancer in 4 regions in the Netherlands, 1997-2008.

AIM: The purpose was to study variations in utilisation rates of external beam radiotherapy (EBRT) and brachytherapy (BT) for prostate cancer patients. MATERIALS AND METHODS: We calculated the proportion and number of EBRT and BT given or planned within 6 months of diagnosis in 4 Dutch regions, according to stage and age in a population-based setting including 47,259 prostate cancer patients diagnosed from 1997 until 2008. RESULTS: During this study period, the overall utilisation rate of EBRT remained stable at around 25%, while the rate of BT for non-metastasized patients increased from 1% (95% CI:0-1%) to 12% (11-13%) in 2006 and slightly decreased towards 10% (9-11%) in 2008. From 2001 on, the overall utilisation rate of EBRT decreased significantly in one region (p<0.05). In this region, a sharp rise in the utilisation rate of BT for non-metastatic patients was noted to 17% (14-20%) in 2008 after a peak of 24% (21-27%) in 2006. For localised disease, BT was used more often at the expense of EBRT while for locally advanced disease the utilisation rate of EBRT increased. In the multivariate analysis, regional differences in the utilisation rate of EBRT persisted with odds ratios ranging from 0.7 to 0.9 compared to the reference region. Moreover, low rates of EBRT were associated with high BT rates. The regional differences could not be explained by differences in risk profiles. CONCLUSIONS: The utilisation rate of EBRT remained stable with limited variation between regions while BT was used increasingly with clear regional differences. To cope with this and in view of the increasing incidence of prostate cancer, adequate resources have to be planned for the optimal care of these patients.

Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.

BACKGROUND: After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life. METHODS: In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756. FINDINGS: At median follow-up of 45 months (range 18-78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1.8% (95% CI 0.6-5.9) for VBT and 1.6% (0.5-4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17-3.49; p=0.74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% (2.8-9.6) for VBT and 2.1% (0.8-5.8) for EBRT (HR 2.08, 0.71-6.09; p=0.17). 1.5% (0.5-4.5) versus 0.5% (0.1-3.4) of patients presented with isolated pelvic recurrence (HR 3.10, 0.32-29.9; p=0.30), and rates of distant metastases were similar (8.3% [5.1-13.4] vs 5.7% [3.3-9.9]; HR 1.32, 0.63-2.74; p=0.46). We recorded no differences in overall (84.8% [95% CI 79.3-90.3] vs 79.6% [71.2-88.0]; HR 1.17, 0.69-1.98; p=0.57) or disease-free survival (82.7% [76.9-88.6] vs 78.1% [69.7-86.5]; HR 1.09, 0.66-1.78; p=0.74). Rates of acute grade 1-2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12.6% [27/215] vs 53.8% [112/208]). INTERPRETATION: VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. FUNDING: Dutch Cancer Society.

The impact of margin status in breast-conserving therapy for lobular carcinoma is age related.

PURPOSE: The aim is to look at the impact of margin status and outcome of invasive lobular carcinoma (ILC) treated with breast-conserving therapy (BCT). METHODS: This manuscript describes an analysis on 330 BCT in 318 patients with ILC. RESULTS: The 12-year local relapse free survival (LRFS) is 89%. In multivariate analysis, positive margin status, age>50 years, contra lateral breast cancer, and adjuvant systemic therapy were significant predictors of local relapse free survival. In a separate analysis limited to a positive margin for invasive carcinoma or carcinoma in situ, only a positive margin for invasive carcinoma was a significant predictor of local relapse free survival. This was limited to women

Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874).

The management of uterine sarcomas continues to present many difficulties. Primary surgery is the optimal treatment but the role of post-operative radiation remains uncertain. In the mid-1980s, the European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study proposed a trial to evaluate adjuvant radiotherapy, as previous non-randomised studies had suggested a survival advantage and improved local control when post-operative radiation was administered. The study opened in 1987 taking 13 years to accrue 224 patients. All uterine sarcoma subtypes were permitted. Patients were required to have undergone as a minimum, TAH and BSO and wahsings (166 patients) but nodal sampling was optional. There were 103 leiomyosarcomas (LMS), 91 carcinosarcomas (CS) and 28 endometrial stromal sarcomas (ESS). Patients were randomised to either observation or pelvic radiation, 51 Gy in 28 fractions over 5 weeks. Hundred and twelve were recruited to each arm. The initial analysis has shown a reduction in local relapse (14 versus 24, p=0.004) but no effect on either OS or PFS. No unexpected toxicity was seen in the radiation arm. No difference in either overall or disease-free survival was demonstrated but there is an increased local control for the CS patients receiving radiation but without any benefit for LMS. Prognostic factor analysis shows that stage, age and histological subtype were important predictors of behaviour which may explain differences between CS and LMS. CS appears to show more kinship to poorly differentiated endometrial carcinomas in behaviour. LMS did not show the same benefit from radiation. These results will help shape future management and clinical trials in uterine sarcomas.

Multicenter cohort study on treatment results and risk factors in stage II endometrial carcinoma.

The aim of this study was to report outcome data and prognostic factors from a large cohort of pathologic stage II endometrioid type endometrial carcinoma. One hundred forty-two stage IIA-B patients were included. A central histopathologic review was performed. Follow-up ranged from 2 to 217 months with a median of 61 months. End points of the study were local and locoregional recurrence rates, distant metastasis-free survival (DMFS), disease-free survival (DFS), and disease-specific survival (DSS). The local failure rate was 5.1% for stage IIA patients and 10.8% for stage IIB patients. Grade was the only significant prognostic factor for local failure. With respect to DMFS, DFS, and DSS, grade 3 showed to be the most prominent prognostic factor in multivariate analyses. Lymphvascular space involvement combined with grades 3 and 2 and myometrial invasion greater than 0.5 also showed to be significant for DMFS and DFS. Our study showed grade 3 to be the most important single independent predictive factor for locoregional and distant recurrences in endometrial carcinoma stage II.