M.F. Ernst

Surgical resection of the primary tumour is associated with improved survival in patients with distant metastatic breast cancer at diagnosis

OBJECTIVE Recent studies indicate that removal of the primary tumour may have a beneficial effect on mortality risk of patients with primary distant metastatic breast cancer (stage IV), although most of them did not rule out confounding by the presence of co-morbidity. In this retrospective study the impact of surgical resection of the primary tumour on the survival of patients with primary distant metastatic disease is investigated, taking into account the presence of co-morbidity and other potential confounders. METHODS Between 1993 and 2004, 15 769 patients with breast cancer were diagnosed in the south of the Netherlands. This study included the 728 patients with distant metastatic disease at initial presentation, which was 5% of all patients. Of them, 40% had surgery of the primary tumour. Follow-up was carried out until 1 July 2006. RESULTS Median survival of the patients who had surgery of their primary tumour was significantly longer than for the patients who did not have surgery (31 vs. 14 months). The 5-year survival rates were 24.5% and 13.1%, respectively (p < 0.0001). In a multivariable Cox regression analysis, adjusting for age, period of diagnosis, T-classification, number of metastatic sites, co-morbidity, use of loco-regional radiotherapy and use of systemic therapy, surgery appeared to be an independent prognostic factor for overall survival (HR = 0.62; 95% CI 0.51-0.76). CONCLUSION Removal of the primary tumour in patients with primary distant metastatic disease was associated with a reduction of the mortality risk of around 40%. The association was independent of age, presence of co-morbidity and other potential confounders, but a randomized controlled trial will be needed to rule out residual confounding.

Impact of breast surgery on survival in patients with distant metastases at initial presentation: a systematic review of the literature.

According to current treatment standards, patients with metastatic breast cancer at diagnosis receive palliative therapy. Local treatment of the breast is only recommended if the primary tumor is symptomatic. Recent studies suggest that surgical removal of the primary tumor has a favorable impact on the prognosis of patients with primary metastatic breast cancer. We performed a systematic review of the literature to weigh the evidence for and against breast surgery in this patient group. Ten retrospective studies were found in which the use of breast surgery in primary metastatic breast cancer and its impact on survival was examined. The hazard ratios of the studies were pooled to provide an estimate of the overall effect of surgery, and the results and conclusions of the studies were analyzed. A crude analysis, without adjustment for potential confounders, showed that surgical removal of the breast lesion in stage-IV disease was associated with a significantly higher overall survival rate in seven of the ten studies, and a trend toward a better survival in the three remaining studies. Surgery of the primary tumor appeared to be an independent factor for an improved survival in the multivariate analyses from the individual studies, with hazard ratios ranging from 0.47 to 0.71. The pooled hazard ratio for overall mortality was 0.65 (95% CI 0.59–0.72) in favor of the patients undergoing surgery. This systematic review of the literature suggests that surgery of the primary breast tumor in patients with stage-IV disease at initial presentation does have a positive impact on survival. In order to provide a definite answer on whether local tumor control in patients with primary metastatic disease improves survival, a randomized controlled trial comparing systemic therapy with and without breast surgery is needed.

Validation of a Nomogram to Predict the Risk of Nonsentinel Lymph Node Metastases in Breast Cancer Patients with a Positive Sentinel Node Biopsy: Validation of the MSKCC Breast Nomogram

BackgroundCompletion axillary lymph node dissection (ALND) remains the standard of care for patients with disease-positive sentinel lymph nodes (SLN). However, approximately two-thirds will have no additional disease-positive nodes. To identify the patient’s individual risk for non-SLN metastases, the Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram.MethodsThe records of 182 breast cancer patients who underwent SLN and ALND were selected. Serial hematoxylin and eosin (HE) analysis and immunohistochemistry were routinely performed on each sentinel node. For application of the nomogram, the detection method was assigned in two ways: for all metastases visible by serial HE, the method of detection was scored as “serial HE” (method 1), independent of the tumor size, and by a combination of size and staining method (method 2); so macrometastasis were scored as detected by routine HE, micrometastasis by serial HE, and isolated tumor cells by immunohistochemistry. A receiver operating characteristic curve (ROC) was drawn, and the area under the curve was calculated to assess the discriminative power of the nomogram.ResultsThe area under the ROC was .71 (range, .64–.79) according to method 1 and .75 (range, .67–.88) according to method 2.ConclusionsBecause the variable “method of detection” in the MSKCC nomogram is a surrogate for SLN metastasis size, the size category of the SLN metastasis can be used in applying the nomogram to patients in whom the SLN histologic analysis is performed by a much different procedure than that used to develop the MSKCC nomogram. This results in an improved predictive accuracy.

The role of surgery in metastatic breast cancer.

Some of the patients who present with breast cancer already have distant metastatic disease. According to recent literature, these patients may benefit from resection of the breast tumour. One explanation for the effect of this resection is that reducing the tumour load influences metastatic growth. Results of future randomised controlled trials should indicate whether surgery of the breast tumour truly improves survival. Selected patients could even benefit from metastasectomy of liver and lung metastases; survival seems to improve and these procedures seldom lead to major complications. When metastasectomy is not possible, minimally invasive techniques can be used in selected patients for the treatment of breast cancer liver metastases, radiofrequency ablation (RFA) being discussed most in the literature. Patients with locally advanced breast cancer are treated multidisciplinarily and with curative intent. Part of the treatment is surgery to reduce tumour load. Regarding treatment of the axilla, in a clinically negative axilla sentinel node biopsy is advised before neoadjuvant treatment; an axillary lymph node dissection is not warranted. In local recurrence, surgery is the primary treatment. Axillary staging can be done in patients with a previous negative sentinel node biopsy. Regional recurrence after breast-conserving surgery or mastectomy is treated with surgery followed by radiotherapy.

Meta-analysis of predictive factors for non-sentinel lymph node metastases in breast cancer patients with a positive SLN

AIMS A meta-analysis was performed to identify the clinicopathological variables most predictive of non-sentinel node (NSN) metastases when the sentinel node is positive. METHODS A Medline search was conducted that ultimately identified 56 candidate studies. Original data were abstracted from each study and used to calculate odds ratios. The random-effects model was used to combine odds ratios to determine the strength of the associations. FINDINGS The 8 individual characteristics found to be significantly associated with the highest likelihood (odds ratio >2) of NSN metastases are SLN metastases >2mm in size, extracapsular extension in the SLN, >1 positive SLN, ≤1 negative SLN, tumour size >2cm, ratio of positive sentinel nodes >50% and lymphovascular invasion in the primary tumour. The histological method of detection, which is associated with the size of metastases, had a correspondingly high odds ratio. CONCLUSIONS We identified 8 factors predictive of NSN metastases that should be recorded and evaluated routinely in SLN databases. These factors should be included in a predictive model that is generally applicable among different populations.

Transanal endoscopic microsurgery for local excision of rectal lesions: is there a learning curve?

Background: Transanal endoscopic microsurgery (TEM) is a minimally invasive technique for the local resection of benign and stage T1 rectal lesions in selected patients, associated with lower morbidity and mortality rates than open surgery. We present our initial results and assess whether experience influences outcome after TEM. Methods: This was a prospective descriptive survey. All patients undergoing TEM for tubulovillous adenoma or carcinoma between 2002 and 2007 were included. Results: A total of 105 patients were included. Median age was 68 years. Median distance of the lesion from the anal verge was 7.0 cm; median operating time was 90 min. In 10 patients, the peritoneum was opened. Six procedures were converted to (low) anterior resections. Postoperative staging revealed 77 tubulovillous adenomas, 22 stage T1, 5 stage T2 and 1 stage T3 carcinomas; tumor resection was radical in 86%. The postoperative complication rate was 7.6%. Length of hospital stay, operating time and complications significantly diminished over time. After a median follow-up of 27 months, 8 recurrences occurred (7.6%). Conclusion: TEM is a safe technique with low morbidity and recurrence rates. Over time, experience leads to a reduction in operation time, lenght of patients’ hospital stay and complication rate. TEM remains the treatment of choice for benign lesions and stage T1 rectal carcinomas in selected patients.

SUBMIT: Systemic therapy with or without up front surgery of the primary tumor in breast cancer patients with distant metastases at initial presentation.

BackgroundFive percent of all patients with breast cancer have distant metastatic disease at initial presentation. Because metastatic breast cancer is considered to be an incurable disease, it is generally treated with a palliative intent. Recent non-randomized studies have demonstrated that (complete) resection of the primary tumor is associated with a significant improvement of the survival of patients with primary metastatic breast cancer. However, other studies have suggested that the claimed survival benefit by surgery may be caused by selection bias. Therefore, a randomized controlled trial will be performed to assess whether breast surgery in patients with primary distant metastatic breast cancer will improve the prognosis.DesignRandomization will take place after the diagnosis of primary distant metastatic breast cancer. Patients will either be randomized to up front surgery of the breast tumor followed by systemic therapy or to systemic therapy, followed by delayed local treatment of the breast tumor if clinically indicated.Patients with primary distant metastatic breast cancer, with no prior treatment of the breast cancer, who are 18 years or older and fit enough to undergo surgery and systemic therapy are eligible. Important exclusion criteria are: prior invasive breast cancer, surgical treatment or radiotherapy of this breast tumor before randomization, irresectable T4 tumor and synchronous bilateral breast cancer. The primary endpoint is 2-year survival. Quality of life and local tumor control are among the secondary endpoints.Based on the results of prior research it was calculated that 258 patients are needed in each treatment arm, assuming a power of 80%. Total accrual time is expected to take 60 months. An interim analysis will be performed to assess any clinically significant safety concerns and to determine whether there is evidence that up front surgery is clinically or statistically inferior to systemic therapy with respect to the primary endpoint.DiscussionThe SUBMIT study is a randomized controlled trial that will provide evidence on whether or not surgery of the primary tumor in breast cancer patients with metastatic disease at initial presentation results in an improved survival.Trial registrationNCT01392586.

Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study)

BackgroundRecent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications.The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas.Methods/designMulticenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma ≥ 3 cm, located between 1–15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment.Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures.Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group.DiscussionThe TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas.Trial registration number(trialregister.nl) NTR1422

Combined anxiety and depressive symptoms before diagnosis of breast cancer

PURPOSE To determine the relationship between pre-diagnosis state anxiety, depressive symptoms, and combined state anxiety and depressive symptoms (CADS) with quality of life (QOL), fatigue, state anxiety and depressive symptoms one and two years after surgery in women with breast cancer. METHODS Women with breast problems referred to a Dutch outpatient clinic were recruited for the study. Participants (N=428) completed a set of questionnaires before diagnosis (Time0) and the women with breast cancer subsequently received questionnaires at 12 (Time1) and 24 months (Time2) after surgical treatment. The questionnaire set consisted of questionnaires on demographics, state anxiety, depressive symptoms, fatigue, QOL, neuroticism, and trait anxiety. Chi-square tests, independent samples T-tests, and multivariate linear regression analyses were used to do the analyses. RESULTS Before their diagnosis of breast cancer, 111 women (28%) had CADS. Of the CADS-group, a higher percentage had elevated levels of anxiety, depressive symptoms, and CADS at all follow-up moments than of the non-CADS-group. CADS-score at before diagnosis and neuroticism were the most important predictors of outcome measures at Time1 and Time2. CONCLUSIONS More than one in four women, who later received the diagnosis breast cancer, had elevated levels of both state anxiety and depressive symptoms (CADS) just before diagnosis. This factor was also a major predictor of QOL, state anxiety, depressive symptoms, and fatigue 12 and 24 months after surgery. This implies that women with a higher score on both state anxiety and depressive symptoms should be identified as soon as possible in the process of diagnosis and treatment of breast cancer using validated questionnaires or screening instruments. Only by identifying this group of patients, tailored psychological care can be accomplished.

Outcome of Colonic Surgery in Elderly Patients with Colon Cancer

Introduction. Colonic cancer is one of the most commonly diagnosed malignancies and most often occurs in patients aged 65 years or older. Aim. To evaluate the outcome of colonic surgery in the elderly in our hospital and to compare five-year survival rates between the younger and elderly patients. Methods. 207 consecutive patients underwent surgery for colon cancer. Patients were separated in patients younger than 75 and older than 75 years. Results. Elderly patients presented significantly more (P < .05) as a surgical emergency, had a longer duration of admission and were more often admitted to the ICU (P < .01). Also, elderly patients had significant more co-morbidities, especially cardiovascular pathology (P < .01). Post-operative complications were seen more often in the elderly, although no significant difference was seen in anastomotic leakage. The five-year survival rate in the younger group was 62% compared with 36% in the elderly (P < .05). DFS was 61% in the younger patients compared with 32% in the elderly (P < .05). Conclusion. Curative resection of colonic carcinoma in the elderly is well tolerated and age alone should not be an indication for less aggressive therapy. However, the type and number of co-morbidities influence post-operative mortality and morbidity.