Marloes Derks

Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial

BACKGROUND After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. METHODS The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4-8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5-3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. FINDINGS 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0-10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65-69) for the exemestane group and 67% (65-69) for the sequential group (hazard ratio 0·96, 0·88-1·05; p=0·39). INTERPRETATION The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. FUNDING Pfizer, Dutch Cancer Foundation.

Lymphatic drainage pathways from the cervix uteri: Implications for radical hysterectomy?

OBJECTIVE Radical hysterectomy with pelvic lymphadenectomy is the treatment of choice for early-stage cervical cancer. Wertheims original technique has been often modified, mainly in the extent of parametrectomy. Okabayashis technique is considered as the most radical variant regarding removal of the ventral parametrium and paracolpal tissues. Surgical outcome concerning recurrence and survival is good, but morbidity is high due to autonomic nerve damage. While the autonomic network has been studied extensively, the lymphatic system is less understood. This study describes the lymphatic drainage pathways of the cervix uteri and specifically the presence of lymphatics in the vesico-uterine ligament (VUL). METHODS A developmental series of 10 human female fetal pelves was studied. Paraffin embedded blocks were sliced in transverse sections of 8 or 10 μm. Analysis was performed by staining with antibodies against LYVE-1 (lymphatic endothelium), S100 (Schwann cells), alpha-Smooth Muscle Actin (smooth muscle cells) and CD68 (macrophages). The results were three-dimensionally represented. RESULTS Two major pathways drained the cervix uteri: a supra-ureteral pathway, running in the cardinal ligament superior to the ureter, and a dorsal pathway, running in the utero-sacral ligament towards the rectal pillars. No lymph vessels draining the cervix uteri were detected in the VUL. In the paracolpal parametrium lymph vessels draining the upper vagina fused with those from the bladder. CONCLUSIONS The VUL does not contain lymphatics from the cervix uteri. Hence, the favorable survival outcomes of the Okabayashi technique cannot be explained by radical removal of lymphatic pathways in the ventrocaudal parametrium.

Results of radical surgery in women with stage IB2/IIA2 cervical cancer

There is ongoing discussion about the primary treatment of women with bulky early‐stage cervical cancer. Because of the high number of patients who need adjuvant (chemo)radiotherapy after initial surgical treatment, some state that primary (chemo)radiotherapy should be the treatment of choice to prevent morbidity. The aim of our study is to assess the results of radical surgery for women with bulky early‐stage cervical cancer in terms of recurrence patterns and survival.

Physical Functioning in Older Patients With Breast Cancer: A Prospective Cohort Study in the TEAM Trial.

BACKGROUND Previous retrospective studies have shown that physical functioning in older cancer survivors is affected after treatment, yet prospective data are lacking. The aim of this study was to assess change in physical functioning in different age groups of patients with hormone receptor-positive breast cancer who were enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase III trial. METHODS Two physical parameters were assessed. Physical functioning was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire 1 year (T1) and 2 years (T2) after diagnosis. Physical activity was measured in metabolic equivalent of task (MET) hours/week at T1 and T2. Physical activity before diagnosis (T0) was assessed retrospectively at the T1 questionnaire. Patients were divided into three age groups: <60, 60-69, and ≥70 years. Decline in physical functioning was assessed using linear regression analysis. Differences in mean values of physical activity levels were calculated using repeated-measures one-way analysis of variance. RESULTS A total of 431 patients were included for analysis. In all age groups, physical activity levels at T1 and T2 were significantly lower than prediagnostic physical activity levels (T0) (p < .001 for all age groups). Age ≥70 years was independently associated with decline in physical functioning between T1 and T2 (β = -4.62, 95% confidence interval -8.73 to -0.51, p = .028). CONCLUSION Patients aged 70 years or older treated with breast surgery and adjuvant hormonal therapy did not improve between years 1 and 2 after diagnosis to the same extent as did younger patients. IMPLICATIONS FOR PRACTICE Although older patients constitute a large share of the breast cancer population, little is known about the effect and consequences of treatment of breast cancer in this specific age group. This study revealed that, unlike younger patients, older patients do not regain their physical abilities after surgical and adjuvant treatment for breast cancer. In older adults, the effect of treatment on physical functioning and independency could be more relevant than survival outcomes. Clinicians and older patients should be aware of the impact of treatment on physical functioning and prevent older patients from experiencing physical decline, which could lead to institutionalization and loss of independence. There is a need for age-specific guidelines that take into account the heterogeneity of the older population and for evidence-based treatment that focuses not only on cancer-specific outcomes but also on the consequences of treatment for physical and cognitive functioning and quality of life.

Long-term Pelvic Floor Function and Quality of Life After Radical Surgery for Cervical Cancer: A Multicenter Comparison Between Different Techniques for Radical Hysterectomy With Pelvic Lymphadenectomy.

Objective This study aimed to compare urinary and bowel symptoms and quality of life (QoL) among women treated with a Wertheim–Meigs (WM, type III) or Wertheim–Okabayashi (WO, type IV) radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. Methods In this cross-sectional observational study, patients treated with a WO or a (nerve sparing) WM radical hysterectomy (with or without adjuvant radiotherapy) between January 2000 and December 2010 in the Center for Gynaecological Oncology Amsterdam or Leiden University Medical Center were included. To assess QoL, urinary and bowel symptoms we used the EORTC QLQ-C30, EORTC QLQ-CX24, and Leiden Questionnaire. We performed a multivariate analysis to identify factors associated with urinary symptoms. Results Two hundred sixty-eight women were included (152 WO and 116 WM). Quality of life was not significantly different in patients treated by WO or WM. Urinary symptoms were more often reported by patients in the WO group compared to the WM group: “feeling of urine retention” (53% vs 32%), “feeling less/no urge to void” (59% vs 14%), and “timed voiding” (49% vs 10%). With regard to bowel symptoms, there was no difference between both. Multivariate analysis showed that surgical technique was an independent factor for differences in urinary symptoms. Conclusions Patients undergoing more radical surgery for early-stage cervical cancer report significantly more urinary dysfunction, whereas bowel function and health-related QoL are not decreased.

Careful Dissection of the Distal Ureter Is Highly Important in Nerve-sparing Radical Pelvic Surgery: A 3D Reconstruction and Immunohistochemical Characterization of the Vesical Plexus.

Objective Radical hysterectomy with pelvic lymphadenectomy (RHL) is the preferred treatment for early-stage cervical cancer. Although oncological outcome is good with regard to recurrence and survival rates, it is well known that RHL might result in postoperative bladder impairments due to autonomic nerve disruption. The pelvic autonomic network has been extensively studied, but the anatomy of nerve fibers branching off the inferior hypogastric plexus to innervate the bladder is less known. Besides, the pathogenesis of bladder dysfunction after RHL is multifactorial but remains unclear. We studied the 3-dimensional anatomy and neuroanatomical composition of the vesical plexus and describe implications for RHL. Materials and Methods Six female adult cadaveric pelvises were macroscopically dissected. Additionally, a series of 10 female fetal pelvises (embryonic age, 10–22 weeks) was studied. Paraffin-embedded blocks were transversely sliced in 8-μm sections. (Immuno) histological analysis was performed with hematoxylin and eosin, azan, and antibodies against S-100 (Schwann cells), tyrosine hydroxylase (postganglionic sympathetic fibers), and vasoactive intestinal peptide (postganglionic parasympathetic fibers). The results were 3-dimensionally visualized. Results The vesical plexus formed a group of nerve fibers branching off the ventral part of the inferior hypogastric plexus to innervate the bladder. In all adult and fetal specimens, the vesical plexus was closely related to the distal ureter and located in both the superficial and deep layers of the vesicouterine ligament. Efferent nerve fibers belonging to the vesical plexus predominantly expressed tyrosine hydroxylase and little vasoactive intestinal peptide. Conclusions The vesical plexus is located in both layers of the vesicouterine ligament and has a very close relationship with the distal ureter. Complete mobilization of the ureter in RHL might cause bladder dysfunction due to sympathetic and parasympathetic denervation. Hence, the distal ureter should be regarded as a risk zone in which the vesical plexus can be damaged.

Completing or Abandoning Radical Hysterectomy in Early-stage Lymph Node–positive Cervical Cancer: Impact on Disease-free Survival and Treatment-related Toxicity

Introduction Management regarding completing hysterectomy in case of intraoperative finding of positive lymph nodes in early-stage cervical cancer differs between institutions. The aim of this study was to compare survival and toxicity after completed hysterectomy followed by adjuvant (chemo-)radiotherapy versus abandoned hysterectomy and primary treatment with chemoradiotherapy (CRT). Methods A retrospective multicenter cohort study was performed. All patients were scheduled for radical hysterectomy with pelvic lymphadenectomy (RHL). In the RHL group, hysterectomy was completed followed by adjuvant (chemo-)radiotherapy. In the second group, hysterectomy was abandoned, and CRT was conducted. Primary outcomes were disease-free survival (DFS) and overall survival. A multivariable analysis on DFS was performed. Toxicity was scored according to the National Cancer Institute CTCAE (Common Terminology Criteria for Adverse Events) v4.03. Results A total of 121 patients were included (RHL, n = 89; CRT, n = 32). There was no difference in overall survival (84% vs 77%). Five-year DFS was in favor of completing RHL (81% vs 67%). Multivariable analysis showed that, corrected for lymph node variables, treatment regimen was not associated with DFS. After RHL, pelvic recurrence rate was significantly lower compared with CRT (2% vs 16%). CTCAE grade 3–4 toxicity rates were higher in the CRT compared with the RHL group (59% vs 30%), mainly because of differences in chemotherapy-related hematologic toxicity. Conclusions In patients with clinically N0 early-stage cervical cancer with intraoperative detection of positive nodes, completing RHL followed by adjuvant (chemo-)radiotherapy may result in a better pelvic control compared with abandoning hysterectomy and treatment with chemoradiotherapy. However, if corrected for lymph node variables, treatment (RHL or CRT) was not associated with DFS.

Targeted therapy in older women with breast cancer – What's the target?

In this review, the results of the FOCUS (Female breast cancer in the elderly: Optimizing Clinical guidelines USing clinico-pathological and molecular data) program are summarized. This study was originally designed with the aim to define guidelines for the treatment of older women with breast cancer. With data from several studies within FOCUS, a prediction model can be constructed. Such a model helps to define individualized treatment for older patients with breast cancer, taking into account tumour characteristics and patient-related factors. At a clinical level, this model can provide the physician and the patient with accurate prediction to assist on the decision making of treatment strategies: this results into individualized treatment, not based on one individual marker, but on different pillars related to the patient, the tumour and the most suitable, appropriate treatment.

Treatment and Survival of Patients with Colon Cancer Aged 80 Years and Older : A EURECCA International Comparison

BACKGROUND Colon cancer in older patients represents a major public health issue. As older patients are hardly included in clinical trials, the optimal treatment of these patients remains unclear. The present international EURECCA comparison explores possible associations between treatment and survival outcomes in elderly colon cancer patients. SUBJECTS, MATERIALS, AND METHODS National data from Belgium, Denmark, The Netherlands, Norway, and Sweden were obtained, as well as a multicenter surgery cohort from Germany. Patients aged 80 years and older, diagnosed with colon cancer between 2001 and 2010, were included. The study interval was divided into two periods: 2001-2006 and 2007-2010. The proportion of surgical treatment and chemotherapy within a country and its relation to relative survival were calculated for each time frame. RESULTS Overall, 50,761 patients were included. At least 94% of patients with stage II and III colon cancer underwent surgical removal of the tumor. For stage II-IV, the proportion of chemotherapy after surgery was highest in Belgium and lowest in The Netherlands and Norway. For stage III, it varied from 24.8% in Belgium and 3.9% in Norway. For stage III, a better adjusted relative survival between 2007 and 2010 was observed in Sweden (adjusted relative excess risk [RER] 0.64, 95% confidence interval [CI]: 0.54-0.76) and Norway (adjusted RER 0.81, 95% CI: 0.69-0.96) compared with Belgium. CONCLUSION There is substantial variation in the rate of treatment and survival between countries for patients with colon cancer aged 80 years or older. Despite higher prescription of adjuvant chemotherapy, poorer survival outcomes were observed in Belgium. No clear linear pattern between the proportion of chemotherapy and better adjusted relative survival was observed. IMPLICATIONS FOR PRACTICE With the increasing growth of the older population, clinicians will be treating an increasing number of older patients diagnosed with colon cancer. No clear linear pattern between adjuvant chemotherapy and better adjusted relative survival was observed. Future studies should also include data on surgical quality.

Breast Cancer Epidemiology

There is global disparity in the incidence of breast cancer, as well as overall and breast cancer-specific mortality. Generally, there is a greater incidence of breast cancer in the developed world but a greater mortality from breast cancer in the developing world. Within Europe, variation of incidence and mortality are present. This is due to a complex combination of factors including risk factors, limitations of data and much inequality in the methods of breast cancer screening, diagnosis and treatment.