Adri C. Voogd

Differences in Risk Factors for Local and Distant Recurrence After Breast-Conserving Therapy or Mastectomy for Stage I and II Breast Cancer: Pooled Results of Two Large European Randomized Trials

PURPOSE Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments. PATIENTS AND METHODS The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%). RESULTS There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P <.01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P <.01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P <.01). CONCLUSION Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.

Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA)

As the mean age of the global population increases, breast cancer in older individuals will be increasingly encountered in clinical practice. Management decisions should not be based on age alone. Establishing recommendations for management of older individuals with breast cancer is challenging because of very limited level 1 evidence in this heterogeneous population. In 2007, the International Society of Geriatric Oncology (SIOG) created a task force to provide evidence-based recommendations for the management of breast cancer in elderly individuals. In 2010, a multidisciplinary SIOG and European Society of Breast Cancer Specialists (EUSOMA) task force gathered to expand and update the 2007 recommendations. The recommendations were expanded to include geriatric assessment, competing causes of mortality, ductal carcinoma in situ, drug safety and compliance, patient preferences, barriers to treatment, and male breast cancer. Recommendations were updated for screening, primary endocrine therapy, surgery, radiotherapy, neoadjuvant and adjuvant systemic therapy, and metastatic breast cancer.

Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas

Oncogenic human papillomavirus (HPV) is a causative agent in a subgroup of head and neck carcinomas, particularly tonsillar squamous cell carcinomas (TSCC). This study was undertaken because controversial data exist on the physical status of HPV‐DNA and the use of p16INK4A overexpression as surrogate HPV marker, and to examine the impact of HPV and tobacco consumption on the clinical course of TSCC. Tissue sections of 81 TSCC were analyzed by HPV 16‐specific fluorescence in situ hybridization (FISH) and p16INK4A‐specific immunohistochemistry. Results were correlated with clinical and demographic data. HPV 16 integration was detected by FISH as punctate signals in 33 out of 81 (41%) TSCC, 32 of which showed p16INK4A accumulation. Only 5 out of 48 HPV‐negative tumors showed p16INK4A immunostaining (p < 0.0001). The presence of HPV furthermore correlates significantly with low tobacco (p = 0.002) and alcohol intake (p = 0.011), poor differentiation grade (p = 0.019), small tumor size (p = 0.024), presence of a local metastasis (p = 0.001) and a decreased (loco)regional recurrence rate (p = 0.039). Statistical analysis revealed that smoking significantly increases the risk of cancer death from TSCC and that non‐smoking patients with HPV‐containing TSCC show a remarkably better disease‐specific survival rate. HPV 16 is integrated in 41% of TSCC and strongly correlates with p16INK4A overexpression, implicating the latter to be a reliable HPV biomarker. Patients with HPV‐positive tumors show a favorable prognosis as compared to those with HPV‐negative tumors, but tobacco use is the strongest prognostic indicator. These findings indicate that oncogenic processes in the tonsils of non‐smokers differ from those occurring in smokers, the former being related to HPV 16 infection.

Risk, severity and predictors of physical and psychological morbidity after axillary lymph node dissection for breast cancer

The aim of this study was to investigate the nature and severity of the arm complaints among breast cancer patients after axillary lymph node dissection (ALND) and to study the effects of this treatment-related morbidity on daily life and well-being. 400 women, who underwent ALND as part of breast cancer surgery, filled out a treatment-specific quality of life questionnaire. The mean time since ALND was 4.7 years (range 0.3-28 years). More than 20% of patients reported pain, numbness, or loss of strength and 9% reported severe oedema. None of the complaints appeared to diminish over time. Irradiation of the axilla and supraclavicular irradiation were associated with a 3.57-fold higher risk of oedema (odds ratio (OR) 3.57; 95% confidence interval (CI) 1.66-7.69) causing many patients to give up leisure activities or sport. Women who underwent irradiation of the breast or chest wall more often reported to have a sensitive scar than women who did not receive radiotherapy. Women <45 years of age had an approximately 6 times higher risk of numbness of the arm (OR 6.49; 95% CI 2.58-16.38) compared with those > or = 65 years of age; they also encountered more problems doing their household chores. The results of the present study support the introduction of less invasive techniques for the staging of the axilla, sentinel node biopsy being the most promising.

Prognosis after Treatment for Loco-regional Recurrence after Mastectomy or Breast Conserving Therapy in Two Randomised Trials (EORTC 10801 and DBCG-82TM)

The aim of this study was to investigate and compare the prognosis after treatment for loco-regional recurrences (LR) after (modified) radical mastectomy (MRM) or breast conserving therapy (BCT), in terms of overall survival and time to subsequent LR, in patients originally treated in two European randomised trials. In EORTC trial 10801 and DBCG trial 82-TM, 1,807 patients with stage I and II breast cancer were randomised to receive MRM or BCT from 1980 to 1989. All patients with a LR in these trials were analysed for survival and time to subsequent LR after salvage treatment. Of these, 133 patients had their LR as a first event, the majority within 5 years after initial treatment. The prognostic significance for survival and time to subsequent LR after salvage treatment was analysed in uni-, and multivariate analyses for a number of original tumour- and recurrence-related variables. After salvage treatment of LR after MRM or BCT, actuarial survival curves and the actuarial locoregional control curves were similar. The 5-year survival rates were 58% and 59% and the 5-year subsequent loco-regional control rates 62% and 63%, respectively. In a multivariate analysis, pN category (P = 0.03), pT category (P = 0.01) and vascular invasion (P = 0.02) of the primary tumour were the only independent prognostic factors for survival, whereas extensive LR (P < 0.001), interval < or = 2 years (P < 0.002) and pN+ at primary treatment (P = 0.004) were significant predictive factors for time to subsequent LR. The type of original treatment (MRM or BCT) did not have any prognostic impact. It is concluded that the survival and time to subsequent LR after treatment for an early loco-regional recurrence after MRM or BCT was similar in these two European randomised trials. This suggests that both after MRM and BCT an early LR is an indicator of a biologically aggressive tumour; early loco-regional relapse carries a poor prognosis and salvage treatment only cures a limited number of patients, whether treated by MRM or BCT originally.

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.

Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer

Endometrial carcinoma (EC) is the most common extracolonic tumor associated with hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC increases the risk of EC compared to the general population. Patients with HNPCC have a better prognosis than patients with common sporadic colorectal cancer. It is unknown, however, whether the survival rate of HNPCC‐associated EC is higher than that of sporadic EC. The aim of our study was to compare the survival rates of HNPCC‐associated EC with sporadic EC. From the registry of the Netherlands Foundation for Hereditary Tumors, 50 patients with HNPCC‐associated EC from 46 families harboring a germline mutation or fulfilling the Amsterdam Criteria II were age‐ and stage‐matched with 100 patients with sporadic EC registered in the Eindhoven Cancer Registry in the Netherlands. Survival rates were analyzed. The overall 5‐year cumulative survival rates for patients with HNPCC‐associated EC was 88% and 82% for patients with sporadic EC (p = 0.59). In Stages IA, IB and IC, the survival rates of patients with HNPCC‐associated EC and sporadic EC were 92% and 91%, respectively (p = 0.90). In Stages IIIA and IIIC, the survival rates for HNPCC‐associated EC and sporadic EC were 72% and 50%, respectively (p = 0.38). Furthermore, there was no significant difference in the distribution of tumor histologic subtypes in the study and control groups (p = 0.55). The outcomes in survival in EC in the general population and in women from families with HNPCC do not differ significantly. These results may have important implications in our understanding of EC and the role of early screening.

Lymphoedema and reduced shoulder function as indicators of quality of life after axillary lymph node dissection for invasive breast cancer.

The aim was to explore measurements of arm circumference and shoulder abduction as indicators of quality of life after axillary lymph node dissection for invasive breast cancer.

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.

Internal mammary lymph drainage and sentinel node biopsy in breast cancer - A study on 1008 patients.

INTRODUCTION Nowadays, axillary sentinel node (SN) biopsy is a standard procedure in the staging of breast cancer. Although the internal mammary (IM) lymph node status is a major independent prognostic factor in breast cancer patients, sampling of IM sentinel nodes (IMSNs) is not performed routinely. The aim of this study was to determine the likelihood of finding IM lymph node metastases in case of IM hotspots on lymphoscintigraphy and evaluate the relevance of IMSN biopsy as a method to improve staging. PATIENTS AND METHODS Between April 1997 and May 2006, a total of 1008 consecutive patients with clinically node-negative operable primary breast cancer were enrolled in a prospective study on SN biopsy. Both axillary and IMSNs were sampled, based on lymphoscintigraphy, intraoperative gamma probe detection and blue dye mapping, using 10 mCi (370 MBq) (99m)Tc-nanocolloid injected peritumorally, and 0.5-1.0 ml Patent Blue V injected intradermally. RESULTS Lymphoscintigraphy showed axillary sentinel nodes in 98% (989/1008) and IMSNs in 20% of the patients (196/1008). Sampling the IM basin, as based on the results of lymphoscintigraphy, was successful in 71% of the patients (139/196) and revealed metastases in 22% (31/139). In 29% of the patients with positive IMSNs (9/31) no axillary metastases were found. CONCLUSION Evaluation of IMSNs improves nodal staging in breast cancer. Patients with IM hotspots on lymphoscintigraphy have a substantial risk (22%) of metastatic involvement of the IM chain. In addition, true IM node-negative patients can be spared the morbidity associated with adjuvant radiotherapy.