Linetta B. Koppert

Surgical Mortality in Patients With Esophageal Cancer: Development and Validation of a Simple Risk Score

PURPOSE Surgery has curative potential in a proportion of patients with esophageal cancer, but is associated with considerable perioperative risks. We aimed to develop and validate a simple risk score for surgical mortality that could be applied to administrative data. PATIENTS AND METHODS We analyzed 3,592 esophagectomy patients from four cohorts. We applied logistic regression analysis to predict mortality occurring within 30 days after esophagectomy for 1,327 esophageal cancer patients older than 65 years of age, diagnosed between 1991 and 1996 in the linked Surveillance, Epidemiology and End Results (SEER)--Medicare database. A simple score chart for preoperative risk assessment of surgical mortality was developed and validated on three other cohorts, including 714 SEER-Medicare patients diagnosed between 1997 and 1999, 349 patients from a population-based registry in the Netherlands diagnosed between 1993 and 2001, and 1,202 patients from a referral hospital in the Netherlands diagnosed between 1980 and 2002. RESULTS Surgical mortality in the four cohorts was 11% (147 of 1,327), 10% (74 of 714), 7% (25 of 349), and 4% (45 of 1,202), respectively. Predictive patient characteristics included age, comorbidity (cardiac, pulmonary, renal, hepatic, and diabetes), preoperative radiotherapy or combined chemoradiotherapy, and a relatively low hospital volume. At validation, the simple score showed good agreement of predicted risks with observed mortality rates (calibration), but low discrimination (area under the receiver operating characteristic curve 0.58 to 0.66). CONCLUSION A simple risk score combining clinical characteristics along with hospital volume to predict surgical mortality after esophagectomy from administrative data may form a basis for risk adjustment in quality of care assessment.

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS)

BackgroundA surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.Methods/designThe CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.DiscussionThis study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.Trial registrationISRCTN80832026

Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis

Data on survival of BRCA1/2‐associated primary breast cancer (PBC) patients who opt for subsequent contralateral risk‐reducing mastectomy (CRRM) are scarce and inconsistent. We examined the efficacy of CRRM on overall survival in mutation carriers with a history of PBC. From a Dutch multicentre cohort, we selected 583 BRCA‐associated PBC patients, being diagnosed between 1980 and 2011. Over time, 242 patients (42%) underwent CRRM and 341 patients (58%) remained under surveillance. Survival analyses were performed using Cox models, with CRRM as a time‐dependent covariate. The median follow‐up after PBC diagnosis was 11.4 years. In the CRRM group, four patients developed contralateral breast cancer (2%), against 64 patients (19%) in the surveillance group (p < 0.001). The mortality was lower in the CRRM group than in the surveillance group (9.6 and 21.6 per 1000 person‐years of observation, respectively; adjusted hazard ratio 0.49, 95% confidence interval 0.29–0.82). Survival benefit was especially seen in young PBC patients (<40 years), in patients having a PBC with differentiation grade 1/2 and/or no triple‐negative phenotype, and in patients not treated with adjuvant chemotherapy. We conclude that CRRM is associated with improved overall survival in BRCA1/2 mutation carriers with a history of PBC. Further research is warranted to develop a model based on age at diagnosis and tumour and treatment characteristics that can predict survival benefit for specific subgroups of patients, aiming at further personalized counselling and improved decision making.

Outcome of Esophagectomy for Cancer in Elderly Patients

BACKGROUND This study analyzes the outcome of esophageal resection in patients 70 or more years of age, compared with patients aged less than 70 years and identifies risk factors for worse outcome in the elderly. METHODS Comorbidity, postoperative morbidity, in-hospital mortality and survival rates were compared between 811 patients aged less than 70 years and 250 patients aged 70 years or more who underwent esophagectomy for esophageal cancer in a single high-volume center from 1985 to 2005. RESULTS Groups were similar regarding surgical approach, resectability, and tumor stage. More patients aged 70 years or more had cardiovascular and respiratory concomitant disease. Among patients aged 70 years or more, the prevalence of adenocarcinoma and Barretts transformation was higher (67% versus 53% for patients aged less than 70 years, and 22% versus 15%, respectively). There were no differences in surgical complications (20% versus 17%). Nonsurgical complications occurred more in patients aged 70 years or more (35% versus 27%) and operative mortality was higher among elderly patients (8.4 versus 3.8%), as was in-hospital mortality (11.6% versus 5.4%). The disease-specific 5-year survival was lower for patients aged 70 years or more (27% versus 34%). The 1-year survival, reflecting the impact of operative morbidity and mortality, was 58% for patients aged 70 years or more and 68% for the patients aged less than 70 years (p = 0.002). Among patients aged 70 years or more, respiratory comorbidity and thoracoabdominal resection were risk factors for the occurrence of nonsurgical complications and respiratory comorbidity for in-hospital mortality. CONCLUSIONS Older patients have increased operative and in-hospital mortality and decreased 5-year survival after esophageal resection for cancer. Our results indicate that especially thoracoabdominal resection for esophageal carcinoma should be carefully considered for patients older than 70 years who suffer from respiratory disease.

Impact of age and co-morbidity on surgical resection rate and survival in patients with oesophageal and gastric cancer

Major surgery for cancer has become safer, including for elderly patients with co‐morbidity. The aim of this study was to investigate the association between patient characteristics, resection rates and survival among patients with oesophageal or gastric cancer.

A standard set of value-based patient-centered outcomes for breast cancer: The International Consortium for Health Outcomes Measurement (ICHOM) initiative

A major challenge in value-based health care is the lack of standardized health outcomes measurements, hindering optimal monitoring and comparison of the quality of health care across different settings globally. The International Consortium for Health Outcomes Measurement (ICHOM) assembled a multidisciplinary international working group, comprised of 26 health care providers and patient advocates, to develop a standard set of value-based patient-centered outcomes for breast cancer (BC). The working group convened via 8 teleconferences and completed a follow-up survey after each meeting. A modified 2-round Delphi method was used to achieve consensus on the outcomes and case-mix variables to be included. Patient focus group meetings (8 early or metastatic BC patients) and online anonymized surveys of 1225 multinational BC patients and survivors were also conducted to obtain patients’ input. The standard set encompasses survival and cancer control, and disutility of care (eg, acute treatment complications) outcomes, to be collected through administrative data and/or clinical records. A combination of multiple patient-reported outcomes measurement (PROM) tools is recommended to capture long-term degree of health outcomes. Selected case-mix factors were recommended to be collected at baseline. The ICHOM will endeavor to achieve wide buy-in of this set and facilitate its implementation in routine clinical practice in various settings and institutions worldwide.

Sternal Resection for Sarcoma, Recurrent Breast Cancer, and Radiation-Induced Necrosis

BACKGROUND The purpose of this study was to investigate the long-term outcome and technical feasibility of sternal resection. METHODS We performed a 25-year retrospective study of 68 patients who underwent a sternectomy for sarcoma, recurrent breast cancer (BC) or radiation-induced necrosis between 1981 and 2006 in two tertiary referral centres (Erasmus Medical Center/Daniel den Hoed Cancer Center and Netherlands Cancer Center/Antoni van Leeuwenhoek Hospital, Netherlands). Patients were treated with curative intent and followed until May 2009. Medical records were reviewed for patient characteristics, indications for surgery, surgical technique, postoperative complications, and survival. RESULTS Sternal resection was performed in 43 sarcoma patients, 17 recurrent BC and 8 patients with radiation-induced necrosis with additional rib resection in the majority of patients and with clavicle resection in 13% of patients. Additional scapula, lung, breast or axilla resection, or both, was performed in 10%. Two patients died postoperatively (3%). Mild complications occurred in 24%, and severe complications (namely, pulmonary complications and reinterventions) in 16% of patients. Radical resection was achieved in 80% and 53% of sarcoma and recurrent BC patients, respectively. Five-year overall survival was 64% and 40% in sarcoma and recurrent BC patients, respectively, with 5-year disease-free survivals of 52% and 15%, respectively. CONCLUSIONS Sarcomas, recurrent BC, and radiation-induced necrosis can be successfully managed by sternal resection and reconstruction with curative intent. Low mortality and acceptable morbidity rates justify this operation in a palliative setting as well. Disease-free survival is poor among recurrent BC patients.

Genomic Analysis of Early Adenocarcinoma of the Esophagus or Gastroesophageal Junction: Tumor Progression Is Associated with Alteration of 1q and 8p Sequences

Early (T1 stage) adenocarcinoma of the esophagus or gastroesophageal junction is a potentially curable disease. We analyzed the genomic spectra of 33 early neoplastic lesions after subdividing the tumors into six depths of invasion (T1–mucosal, m1–m3; T1–submucosal, sm1–sm3). Two subgroups were defined, T1m1–sm1 (n = 18) and T1sm2–sm3 (n = 15). The latter group is associated with frequent lymphatic spread and a high percentage of local and/or distant recurrence. Comparative genomic hybridization with a genomewide 3,500‐element BAC‐PAC array revealed a characteristic gastroesophageal adenocarcinoma pattern of changes, with losses on chromosome arms 4pq, 5q, 8p, 9p, 17p, and 18q and gains on 1q, 6p, 7pq, 11q, 15q, 17q, and 20pq. However, when the two groups were compared, the following BAC clones showed significantly more alterations in the T1sm2–sm3 group: RP11‐534L20 (1q32.1) and RP11‐175A4 (6p21.32), showing gains, and RP11‐356F24, RP11‐433L7, and RP11‐241P12 (all at 8p), showing losses. Gain of RP11‐534L20 (1q32.1) and loss of RP11‐433L7 (8p22) were associated not only with a recurrence‐free period (P = 0.0007 and 0.007, respectively), but also with regional lymphatic dissemination (P = 0.005 and 0.003, respectively). These DNA clones can be considered genomic markers for the aggressive behavior of early esophageal and gastroesophageal junction adenocarcinoma.

Breast density as indicator for the use of mammography or MRI to screen women with familial risk for breast cancer (FaMRIsc): a multicentre randomized controlled trial

BackgroundTo reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test.The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density.Methods/DesignThis Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of ≥20%, aged 30–55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000).Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value of both screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor.DiscussionPersonalized breast cancer screening might optimize mortality reduction with less over diagnosis. Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition.Trial registrationNetherland Trial Register NTR2789

Oncological safety of prophylactic breast surgery: skin-sparing and nipple-sparing versus total mastectomy

Women with a BRCA1/2 gene mutation and others with a high breast cancer risk may opt for bilateral prophylactic mastectomy. To allow for immediate breast reconstruction the skin envelope is left in situ with or without the nipple-areola complex (NAC). Although possibly leading to a more natural aesthetic outcome than the conventional total mastectomy, so-called skin-sparing mastectomies (SSM) and nipple-sparing mastectomies (NSM) may leave some breast glandular tissue in situ. The oncological risk associated with remaining breast glandular tissue is unclear. We present a case of primary breast cancer after prophylactic mastectomy followed by a review of the literature on remaining breast glandular tissue after various mastectomy techniques and oncological safety of prophylactic mastectomies.