Synchronous colorectal liver metastases: focus on the elderly : An Effectiveness Study from Routine Care.

PURPOSE: The goal of this study was to analyze the use and the effectiveness of both surgery and different chemotherapies in patients with synchronous colorectal liver metastases (CLMs) ≥70 years compared to younger patients. METHODS: Survival was analyzed in 456 patients (24.3% ≥70 years) treated for CLM in a single center using Kaplan-Meier estimation of overall survival (OS), calculation of relative survival as estimate for disease-specific survival, and a Cox regression model. RESULTS: Complete surgical resections were achieved more often in patients aged <70 years (39.2 vs. 28.1%, P = 0.056), and young patients more frequently received irinotecan or platin-based chemotherapies (70.3 vs. 41.6%, P < 0.001). Three-year OS and relative survival of patients ≥70 years were significantly lower compared to younger patients (OS 34.3 vs. 43.5%, P = 0.0114). In a Cox regression model, complete surgical removal of liver metastases was the most effective treatment (HR 0.313, P < 0.001) followed by chemotherapy (irinotecan/platin-based: HR 0.371, 5-FU only: HR 0.673, P < 0.001). Having >5 liver metastases, the presence of extrahepatic metastases, high grading, and a nodal positive primary but not age ≥70 years were associated with an increased risk of death. CONCLUSIONS: Our data support radical resection and highly effective chemotherapy in selected elderly patients with CLM.

Quality of life in women with localised breast cancer or malignant melanoma 2 years after initial treatment: a comparison.

BACKGROUND: Two thirds of female breast cancer patients and more than 80 % of malignant melanoma patients are diagnosed with localised disease and good prognosis with a 5-year relative survival of more than 90 % in Germany. PURPOSE: This study was conducted to present quality of life (QoL) data from a German population-based cohort of female breast cancer and melanoma patients without recurrence for approximately 2 years after initial diagnosis. METHODS: In 2003-2004, patients with localised breast cancer and melanoma were recruited from the Munich Cancer Registry (Upper Bavaria, Germany) to answer QoL questionnaires. Differences between breast cancer and melanoma patients were investigated with regard to age and aspects of communication with their medical caregivers. RESULTS: One thousand three hundred and four breast cancer and 348 melanoma patients were included. Breast cancer patients were about 7 years older and had significantly lower QoL and higher symptom scores than melanoma patients. Communication needs were generally similar in both groups; however, breast cancer patients experienced more empathy from their medical caregivers. In breast cancer patients, communication was an independent factor for all QoL functioning scores. CONCLUSIONS: Even when faced with a similarly good prognosis, breast cancer patients have a worse QoL than melanoma patients 2 years after diagnosis. An explanation may be more distinctive surgery and systemic therapy, older patients with comorbidities and misunderstood risk communication in breast cancer patients that may stoke anxiety and fears. Further reasons could be unceasing public discussion about breast cancer and its instrumentalisation for political purposes.

Positive lymph nodes do not metastasize.

Our understanding of the role of lymph nodes (LN) in the metastasization process (MET) is marginal. Positive LNs (pLN) are the most important prognostic factor and lymph node dissection (LND) is still standard practice in primary treatment. However, up to now, there is almost no evidence that elective LND has a survival benefit. Based on many clinical and experimental findings, we propose that tumor foci in regional LN are incapable of metastasization and can therefore not infiltrate further LN and organs. Available data demonstrate a very early infiltration of MET capable tumor cells from the primary tumor into regional LN, and thereafter an increased probability of subsequent LN infiltrations. Disparate growth rates of the first versus subsequent infiltrating tumors as well as the asymptotic growth and prognosis of large tumor foci in LN explain many clinical observations for solid tumors. The consequence of the hypothesis "pLN do not metastasize" would impact clinical treatment and research and contribute to understanding the mounting evidence against LND.

Expanding mammography screening for women aged 40-80 years: evidence from a modeling approach using real-world data.

If a mammography screening program (MS) is to be expanded, the benefit must be demonstrated for each additional age cohort. For the age interval between 40 and 80 years, the association between tumor-related and tumor-independent mortality of 21 2-year cohorts is modeled using up-to-date, valid data to determine MS outcome. Disease trajectories with and without biennial MS are extrapolated for each age cohort using the available data and knowledge on MS. The competing mortality is randomly generated for each age cohort with and without MS for a follow-up period of 20 years. Analyses of the modeled cohorts describe incremental change for each year, quantifying the changing benefits of MS. With increasing age, the proportion of tumor-independent mortality before and with metastatic disease increases and the benefit decreases. The simulations with 21 studies on the age interval 40-80 years provide four parameters to determine the benefits and costs of MS: The number of prevented deaths, required mammography screening exams (MSE) and their costs, life-years gained, and the required MSEs. If one additional MSE is offered for age groups 48/70 years, this will result in 311/320 prevented breast cancer (BC) deaths with 1742/1494 required MSEs or 8784/4168 life-years gained with 64/140 required MSEs. A rational cutoff cannot be quantified. The mortality effect of MS between 40 and 80 years is quantified in 21 steps using two metrics, number of MSEs per tumor-related mortality prevented and per life-year gained. This provides a decision support for stepwise expansions. Given this real-world evidence no rational age cutoffs for MS becomes evident. A society has to decide which MS costs, including side effects of MS for women who remain BC-free, it is willing and able to accept in order to reduce breast cancer mortality.

Breast cancer: emerging principles of metastasis, adjuvant and neoadjuvant treatment from cancer registry data.

PURPOSE: Growing primary breast cancers (PT) can initiate local recurrences (LR), regional lymph nodes (pLN) and distant metastases (MET). Components of these progressions are initiation, frequency, growth duration, and survival. These characteristics describe principles which proposed molecular concepts and hypotheses must align with. METHODS: In a population-based retrospective modeling approach using data from the Munich Cancer Registry key steps and factors associated with metastasis were identified and quantified. Analysis of 66.800 patient datasets over four time periods since 1978, reliable evidence is obtained even in small subgroups. Together with results of clinical trials on prevention and adjuvant treatment (AT) principles for the MET process and AT are derived. RESULTS: The median growth periods for PT/MET/LR/pLN comes to 12.5/8.8/5/3.5 years, respectively. Even if 30% of METs only appear after 10 years, a pre-diagnosis MET initiation principle not a delayed one should be true. The growth times of PTs and METs vary by a factor of 10 or more but their ratio is robust at about 1.4. Principles of AT are 50% PT eradication, the selective and partial eradication of bone and lung METs. This cannot be improved by extending the duration of the previously known ATs. CONCLUSION: A paradigm of ten principles for the MET process and ATs is derived from real world data and clinical trials indicates that there is no rationale for the long-term application of endocrine ATs, risk of PTs by hormone replacement therapies, or cascading initiation of METs. The principles show limits and opportunities for innovation also through alternative interpretations of well-known studies. The outlined MET process should be generalizable to all solid tumors.

True local recurrences do not metastasize.

Generally, the limits of local tumor control are in part connected with the term "field cancerization" and are known from oral, lung, prostate, or mammary cancer. With the example of breast cancer (BC), the problem of ipsilateral breast tumor recurrences (IBTR) after breast-conserving surgery will be reviewed. Three types of local recurrences are distinguished: true recurrences, new primaries, or residual tumors. Good data for BC allow the description of the time-dependent risk of these three types, relative to the diagnosis of the primary tumor, because the time of initiation and the growth duration of the IBTR can be estimated. Two hypotheses explain the data: first, local recurrences may be initiated years before the diagnosis of a primary tumor (PT) and can then appear as multifocal PT at diagnosis, and second, true local recurrences probably do not metastasize. The generalizability of these hypotheses for other tumors will be discussed.

Distant metastases do not metastasize.

Distant metastases (MET) are for most solid cancers decisive life-threatening events. Data about MET-free survival and survival after MET show a strong dependency on the kind of cancer and the prognostic features. Nonetheless, within biological subgroups, the MET process is very homogenous. Therefore, the growth rate can be estimated from initiation of MET to MET diagnosis and to time of death. Based on the known volume doubling time of breast cancer, the time of the first possible dissemination can also be estimated. Important consequences of these MET-initiation estimates are the hypotheses that almost all MET are initiated before removal of the primary tumor and that MET do not metastasize in a clinically relevant magnitude. Although breast cancer data were primarily used to form these hypotheses, the discussed MET process can be generalized to all solid cancers. The impact of these hypotheses on diagnostic, curative and palliative treatment, aftercare, and especially on clinical research would be important.

Unfavourable pattern of metastases in M0 breast cancer patients during 1978-2008: a population-based analysis of the Munich Cancer Registry.

Little is known about time trends in metastases in the patients treated in routine health care facilities without metastases at diagnosis (M0) and about survival after these metastases. Data on 33,771 M0 patients with primary breast cancer diagnosed between 1978 and 2003 were obtained from the Munich Cancer Registry. Survival analyses were restricted to the patients with metastases within 5 years of the initial diagnosis. The incident number of the patients approximately doubled each period and 5-year overall survival increased from 77% in the first to 82% percent in the last period. 5490 (16%) M0 patients developed metastases within 5 years after the initial diagnosis. The hazard of developing metastases was lowest in the most recent period compared to the first period (HR = 0.50, P < 0.001). The hazard of dying after metastases was equal for patients diagnosed between 1978-1984 and 1995-2003 (HR 1.08, P = 0.3). The percentage of the patients that developed bone metastases decreased each time period, but the percentage primary liver and CNS metastases increased. Exclusion of site of metastases in the multivariate analysis led to a 20% (P = 0.02) higher hazard of dying following metastases in the last versus the first period. In the period 1978-2008, unfavourable changes in the pattern of metastases were exhibited and no improvement was observed in survival of the patients after occurrence of metastases. An explanation might be the increased use of adjuvant systemic treatment, which has less effect on the highly lethal liver and CNS metastases than on bone metastases. The increased use also appeared to contribute to the overall prevention of metastases in breast cancer and therefore to improve overall survival.

Colonoscopy and polypectomy: beside age, size of polyps main factor for long-term risk of colorectal cancer in a screening population.

PURPOSE: Despite national and international guideline recommendations, few studies have been conducted to estimate the impact of colonoscopy screening on long-term colorectal cancer incidence. Aim of this study was to determine the long-term impact of a full colonoscopy with polypectomy on colorectal cancer incidence in a large screening population. METHODS: In this prospective observational cohort study, a total of 10,947 colonoscopy screening participants from within the scope of the Munich Cancer Registry were consecutively recruited from participating gastroenterology practices and their subsequent colorectal cancer incidence assessed. Predictive factors associated with colorectal cancer were also evaluated in univariate and multivariate analyses. RESULTS: After a median follow-up of 14.24 years (95% CI [14.21-14.25]), 93 colorectal cancer cases were observed. This is equivalent to a truncated age-standardized rate of 69.0 (95% CI [43.3-94.7]) for male and 43.4 (95% CI [29.4-57.5]) for female participants (≥ 50 years at colonoscopy). The ratio of this observed to the expected rate from cancer registry data showed a 67% decrease in colorectal cancer incidence in the male and 65% in the female participants (p < 0.0001). In multivariate analysis of screening patients, age at screening (p < 0.0001) was the main predictive factor for colorectal cancer. In the subgroup with positive polyp findings, age (p < 0.0001) and the polyp size (p = 0.0002) were associated with colorectal cancer. CONCLUSION: These results underline the significance of a full colonoscopy screening combined with polypectomy in reducing the total disease burden of colorectal cancer.

The prognostic value of lymph node ratio in a population-based collective of colorectal cancer patients.

OBJECTIVE: We analyzed 3 previously identified cut-off values of lymph node ratios (0.17, 0.41, and 0.69) in a large population-based collective of patients with colorectal cancer for their prognostic value. SUMMARY BACKGROUND DATA: The lymph node ratio (LNR) (relation of tumor-infiltrated to total examined lymph nodes) has a high prognostic impact, but the relevant cut-off values are not determined. METHODS: Patients (N = 27,803) with a primary colorectal cancer diagnosed and operated in the Munich region between 1991 and 2006 were registered in the Munich Cancer Registry. Lymph node numbers and survival data were available for 17,309 patients with a mean follow-up of 5.9 years. RESULTS: The mean number (+/-SD) of resected lymph nodes was 16.8 +/- 8.4. Twelve or more lymph nodes were resected in 76.8%. Estimated 5-year overall survival decreased significantly with increasing LNR: LNR = 0 in 71.4%, LNR 0.01 to 0.17 in 52.4%, LNR 0.18 to 0.41 in 33.3%, LNR 0.42 to 0.69 in 19.8%, and LNR > or = 0.70 in 8.3% (P < 0.001). Multivariable survival analyses identified separately both LNR and pN- category, as well as number of resected lymph nodes, patient's age, tumor location, pT-category, pM-status, R-status, tumor grade, and year of operation as independent prognostic factors. CONCLUSION: : The 3 cut-off values of LNRs had strong independent prognostic value in a population-based collective of patients with colorectal cancer. The LNR should be routinely reported and included in the American Joint Committee on Cancer staging system. Nevertheless, the benefit of lymphadenectomy on survival is still unclear.

Long-term outcome of mitomycin C- and 5-FU-based primary radiochemotherapy for esophageal cancer.

BACKGROUND AND PURPOSE: For definitive radiochemotherapy, 5-fluorouracil/cisplatin protocols have been considered the standard of care for esophageal carcinoma over the last 2 decades. By contrast, most patients treated at the University Hospital, LMU Munich, Germany, received 5-fluorouracil/mitomycin C. The objective of this retrospective analysis was to determine the value of 5-fluorouracil/mitomycin-C-based therapy. PATIENTS AND METHODS: Tumor stage, treatment received, and outcome data of patients treated for esophageal cancer between 1982 and 2007 were collected; endpoint of the analysis was overall survival. RESULTS: 298 patients with inoperable cancer of the esophagus were identified (16.8% adenocarcinoma, 77.5% squamous cell carcinoma). At diagnosis, 61.7% (184/298) had UICC stage III-IV, 54.4% (162/298) positive lymph nodes, and 26.5% (79/298) metastatic disease. 74.5% of all patients (222/298) received radiation doses between 55 and 65 Gy, 65.8% (196/298) were subjected to concomitant chemotherapy. The median follow-up period (patients alive) was 4.1 years. A significant increase of overall survival (p < 0.0001) in the radiochemotherapy versus the radiotherapy-alone group was observed. 52% (102/196) in the 5-fluorouracil/ mitomycin C group had tumor stages comparable to the RTOG 85-01 study cohort (T1-3 N0-1 M0). The median survival in this subgroup was 18.2 months, 3- and 5-year survival rates were 22.7% (21/102) and 15.0% (13/102), respectively. CONCLUSION: Despite being nominally inferior to platinum-based radiochemotherapy, the overall survival rates are in a similar range. Thus, the mitomycin-C-based radiochemotherapy approach may considered to be as effective as the standard therapy. However, there is no randomized trial available in order to prove the equality.

Breast cancer: are long-term and intermittent endocrine therapies equally effective?

PURPOSE: In breast cancer (BC), the duration of endocrine adjuvant therapies (AT) has been extended continuously up to 10 years. We present an alternative explanation for the effect, which could enable shorter treatments. METHOD: The relevant literature on chemoprevention and (neo-)adjuvant therapy was reviewed. Data for initiation and growth of primary and contralateral BCs and their metastases (MET) were considered. Also, population-based data from the Munich Cancer Registry for MET-free survival, time trends of MET patterns, and survival achieved by improved ATs are used to estimate all events in the long-term follow-up. RESULTS: Extended ATs (EAT) that continue after 1, 2, or 5 years reduce mortality only slightly. The effect is delayed, occurring more than 5 years after extension. EATs does not affect the prognosis of 1stBCs, they preventively eradicate contralateral 2ndBCs and thus their future life-threatening METs. Because chemoprevention can eradicate BCs from the smallest clusters to almost detectable BCs, ATs can be temporarily suspended without imposing harm. Results equal to EATs can be achieved by short-term ATs of the 1stBC and by repeated neo-ATs targeted at the indefinitely developing 2ndBCs. Considering this potential in de-escalation, a 70-80% reduction of overtreatment seems possible. CONCLUSION: Knowledge of initiation and growth of tumors with known effects of neo-ATs suggest that intermittent endocrine ATs may achieve the same results as EATs but with improved quality of life and survival because of fewer side effects and better compliance. The challenge for developments of repeated ATs becomes: how short is short enough.

A semiparametric Bayesian proportional hazards model for interval censored data with frailty effects.

BACKGROUND: Multivariate analysis of interval censored event data based on classical likelihood methods is notoriously cumbersome. Likelihood inference for models which additionally include random effects are not available at all. Developed algorithms bear problems for practical users like: matrix inversion, slow convergence, no assessment of statistical uncertainty. METHODS: MCMC procedures combined with imputation are used to implement hierarchical models for interval censored data within a Bayesian framework. RESULTS: Two examples from clinical practice demonstrate the handling of clustered interval censored event times as well as multilayer random effects for inter-institutional quality assessment. The software developed is called survBayes and is freely available at CRAN. CONCLUSION: The proposed software supports the solution of complex analyses in many fields of clinical epidemiology as well as health services research.

Lymph node infiltration, parallel metastasis and treatment success in breast cancer.

BACKGROUND: The number of axillary positive lymph nodes (pLN) is the most important clinical prognostic factor in breast cancer (BC). To date, there is limited knowledge of LN-spreading and metastasization (MET). PATIENTS AND METHODS: In the Munich Cancer Registry, 30,170 hormone receptor positive BC patients were analysed for the variation in tumor diameter (TD) and number of pLNs. A total of 144 combinations were described with Gompertz functions for each LN-subgroup and linked with patient outcomes, MET and 20-years survival. RESULTS: Every additional millimeter of BC diameter decreased the likelihood of 0pLN-status by 1.6%-0.3%. The infiltration accelerates from the 1pLN and the percentage of successive pLNs subgroups becomes smaller. BCs with increasing TDs continuously reduce the proportion of 0pLN-status and increase it with >10pLNs. The proportion of 1-10 pLNs at 10 mm is 16% and increases to 50% with prognostically favorable 1-2pLNs of 75% and 40%, respectively. After 20 years, tumor-specific mortality is about 17% for 0pLNs, twice that for 1pLN, and 3 times higher for 4-5 pLNs. The more LNs are positive, the less survival is affected. The subgroups with 0/1pLNs cause 41/16% of all cancer related death. CONCLUSION: The number of pLNs is an epiphenomenon of the onset and chronometer for the duration of TCs disseminating from growing BCs. METs are initiated parallel to LNs by PTs and not caused by pLNs. This LN process without cascade-like MET initiation should be generalizable to all common solid tumors.

Age and Outcome in Gastrointestinal Cancers: A Population-Based Evaluation of Oesophageal, Gastric and Colorectal Cancer.

BACKGROUND: With demographic changes and partial representativeness of randomized studies the question arises which results are achieved in the treatment of the elderly. The objective was to analyse population-based data on gastrointestinal cancers in terms of age. METHODS: Analyses included data of the Munich Cancer Registry, i.e. 4,014, 10,127 and 42,809 invasive oesophageal, gastric and colorectal cancer patients, respectively, which were diagnosed between 1998 and 2014. Tumour characteristics and outcome were analysed by age groups and therapy. Overall survival was analysed using the Kaplan-Meier method, and relative survival was computed as estimation for cancer-specific survival. Additionally, conditional survival of patients surviving at least 6 or 12 months was analysed by age. RESULTS: 21, 44 and 38% of oesophageal, gastric and colorectal cancer patients, respectively, were aged >75 years. Of these, 15, 46 and 73% were surgically treated with curative intent, respectively, which is significantly less than in younger patients. The total 5-year relative survival was 24, 33 and 66%, respectively. The differences in median survival by age group were diminished by selecting those surviving at least 6 or 12 months and those with curatively intended treatment. CONCLUSION: An adequate patient selection for therapies of these gastrointestinal cancers was demonstrated at large. If the patients' general conditions allowed curatively intended treatment, it was applied and led to similar outcomes irrespective of age.

Value of Digital Breast Tomosynthesis versus Additional Views for the Assessment of Screen-Detected Abnormalities - a First Analysis.

BACKGROUND: The purpose of this study was to countercheck the equivalence of single-view digital breast tomosynthesis (DBT) or DBT with additional views (DBT+AV) compared to traditional standard assessment by additional views (AV) in patients with a screen-detected abnormality. PATIENTS AND METHODS: Patients with a screen-detected abnormality were consecutively invited to obtain 1 single-view wide-angle DBT in addition to the indicated AV. The study was approved by the local ethics committee and by the Federal Office for Radiation Protection. RESULTS: This study is based on 311 lesions in 285 patients with a follow-up of > 2 years and/or biopsy. Counting BI-RADS 0 and 3 as positive calls, the sensitivity/specificity of DBT+AV versus DBT only versus AV only were 96.4/54.3%, 96.4/56.6%, and 90.9/42.2%, respectively. The specificities and BI-RADS classifications differed significantly (p < 0.01). AV appeared unnecessary in 88.8% of the cases. CONCLUSION: DBT appeared to be at least equivalent to AV for assessing indeterminate screen-detected lesions and could replace AV for most lesions. To obtain the extra information appears possible without increasing the overall radiation dose. Subsequent blinded reader studies are ongoing.

Risk of second cancer following radiotherapy for prostate cancer: a population-based analysis.

BACKGROUND: To investigate the risk of second cancer and radiation induced second cancer following prostate cancer radiotherapy. METHODS: We compared men with radiotherapy only with those treated with radical prostatectomy only and those with radiotherapy after radical prostatectomy. Cumulative incidences of second cancers were calculated. Cox analyses were performed to identify determinants influencing second cancer incidence. RESULTS: Nineteen thousand five hundred thirty eight patients were analyzed. Age and median follow-up differed significantly with radiotherapy only patients having the highest median age (70.3 years) and radical prostatectomy only patients the longest median follow-up (10.2 years). Ten-year cumulative incidence of second cancer was 15.9%, 13.2% and 10.5% for patients with radiotherapy only, radiotherapy after radical prostatectomy and radical prostatectomy only (p <0.0001). Increasing age and belonging to the radiotherapy only group were associated with a higher risk of second cancer-no significant increase was seen in radiotherapy after radical prostatectomy patients. A significantly higher rate of smoking related malignancies, like lung, bladder and non-melanoma skin cancer, was seen in radiotherapy only patients. CONCLUSIONS: No clear increase in radiation induced second cancer was found in patients after radiotherapy for prostate cancer. Whereas the rate of second cancer was increased in radiotherapy only patients, no such increase was seen in patients with radiotherapy after radical prostatectomy. The increase of second cancer following radiotherapy only is highly likely to reflect advanced age and lifestyle habits and comorbidities.

Trends in use and outcome of postoperative radiotherapy following mastectomy: A population-based study.

PURPOSE: The objective of the present population-based study was to evaluate the role and effectiveness of postmastectomy radiation therapy (PMRT) in clinical practice. METHODS: The study included 16,675 patients diagnosed with invasive breast cancer from 1988 to 2012 and resident within the catchment area of the Munich Cancer Registry. Use of PMRT, local recurrence-free survival (LRFS), cumulative incidence of time to local recurrence, relative survival and conditional overall survival (cOS), were analysed for different time periods (1988-1997 and 1998-2012). RESULTS: Variables favouring the use of PMRT on multivariate logistic regression analysis included young age, large tumour size, positive resection margin and positive nodal status. Over time, a significant increase of PMRT was registered for patients with ⩾4 positive lymph nodes. Moreover, the present findings track a less frequent use of PMRT in elderly patients. After adjusting for age, tumour characteristics and therapies, the Cox regression analysis for LRFS identified PMRT as an independent predictor for improved local control (HR: 2.145; 95% CI: 1.787-2.574, p<0.0001). Patients with 1-3 involved lymph nodes had a 10-year cumulative incidence of local recurrence of 13.7% following mastectomy, compared to 6.5% following PMRT (p=0.0001). Comparable findings were obtained for patients presenting with ⩾4 positive lymph nodes. All effects were smaller or extinct in elderly patients aged ⩾70years. On multivariate analysis for cOS, no significant advantage for PMRT could be detected (HR: 1.084; 95% CI: 0.986-1.191, p=0.095). CONCLUSION: The present study was useful in providing an overview on trends in the adoption of PMRT over a 25-year period. An increase in the use of PMRT from 1988 to 2012 was observed, especially in high-risk patients with ⩾4 positive lymph nodes. Patients selected for PMRT had an improved local control and an equivalent relative survival compared to patients who had no indication for PMRT.