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.

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.

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.

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.

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.

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.

Improved systemic treatment for early breast cancer improves cure rates, modifies metastatic pattern and shortens post-metastatic survival: 35-year results from the Munich Cancer Registry.

PURPOSE: Systemic therapies (ATHs) in early breast cancer have improved the survival of breast cancer (BC) patients in recent decades. The magnitude of the changes in overall, metastasis-free (MFS) and post-metastatic (PMS) survival and in the metastasis (MET) pattern will be described. PATIENT AND METHODS: We analysed 60,227 patients with a diagnosis of T-N-M0 BC between 1978 and 2013 and 11,983 patients with metastases (MET) in the Munich Cancer Registry. Patients will be divided into four time periods to identify relationships between BC and METs. Survival was estimated using Kaplan-Meier curves, and Cox proportional hazards models were used to explore the impact of the BC subtype and MET status on survival with the time periods as surrogate markers for ATH evolution. RESULTS: During the observation period, 5-year relative survival has improved from 80.3 to 93.6% with an adjusted hazard ratio of 0.54 (P < 0.0001). Successful implementation of ATH has changed the MET pattern. The percentage of liver and CNS METs has more than doubled, the rate of lung METs remains stable, and the rate of bone METs has been reduced by approximately 50%. MFS has been prolonged with a hazard ratio 0.75 (P < 0.0001), but PMS has declined (hazard ratio 1.36; P < 0.0001); however, effects of adjuvant and palliative treatments cannot be separated. These results do not contradict improvements in advanced BC and do not suggest alterations of MET tumour biology by ATH. CONCLUSIONS: Over the past three decades, ATHs have dramatically improved patient survival after BC diagnosis-most likely, by eradicating prevalent micro-METs; as a result, the MET pattern has changed. Eradicating only a portion of the first METs results in delaying the onset of subsequent MET, which leads to an apparently paradoxical effect: an extension of the MET-free interval and a reduction in PMS.

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.

Survival of de novo stage IV breast cancer patients over three decades.

BACKGROUND: De novo stage IV breast cancer patients (BCIV) depict a clinical picture not influenced by adjuvant therapy. Therefore, the time-dependent impact of changes in diagnostics and treatments on progression and survival can best be evaluated in this subgroup. METHODS: BCIV patients from 1978 to 2013 registered in the Munich Cancer Registry were divided into four periods, and the trends were analysed. Survival was estimated by Kaplan-Meier methods, and prognostic factors were fitted with Cox proportional hazard models. RESULTS: Between 1978 and 2013, 88,759 patients were diagnosed with 92,807 cases of invasive and non-invasive BC. Of these patients, 4756 patients had distant metastases (MET) at diagnosis. The 5-year survival rate improved from 17.4 to 24.7%, while the pattern of metastases did not change. Improved staging diagnostics, a screening programme and primary systemic therapy changed the composition of prognostic strata. Patients with a similar composition as the 1978-1987 cohort exhibited a median survival difference of 13 months; however, neither univariate nor multivariate analysis showed a survival effect for the four periods as a surrogate indicator for changing treatments. HER2+ patients have with 27.6 months a slightly longer survival than all other BCIV patients. CONCLUSIONS: Survival of de novo BCIV has only modestly improved since the late 1970s, partially masked by changing distributions of prognostic factors due to changes in diagnostics.

Changes in prognostic and therapeutic parameters in prostate cancer from an epidemiological view over 20 years.

BACKGROUND: The study objective was to examine changes in prognosis and treatment of prostate cancer patients over 20 years and to evaluate their impact on survival. PATIENTS AND METHODS: 38,861 prostate cancer patients diagnosed between 1990 and 2010 and living in the catchment area of the Munich Cancer Registry were analysed. RESULTS: Pre-therapeutic prostate-specific antigen (PSA) testing increased substantially in the early 1990s. A shift from capsule-exceeding tumours to capsule-limited tumours also took place especially in the 1990s. The proportion of radical prostatectomy increased continuously over the last 20 years from 20% to almost 50% whereas hormone therapy decreased from 55% to 18%. Radiation therapy and transurethral resection of the prostate increased slightly from about 5% to 10%. The 5- and 10-year relative survival rates increased from 92% to 97% and from 86% to 92%, respectively. CONCLUSIONS: 2 reasons may account for the rise in survival rates over 20 years: First, the establishment of widely used PSA testing resulted in a shift towards more favourable T categories due to the detection of many additional small tumours as well as the noticeable change in initial treatment strategy towards more radical prostatectomies. The second factor that likely increased survival was improvements in the therapies themselves.

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.

Quality of life and comorbidity in localized malignant melanoma: results of a German population-based cohort study.

BACKGROUND: Incidences of malignant melanoma continue to increase in fair-skinned populations. At least 80% of patients are diagnosed with localized disease and can expect a 5-year relative survival rate of >90%. Given that the median age at diagnosis of malignant melanoma is 59 years, many patients already suffer chronic diseases when they are confronted with cancer. OBJECTIVES: The aim of this study was to analyze the effect of additional chronic diseases on health-related quality of life (QoL) in a population-based cohort of melanoma patients two years after presumably curative treatment. METHODS: In 2003-2004, 1085 patients with localized malignant melanoma were recruited from the population-based Munich Cancer Registry to answer validated QoL questionnaires. Information about comorbidities was also obtained. Factors predicting QoL were analyzed using multivariate logistic regression models. RESULTS: A total of 781 patients (72%) returned completed questionnaires, of which 664 (61%) could be included in the analyses. Quality of life scores and differences in subgroups (e.g., sex and age) were essentially similar to those in the general population. Age, number of comorbidities, and several chronic diseases (e.g. heart and kidney disease, diabetes, former depression) were the strongest predicting factors and influenced almost every aspect of QoL. CONCLUSIONS: Localized malignant melanoma does not worsen QoL per se, compared with QoL in the general population. Comorbidities have similar effects on QoL in malignant melanoma patients as they do in the general population. Therefore, cohorts of patients with localized malignant melanoma can represent a basis for comparisons with other cohorts of cancer patients to determine the respective impacts of cancer-related and non-cancer-related factors on QoL.

Treatment strategies for oesophageal cancer - time-trends and long term outcome data from a large tertiary referral centre.

BACKGROUND AND OBJECTIVES: Treatment options for oesophageal cancer have changed considerably over the last decades with the introduction of multimodal treatment concepts dominating the progress in the field. However, it remains unclear in how far the documented scientific progress influenced and changed the daily routine practice. Since most patients with oesophageal cancer generally suffer from reduced overall health conditions it is uncertain how high the proportion of aggressive treatments is and whether outcomes are improved substantially. In order to gain insight into this we performed a retrospective analysis of patients treated at a larger tertiary referral centre over time course of 25 years. PATIENTS AND METHODS: Data of all patients diagnosed with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the oesophagus, treated between 1983 and 2007 in the department of radiation oncology of the LMU, were obtained. The primary endpoint of the data collection was overall survival (calculated from the date of diagnosis until death or last follow up). Changes in basic clinical characteristics, treatment approach and the effect on survival were analysed after dividing the cohort into five subsequent time periods (I-V) with 5 years each. In a second analysis any pattern of change regarding the use of radio(chemo)therapy (R(C)T) with and without surgery was determined. RESULTS: In total, 503 patients with SCC (78.5%) and AC (18.9%) of the oesophagus were identified. The average age was 60 years (range 35-91 years). 56.5% of the patients were diagnose with advanced UICC stages III-IV. R(C)T was applied to 353 (70.2%) patients; R(C)T+ surgery was performed in 134 (26.6%) patients, 63.8% of all received chemotherapy (platinum-based 5.8%, 5-fluorouracil (5-FU)12.1%, 42.3% 5-FU and mitomycin C (MMC)). The median follow-up period was 4.3 years. The median overall survival was 21.4 months. Over the time, patients were older, the formal tumour stage was more advanced, the incidence of AC was higher and the intensified treatment had a higher prevalence. However there was only a trend for an improved OS over the years with no difference between RCT with or without surgery (p = 0.09). The use of radiation doses over 54 Gy and the addition of chemotherapy (p = 0.002) were associated with improved OS. CONCLUSION: Although more complex treatment protocols were introduced into clinical routine, only a minor progress in OS rates was detectable. Main predictors of outcome in this cohort was the addition of chemotherapy. The addition of surgery to radio-chemotherapy may only be of value for very limited patient groups.

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.