Perioperative chemotherapy vs. neoadjuvant chemoradiation in gastroesophageal junction adenocarcinoma : A population-based evaluation of the Munich Cancer Registry.

BACKGROUND: To date, it remains unclear whether locally advanced adenocarcinoma of the gastroesophageal junction (AEG) should be treated with neoadjuvant chemoradiation (nCRT), analogous to esophageal cancer, or with perioperative chemotherapy (pCT), analogous to gastric cancer. The purpose of this study was to analyze the data of the Munich Cancer Registry (MCR) and to compare pCT and nCRT in AEG patients. PATIENTS AND METHODS: A total of 2,992 AEG patients, treated between 1998 and 2014, were included in the study. Baseline and tumor parameters as well as overall survival (OS) and tumor recurrence were compared between 56 patients undergoing nCRT and 64 patients undergoing pCT with UICC stage II/III cancer. In addition, uni- and multivariate analyses using Cox regression models were performed to evaluate the effect of tumor characteristics and treatment regimens on OS. RESULTS: In patients with UICC stage II/III AEG treated with either nCRT or pCT, no significant differences were seen for baseline and tumor characteristics. While there was a significantly higher cumulative incidence of locoregional treatment failure after pCT (32.8%; 95% CI: 18.0-48.4%) compared with nCRT (7.4%; 95% CI: 2.3-16.5%; p = 0.007), there was no significant difference for distant treatment failure (52.9%; 95% CI: 35.4-67.7% and 38.4%; 95% CI: 23.7-52.9%; p = 0.347). When analyzing the whole cohort, patients who received pCT were younger (58.3 years vs. 63.0 years; p = 0.016), had a higher chance of complete tumor resection (81% vs. 67%; p = 0.033), more resected lymph nodes (p = 0.036), and fewer lymph node metastases (p = 0.038) compared with patients who received nCRT. Nevertheless, there was still a strong trend toward a higher incidence of local treatment failure after pCT (25.8%; 95% CI: 14.7-38.3% vs. 12.6%; 95% CI: 5.5-22.8%; p = 0.053). Comparable to the results for patients with UICC stage II/III, no difference was seen for the incidence of distant treatment failure. When excluding patients with UICC stage IV cancer, no significant difference was found for OS. CONCLUSION: For UICC stage II/III carcinoma, nCRT was associated with an improved locoregional tumor control compared with pCT, while no further significant differences were seen between nCRT and pCT for UICC stage II/III AEG. Moreover, there was a strong trend toward improved locoregional tumor control after nCRT when analyzing all patients treated with nCRT or pCT, despite these patients having higher risk factors.

Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care.

BACKGROUND: Hotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear. METHODS: The mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed. RESULTS: Mutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p < 0.001) and truncal localization of the culprit primary (p = 0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p = 0.013) and development of metastatic disease (p = 0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p = 0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02 - 3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15 - 6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06-0.48) were significant multivariate risk factors. CONCLUSIONS: NRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting.

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.

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.

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.

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.

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.

Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma.

BACKGROUND: Mucosal melanoma (MM) is a rare but diverse cancer entity. Prognostic factors are not well established for Caucasians with MM. PATIENTS AND METHODS: We analysed the disease course of 444 patients from 15 German skin cancer centres. Disease progression was determined with the cumulative incidence function. Survival times were estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariate Cox regression analysis. RESULTS: Common anatomic sites of primary tumours were head and neck (MMHN, 37.2%), female genital tract (MMFG, 30.4%) and anorectal region (MMAN, 21.8%). MMAN patients showed the highest vertical tumour thickness (p = 0.001), had a more advanced nodal status (p = 0.014) and a higher percentage of metastatic disease (p = 0.001) at diagnosis. Mutations of NRAS (13.8%), KIT (8.6%) and BRAF (6.4%) were evenly distributed across all tumour site groups. Local relapses were observed in 32.4% and most commonly occurred in the MMHN group (p = 0.016). Male gender (p = 0.047), advanced tumour stage (p = 0.001), nodal disease (p = 0.001) and incomplete resection status (p = 0.001) were independent risk factors for disease progression. Overall survival (OS) was highest in the MMFG group (p = 0.030) and in patients without ulceration (p = 0.004). Multivariate risk factors for OS were M stage at diagnosis (p = 0.002) and incomplete resection of the primary tumour (p = 0.001). CONCLUSION: In this large series of MM patients in a European population, anorectal MM was associated with the poorest prognosis.

Prognosis of mucinous and signet-ring cell colorectal cancer in a population-based cohort.

PURPOSE: Besides classical colorectal adenocarcinomas (AC), mucinous adenocarcinomas (MAC) and signet-ring cell carcinomas (SC) occur. Controversy remains regarding their prognostic role. Aim of this study was to define prognostic and histopathological specifications of mucinous and signet-ring cell colorectal cancer. METHODS: A total of 28,056 patients with AC, MAC, and SC between 1998 and 2012 in the catchment area of the Munich Cancer Registry were analyzed. Time to locoregional recurrence and distant recurrence was calculated by cumulative incidence. Survival was analyzed by the Kaplan-Meier method, calculation of relative survival, and Cox proportional hazards regression. RESULTS: AC occurred in 25,172 patients (90 %), MAC in 2724 (9.7 %), and SC in 160 (0.6 %). AC were less frequently localized in the proximal colon (34 %) compared to MAC (57 %, p < 0.001) and SC (76 %, p < 0.001). Both, MAC and SC had higher T, N, and M categories, lymphatic invasion, and worse grading (p < 0.001 for each). There were significant differences regarding the 10-year cumulative incidence of locoregional recurrence (p < 0.001), and distant recurrence (p < 0.001). For AC, the 5-year overall survival was 59 % (95 % confidence interval 58.0; 59.3), for MAC 52 % (50.2; 54.2), and for SC 40 % (32.1; 48.5; p < 0.001). However, MAC or SC did not remain independent prognostic factors for overall survival compared to AC upon multivariable analysis (p = 0.981). CONCLUSION: This large cohort reveals specific histopathological and recurrence patterns for patients with colorectal AC, MAC, and SC. MAC and SC are diagnosed at more advanced tumor stages and therefore entail reduced survival rates.

Adjuvant radiotherapy after breast conserving surgery - a comparative effectiveness research study.

PURPOSE: The purpose of this retrospective outcome study was to validate the effectiveness of postoperative radiotherapy in breast conserving therapy (BCT) and to evaluate possible causes for omission of radiotherapy after breast conserving surgery (BCS) in a non-trial population. METHODS: Data were provided by the population-based Munich Cancer Registry. The study included epidemiological data of 30.811 patients diagnosed with breast cancer from 1998 to 2012. The effect of omitting radiotherapy was analysed using Kaplan-Meier-estimates and Cox proportional hazard regression. Variables predicting omission of radiotherapy were analysed using multivariate logistic regression. RESULTS: Use of postoperative radiotherapy after BCS was associated with significant improvements in local control and survival. 10-year loco-regional recurrence-free-survival was 90.8% with postoperative radiotherapy vs. 77.6% with surgery alone (p<0.001). 10-year overall survival rates were 55.2% with surgery alone vs. 82.2% following postoperative radiotherapy (p<0.001). Variables predicting omission of postoperative radiotherapy included advanced age (women ⩾80 years; OR: 0.082; 95% CI: 0.071-0.094, p<0.001). CONCLUSIONS: This study shows a decrease in local control and a survival disadvantage if postoperative radiotherapy after breast conserving surgery is omitted in an unselected cohort of primary breast cancer patients. Due to its epidemiological nature, it cannot answer the question in whom postoperative radiotherapy can be safely omitted.

Determinants and prognoses of locoregional and distant progression in breast cancer.

PURPOSE: To describe locoregional and distant progression in a population-based breast cancer sample. METHODS AND MATERIALS: Between 1978 and 1998, the Munich Cancer Registry evaluated 14,429 patients. The mean follow-up of survivors was 8.3 years. Metastases (MET), local recurrence (LR), and lymph node recurrence (LNR) were considered as outcome measures. The prognostic factor for, and effects of, LR and MET were assessed multivariately by the Cox and dynamic Aalen models. RESULTS: The LR and MET rate increased with increasing tumor size, with the latter described by pT category. Distant MET occurred earlier than local progression. MET was recorded even earlier for MET alone. The mean time from diagnosis to MET for MET and LR was 54.9, 43.4, 29.4, and 24.7 months and for MET only was 36.5, 31.0, 22.6, and 12.9 months for pT1, pT2, pT3, and pT4, respectively. After MET, survival varied only slightly by pT stage; after LR, a more favorable prognosis, especially for pT1 and pT2, was evident. The prognosis after MET depended mainly on the MET location; 50% of patients with cerebral or nervous system MET survived <1 year and 50% of those with skeletal MET survived >2 years. In the Cox model, the relative risk of LR for MET was 3.0. In the Aalen model, after 30 months, when the hazard rates of MET began to decline, there was still an excess risk of MET after LR. CONCLUSION: This disease description highlights the importance of long-term observational studies. Empiric evidence that LR is both an indicator for, and in part a cause of, MET has been provided. In the future, the MET location should be reported. Variations in guidelines or health care systems that influence the time to MET and survival after MET through different diagnostic procedures should also be considered.

Gender differences in melanoma survival: female patients have a decreased risk of metastasis.

Female melanoma patients generally exhibit significantly longer survival than male patients. This population-based cohort study aimed to investigate gender differences in survival and disease progression across all stages of cutaneous melanoma. A total of 11,774 melanoma cases extracted from the Munich Cancer Registry (Germany), diagnosed between 1978 and September 2007, were eligible to enter the study. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for tumor and patient characteristics, were estimated for the end points of survival, regional and systemic progression, and survival after progression. A significant female advantage was observed for melanoma-specific survival (adjusted HR 0.62; 95% CI 0.56-0.70). Women were at a lower risk of progression (HR 0.68; 95% CI 0.62-0.75), including a lower risk of lymph node metastasis (HR 0.58; 95% CI 0.51-0.65) and visceral metastases (HR 0.56; 95% CI 0.49-0.65). They retained a significant survival advantage after first progression (HR 0.81; 95% CI 0.71-0.92) and lymph node metastasis (HR 0.80; 95% CI 0.66-0.96), but this became borderline significant (HR 0.88; 95% CI 0.76-1.03) after visceral metastasis. Localized melanomas in women had a lower propensity to metastasize, resulting in a better survival when compared with men, even after first disease progression. These results suggest differences in tumor-host interaction across gender.

Quality of treatment in routine care in a population sample of rectal cancer patients.

Variations in compliance with rectal cancer treatment guidelines and the effect of quality indicators on long-term outcomes were investigated with data from the Munich Cancer Registry. Patients diagnosed between 1996 and 1998 with an invasive primary rectal tumor which was resected were included in these analyses (n=884). Median follow up was 5.7 years. Relative and overall survival was examined. Adjusted survival was predicted by UICC stage, grade, age, local recurrence, and residual tumor status. UICC III patients receiving the recommended adjuvant therapy had a significant survival advantage in the multivariate model; UICC II patients did not. Even if there were no significant survival differences there were significant treatment and outcome (regarding local recurrence) variations between hospitals. The variations between hospitals refer to different quality indicators in the individual hospitals. The outcome (regarding survival) appears good in Munich and is comparable with other population studies. Fewer local recurrences, better reporting of the TME technique, greater use of combined therapy and fewer stomas, however, may improve the quality of care in Munich. Variations in care between hospitals should therefore be monitored and controlled. Detailed and frequent feedback to the clinicians is vital to improve quality of care and is possible with cancer registries.

Predictors of quality of life of breast cancer patients.

Research has indicated that several demographic and clinical factors may affect the quality of life of breast cancer patients. Few studies, however, have sufficient sample sizes for multivariate analyses to be tested. Furthermore, several important factors, such as arm morbidity, communication and comorbid illness, have not been included in quality of life models The aim of this study was to predict the simultaneous effect of these factors on long-term quality of life. Breast cancer patients (n = 990) completed a quality of life survey, including the EORTC QLQ-C30, over five years. Clinical details were registered in the Munich Cancer Registry. Eleven predictors across eight quality of life domains were analyzed over a period of five years using a logistic regression model. Arm problems, communication, comorbidity, age, surgery. and, to a lesser extent, marital, educational and employment status were significantly associated with quality of life. Adjuvant therapy, medical insurance and pT category were not significant predictors. This study is the first to demonstrate the consistency and strength of arm dysfunction and doctor-patient communication on breast cancer patients' quality of life. These important factors in breast cancer care can be improved and should be regarded as a priority.

Quality of life in rectal cancer patients: a four-year prospective study.

OBJECTIVE: To assess long-term quality of life in a population-based sample of rectal cancer patients. SUMMARY BACKGROUND DATA: Quality of life in rectal cancer patients who suffer reduced bowel and sexual function is very important. Few studies, however, have long term follow-up data or sufficient sample sizes for reliable comparisons between operation groups. PATIENTS AND METHODS: A 4-year prospective study of rectal cancer patients' quality of life was assessed by using the European Organization for Research and Treatment of Cancer QLQ-30 and CR38 questionnaires. RESULTS: A total of 329 patients returned questionnaires. Overall, anterior resection patients had better quality of life scores than abdominoperineal extirpation patients. High-anterior resection patients had significantly better scores than both low-anterior resection and abdominoperineal extirpation patients. Low-anterior resection patients, however, overall had a better quality of life than abdominoperineal extirpation patients, especially after 4 years. Abdominoperineal extirpation patients' quality of life scores did not improve over time. Stoma patients had significantly worse quality of life scores than nonstoma patients. Quality of life improved greatly for patients whose stoma was reversed. CONCLUSIONS: Anterior resection and nonstoma patients, despite suffering micturition and defecation problems, had better quality of life scores than abdominoperineal extirpation and stoma patients. Comparisons between abdominoperineal extirpation and anterior resection patients should consider the effect of temporary stomas. Improvements in quality of life scores over time may be explained by reversal of temporary stomas or physiologic adaptation.