Chondrosarcoma: the impact of comorbidity - 30 years of experience from a population-based database including 199 consecutive chondrosarcoma patients.

BACKGROUND: Adjustment for comorbidity when investigating potential prognostic factors, especially in elderly cancer patients, is imperative. Patients diagnosed with chondrosarcoma are elderly and more comorbidity is expected for these patients. Demographic changes are awaited in the future resulting in more and more elderly patients with comorbidity. The aims of this study were to characterize patients with chondrosarcoma treated at a single institute and to evaluate various prognostic factors for survival adjusted for comorbidity. MATERIAL AND METHODS: Between 1979 and 2008, 199 patients were treated at the Sarcoma Centre of Aarhus University Hospital, for chondrosarcoma. The incidence was calculated as a WHO age-standardized incidence rate (IR) per million per year. The endpoints were overall mortality and disease-specific mortality. Possible prognostic factors were analyzed for patients with intermediate/high-grade localized tumors by the uni- and multivariate Cox-proportional hazard method. RESULTS: The WHO age-standardized IR in western Denmark in the period 1979-2008 was 2.4/million inhabitants/year (95% CI: 2.2;2.6). The 5-year overall and disease-specific mortality for the 199 patients were 29% (95% CI: 23;36) and 22% (95% CI: 16;27), respectively. The 5-year disease-specific mortality for patients with metastatic disease was significantly higher than for patients with localized disease. The median time to relapse was 2.0 years. Patients who relapse within 1 year after the primary diagnosis have a significantly higher 5-year overall mortality compared to patients who relapse after 1 year. The presence of comorbidity and high-grade tumors were independent prognostic factors for both the overall mortality and the disease-specific mortality of chondrosarcoma patients. CONCLUSION: Patients with comorbidity had a significantly increased overall mortality and disease-specific mortality. We found that adjusting for comorbidity is important when investigating a cohort of elderly patients.

The importance of standardized treatment in high-grade osteosarcoma: 30 years of experience from a hospital-based database.

BACKGROUND: Treatment of high-grade osteosarcoma remains a major challenge in orthopedic oncology as no major breakthrough in overall survival has occurred in the past 20 years. Due to the rarity of the disease, comparing the results of a single institution to best standard practice needs the establishment of clinical databases. The aim of this study was to report the cumulative 30-years' experience of a single institution and to assess the incidence, survival and prognostic factors of high-grade osteosarcoma using a recently validated, hospital-based database, representing all citizens living in western Denmark, the Aarhus Sarcoma Registry. MATERIAL AND METHODS: Between 1979 and 2008, 169 patients were treated at the Sarcoma Centre of Aarhus University Hospital for high-grade osteosarcoma. The incidence was calculated as a WHO age-standardized incidence per million per year. The endpoint was overall survival, analyzed by the Kaplan-Meier method and log-rank. Possible prognostic factors were analyzed by the uni- and multivariate Cox proportional hazard method. RESULTS: The incidence of high-grade osteosarcoma in western Denmark from 1979 to 2008 was 2.7/million inhabitants/year. The five-year overall survival was 42% (95% CI 34; 49) for the whole cohort of patients with high-grade osteosarcoma and 54% (95% CI 43; 64) for patients with localized disease treated with wide excision and chemotherapy. For patients treated with curative intent, no soft tissue extension, treatment with sufficient surgical margin and standard chemotherapy, as well as a high degree of necrosis after chemotherapy were all independent prognostic factors for overall survival. CONCLUSION: The data from this hospital-based, validated database confirms the relevance of the known prognostic factors of high-grade osteosarcoma and emphasizes the importance of adequate surgical margins and chemotherapy.

Prognostic factors in soft tissue sarcoma.

Despite major advances in the knowledge of soft tissue sarcoma (STS) during the last decades, no significant improvement in survival has been observed. Detailed data on the prognosis of STS are crucial in order to identify patients who might benefit from more aggressive treatment. Such data can be obtained from properly designed databases; however, the validation of data is crucial in order to obtain valid, reliable results. Furthermore, the majority of prognostic studies in STS have been limited by potential selection bias, low power, and biased estimates due to the statistical methods used, e.g., dichotomizing continuous variables, censoring competing events, as well as not adjusting for important confounders. The overall aim of this thesis was to investigate the prognosis of STS patients using data from the Aarhus Sarcoma Registry (ASR), covering western Denmark in the period from 1979 to 2008. In study I, we systematically validated data in the ASR and evaluated the validity, including completeness of patient registration and accuracy of data. In study II, we investigated the prognostic impact of patient-, tumor-, and treatment-related factors on local recurrence and disease-specific mortality. These were analyzed in a competing risk model in which continuous variables were included as cubic splines and possible confounders were selected based on directed acyclic graphs. In study III, we examined the impact of comorbidity on overall and disease-specific mortality. In study IV, we compared mortality in patients with abnormal biomarkers to those with normal values, assessed the significance of adjusting for comorbidity, as well as constructed a prognostic biomarker score. In study V, we described the relative mortality, i.e., the mortality in STS patients compared with the mortality in a general population, and compared relative and disease-specific estimates. The mortality in the general population was determined using an individually age- and sex-matched comparison cohort. All five studies were conducted in western Denmark within a population of approximately 2.5 million. Individual linkage between the ASR and national registries was made possible by the unique Danish civil registration number. The National Patient Registry and the LABKA research database were used to obtain data on comorbidity and biomarkers. In studies II to V we used a time-to-event-analysis approach that included cumulative incidence functions as well as crude and confounder adjusted Cox proportional hazard regression. In study I, we established that the overall validity of data in the ASR, after validation, was satisfactory and that the ASR included 85.3% of sarcoma patients from western Denmark between 1979 and 2008. In study II, we found a five-year local recurrence and disease-specific mortality of 16% and 24%, respectively. We excluded depth as a prognostic factor, and established that age, duration of symptoms, tumor size, anatomical and compartmental location, as well as radiotherapy were important prognostic factors for disease-specific mortality. In study III, we found that the level of comorbidity before or at diagnosis was an independent prognostic factor for both overall and disease-specific mortality, even after adjustment for age. In study IV, we showed that pretreatment levels of albumin, hemoglobin, and neutrophil to lymphocyte ratios were independently correlated with disease-specific mortality, and that adjusting for comorbidity was significant. In study V, we found five- and ten-year relative mortalities of 32.8% and 36.0%, respectively. The mortality in patients with low-grade STS was not significantly increased compared with the general population. The five- and ten-year disease-specific mortalities were underestimated by 3.1 and 1.9 percentage points compared to the relative mortality, respectively. We showed that relative mortality provided an accurate method to differentiate between cancer-specific and non-cancer-specific deaths. In conclusion, we showed that the ASR is a valid source of population-based data on STS. Improving the statistical methods used in prognostic studies of STS is important in order to obtain unbiased and reliable results. The level of comorbidity and bio-markers were important prognostic factors and should be used to identify high-risk STS patients who might benefit from more aggressive treatment.

Relative mortality in soft tissue sarcoma patients: a Danish population-based cohort study.

BACKGROUND: Cancer-specific survival estimates rely on precise and correct data on the cause of death; however, these data can be difficult to acquire, particularly in elderly patients where comorbidity is common. Furthermore, while some deaths are directly related to cancer, others are more complex, with cancer merely contributing. Another, more precise, method is to assess the relative mortality, i.e., mortality in patients compared to the general population. The aims of this study were to describe the relative mortality in soft tissue sarcoma, and to compare the relative mortality with the cancer-specific mortality. METHODS: We included 1246 patients treated for soft tissue sarcoma and 6230 individually age- and sex-matched individuals from the general population. The relative mortality was estimated as rates, and rate ratios adjusted for comorbidity. Mortality rate ratios were computed using the Cox proportional hazard model for 0-5 years and 5-10 years, according to age, sex and level of comorbidity. The cancer-specific mortality was compared to the corresponding relative mortality. RESULTS: The overall 5- and 10-year relative mortality was 32.8% and 36.0%. Patients with low-grade soft tissue sarcoma did not have increased mortality compared with the general population. Soft tissue sarcoma patients had a 4.4 times higher risk of dying within the first five years after diagnosis and a 1.6 times higher risk between five and ten years compared with the general comparison cohort. The relative mortality varied according to age, grade, stage at diagnosis, and level of comorbidity, being highest in younger patients and in patients without comorbidity. The overall 5- and 10-year cancer-specific mortality was underestimated by 1.5 and overestimated by 0.7 percentage points compared to the relative mortality, respectively. No statistical significant difference between the relative and the cancer-specific mortality was found. CONCLUSION: The relative mortality provides an unbiased and accurate method to differentiate between cancer-specific and non-cancer-specific deaths. However, when data on the cause of death is of a sufficient quality, there is no difference between relative mortality and disease-specific mortality based on death certificates.

Alarm symptoms of soft-tissue and bone sarcoma in patients referred to a specialist center.

BACKGROUND AND PURPOSE: The Danish Cancer Patient Pathway for sarcoma defines a set of alarm symptoms as criteria for referral to a sarcoma center. This may exclude cancer patients without alarm symptoms, so we investigated the presence of alarm symptoms (defined as being indicative of a sarcoma) in patients who had been referred to the Aarhus Sarcoma Center. PATIENTS AND METHODS: We reviewed the medical records of all 1,126 patients who had been referred, with suspected sarcoma, from other hospitals in the period 2007-2010 for information on symptoms, clinical findings, and diagnosis. Alarm symptoms were analyzed for predictive values in diagnosing sarcoma. RESULTS: 179 (69%) of 258 sarcoma patients were referred with alarm symptoms (soft-tissue tumor>5 cm or deep-seated, fast-growing soft-tissue tumor, palpable bone tumor, or deep persisting bone pain). The remaining 79 sarcomas were found accidentally. "Size over 5 cm" for soft-tissue tumors, and "deep persisting bone pain" for bone tumors had the highest sensitivity and positive predictive value. Of the 79 sarcoma patients who were referred without alarm symptoms, 7 were found accidentally on imaging, 5 were referred with suspected recurrence of a sarcoma, 64 were referred with a confirmed histological diagnosis, and 3 were referred for other reasons. INTERPRETATION: Defined alarm symptoms are predictive of sarcoma, but one-third of the patients were found accidentally. Further studies on presenting symptoms in primary care are needed to assess the true value of alarm symptoms.

Comorbidity in adult bone sarcoma patients: a population-based cohort study.

Background. Comorbidity is an important prognostic factor for survival in different cancers; however, neither the prevalence nor the impact of comorbidity has been investigated in bone sarcoma. Methods. All adult bone sarcoma patients from western Denmark treated at the Aarhus Sarcoma Centre in the period from 1979 to 2008 were identified through a validated population-based database. Charlson Comorbidity Index scores were computed, using discharge diagnoses from the Danish National Patient Registry. Survival was assessed as overall and disease-specific mortality. The impact of comorbidity was examined as rates according to the level of comorbidity as well as uni- and multivariately using proportional hazard models. Results. A total of 453 patients were identified. The overall prevalence of comorbidity was 19%. The prevalence increased with age and over the study period. In patients with Ewing/osteosarcoma, comorbidity was not associated with an increased overall or disease-specific mortality. However, patients with bone sarcomas other than Ewing/osteosarcoma had increased overall mortality. Independent prognostic factors for disease-specific survival were age, tumor size, stage at diagnosis, soft tissue involvement, grade, and surgery. Conclusion. The prevalence of comorbidity in bone sarcoma patients is low. Comorbidity impaired survival in patients with non-Ewing/nonosteosarcoma, histology. This emphasizes the importance of not only treating the sarcoma but also comorbidity.

Prognostic factors for local recurrence and mortality in adult soft tissue sarcoma of the extremities and trunk wall: a cohort study of 922 consecutive patients.

BACKGROUND AND PURPOSE: Previous studies of soft tissue sarcoma (STS) have identified a number of possible prognostic factors; however, the majority of these include highly selected populations, with unclear validation of data and insufficient statistical methods. We identified prognostic factors in a validated, population-based 30-year series of STS treated at a single institution, using an advanced statistical approach. PATIENTS AND METHODS: Between 1979 and 2008, 922 adult patients from western Denmark were treated at the Aarhus Sarcoma Center for non-metastatic STS in the extremities or trunk. The endpoints were local recurrence (LR) and disease-specific mortality (DSM). Prognostic factors were analyzed using a proportional hazard model, including continuous variables as cubic splines. Directed acyclic graphs were used to depict the causal structure. RESULTS: The 5-year LR was 16% and the 5-year DSM was 24%. Important prognostic factors for both LR and DSM were age, duration of symptoms, tumor size, grade, margin, and radiotherapy, while anatomical location (upper, lower extremity, trunk) was prognostic for DSM. INTERPRETATION: In this population-based series of adult, non-metastatic STS, we included directed acyclic graphs, cubic splines, and a competing risk model in order to minimize bias, and demonstrated that these statistical methods are feasible. Using these statistical methods on a large, validated dataset, we excluded depth as a prognostic factor and established that age, duration of symptoms, size, grade, margin, and radiotherapy were important prognostic factors for both local recurrence and disease-specific mortality.

Prevalence and prognostic impact of comorbidity in soft tissue sarcoma: a population-based cohort study.

BACKGROUND: Comorbidity is an important prognostic factor for survival in other cancers, but the importance in soft tissue sarcoma has not yet been clarified. The aims of this study were to examine the prevalence of comorbidity in soft tissue sarcoma patients, and estimate the impact of comorbidity on overall and disease-specific mortality. MATERIAL AND METHODS: Overall, 1210 adult patients with soft tissue sarcoma in the extremities or trunk wall were identified through the Aarhus Sarcoma Registry, a validated population-based database. Information on comorbidity was obtained through the National Patient Registry, and a Charlson's Comorbidity score was calculated for each patient. The prevalence of comorbidity was assessed overall, as well as according to age and year of diagnosis. Overall and disease-specific mortality rates according to level of comorbidity were computed. The prognostic value of comorbidity was estimated using crude and adjusted Cox proportional hazard models. RESULTS: The overall prevalence of comorbidity was 25%. The prevalence increased with increasing age, and patients with comorbidity had a larger proportion of adverse prognostic factors when compared to patients without comorbidity. The five-year disease-specific mortality was 26% (95% CI 24-29) for patients without comorbidity, compared to 33% (95% CI 24-42), 41% (95% CI 32-50), and 44% (95% CI 33-55) for patients with mild, moderate, and severe comorbidity, respectively. After adjusting for age, sex, stage, tumor size, depth, grade, surgical margin, radiotherapy, and chemotherapy, comorbidity was independently associated with an increased overall and disease-specific mortality. CONCLUSION: Patients with comorbidity had significantly increased overall and disease-specific mortality compared to patients without comorbidity, even when adjusting for important prognostic factors including age.

Cancer Patient Pathways shortens waiting times and accelerates the diagnostic process of suspected sarcoma patients in Denmark.

Cancer Patient Pathways (CPPs) for suspected cancer were implemented in Denmark to reduce waiting times for cancer diagnosis and treatment. Our study describes developments in time intervals and tumour size in a natural experiment before and after implementation of the CPP for sarcomas (January 1st, 2009). Medical files for patients referred with suspected sarcoma from other hospitals to Aarhus Sarcoma Centre during 2007-2010 (n=1126) were reviewed for data on milestones, time intervals, performed diagnostics, and tumour size. Results showed a statistically significant reduction in median number of work days in the phase "referral to first appointment" for all patients. For bone sarcomas, median time was significantly reduced from 11 to five work days in the phase "first appointment to decision of treatment", for soft tissue sarcomas it was reduced from 28 to 18 work days in the phase "referral to start of treatment". Passive waiting time was reduced, and delays in the fast-track programme were caused mostly by supplementary diagnostics. Median tumour size for soft tissue sarcomas was reduced from 7.0 to 4.9cm, possibly a secondary effect of increased awareness. CPPs have accelerated the diagnostic process for sarcomas, and our results may aid international development of similar initiatives.

Low-Grade Fibromyxoid Sarcoma: Incidence, Treatment Strategy of Metastases, and Clinical Significance of the FUS Gene.

Aim. The aim of this study was to assess the incidence of low-grade fibromyxoid sarcoma (LGFMS), present treatment results of metastatic LGFMS, and investigate the clinical significance of the FUS gene rearrangement. Methods. This study included 14 consecutive LGFMS patients treated at the Aarhus Sarcoma Centre in 1979-2010. Fluorescent in situ hybridization (FISH) analysis for FUS break-apart was performed for all patients. Results. The incidence of LGFMS was 0.18 per million, representing 0.6% of all soft tissue sarcomas. Four patients needed multiple biopsies/resections before the correct diagnosis was made. Four patients experienced local recurrence, and three patients developed metastases. The treatment of metastatic LGFMS varied from multiagent chemotherapy to repeated, selective surgery of operable metastases. The best response to chemotherapy was short-term stabilization of disease progression, seen with Trabectedin. The prevalence of the FUS break-apart was 21.4%. We found no significant difference in clinical characteristics and outcomes in correlation with the FUS break-apart. Conclusion. LGFMS is a rare disease with multiple challenges. The FUS break-apart was not associated with local recurrence or metastases in our study. To date the only treatment resulting in disease-free periods is surgery; however further investigation into the management of metastatic LGFMS is necessary.

Metastatic pattern, local relapse, and survival of patients with myxoid liposarcoma: a retrospective study of 45 patients.

Purpose. To assess the metastatic pattern of the histological subtype myxoid liposarcoma (MLS) with no or few round cells. Methods. Forty-five patients (F/M = 27/18, mean age 49 (range 17-85) years) were diagnosed with MLS at two Danish sarcoma centres in the period 1995-2004. A retrospective review of patients' files combined with an extraction of survival data from the Danish Centralised Civil Register was performed. Results. Seven patients had distant metastases during the observation period. Two patients had metastases at the time of diagnosis, while metastases occurred within 2.5 years in four patients, and in one patient 11.9 years after primary diagnosis. All metastases occurred at extrapulmonary sites. The first local relapse occurred within 3 years after surgery in six patients, in one patient after 4.0 years, and in one patient 7.7 years after surgery. The 5- and 10-year overall survival was 80% and 69%, respectively. Both the 5- and 10-year distant metastases-free survival was, respectively, 86%. The 5- and 10-year local relapse-free survival was, respectively, 83% and 80%. Conclusions. Patients with MLS had only extra-pulmonary metastases, and no lung metastases were found. Most local relapses and distant metastases occurred within the first 2-3 years after surgery.

Population-based Aarhus Sarcoma Registry: validity, completeness of registration, and incidence of bone and soft tissue sarcomas in western Denmark.

BACKGROUND: The aim of the present study was to validate the data in the Aarhus Sarcoma Registry (ASR), to determine if this registry is population-based for western Denmark, and to examine the incidence of sarcomas using validated, population-based registry data. METHODS: This study was based on patients with bone and soft tissue sarcoma treated at the Sarcoma Centre of Aarhus University Hospital between January 1, 1979 and December 31, 2008. The validation process included a review of all medical files by two researchers using a standardized form. The Danish Cancer Registry was used as a reference to assess the completeness of registration of patients in the ASR. Crude and World Health Organization age-standardized incidence, as well as age-, gender-, and year-specific incidences were estimated. RESULTS: The validation process added 385 to the 1442 patients who were registered in the ASR. Before validation, on average, 70.5% of the data for the variables was correct. Validation improved the average completeness of the registered variables from 83.7% to 99.3%. The 1827 patients in the ASR after validation include 85.3% of the patients registered in the Danish Cancer Registry. The overall World Health Organization age-standardized incidence of sarcoma in the trunk or extremities in western Denmark in the period 1979-2008 was 2.2 per 100,000, being 0.8 for bone sarcomas and 1.4 for soft tissue sarcomas. CONCLUSION: The validation process significantly improved the completeness of the variables and the quality of the ASR data. ASR is now a valuable population-based tool for epidemiological research and quality improvement in the treatment of sarcoma. It is our recommendation that documented validation of registries should be a prerequisite for publishing studies derived from them.