Including 66,852 patients, this is the largest study with epidemiological and clinical aspects of STS in Brazil, with data from all states of the five Brazilian regions and covering a long time-frame (16 years). Some international studies have been conducted by compiling health-care generated data in order to better know the STS patient profile and to acknowledge the impact of this disease all over the world, such as Saltus, in 2018(3) in Germany, and Burningham, in 2012(1)in the United States. Brazil has more than 210 million inhabitants, a highly admixed population and peculiar access to health care, since more than 70% of the Brazilian population count on its public health services for cancer care. Exploring potentiality of available Brazilian data to explore epidemiology STS profile is fundamental for governmental planning, health technologies and health economics assessment, and it may help other LMICs by mirroring their realities.
Epidemiologically, there was an almost even distribution between genres, with a slight majority of the patients being female (50.7%), aged above 65 years old (33%), of white race (18,1%) and living in the Northeast region (40,2%). However, the male gender, aged above 65 years old and with STS of the peritoneum and retroperitoneum, thorax and torso showed worst prognostic predictors. The epidemiological profile of the Brazilian STS patient showed to be similar to the ones described by other international cohorts. In Germany, Saltus(3) describes their patients as evenly distributed between males and females, aged above 65 years old and with tumors located most commonly in the lower extremity, trunk and head and neck. In Canada, Bozzo(4) described the STS population with a slight tendency to male (1.5:1 ratio male to female) and aged above 50 years old in 68% of the cases. Regarding the American population of STS patients, the AJCC described the STS patients as with a tendency to male (53,7%), with STS mostly located on lower extremities (57,5%) and with a mean age of 59 years old(5).
Regarding the STS localization results, the large number of head and neck STS patients was cautiously analyzed. As mentioned, the anatomical location was identified and determined according to the ICD-10, and it is important to highlight that “Malignant neoplasm of connective and soft tissue of head, face and neck” and “Malignant neoplasm of other connective and soft tissue” have a slight similar coding, (respectively C49.0 and C49), and the original SIM and SIA registry requires a 3 digit ICD-10 code, which may have mistakenly increased the notification under “head and neck” anatomic location by the erroneous addition of an extra 0 during the digitalization of official forms. This analysis is corroborated after the analysis of the correlation of procedures performed according to each specific anatomic location (TABLE IN ATTACHMENTS).
ATTACHMENT 1: Distribution of procedures based on anatomic location
Anatomic Location
Type of Procedure
|
C49.4 + C49.5
|
C49.0
|
C49.8
|
C49.9
|
C49.2
|
C49.1
|
Any C48
|
C49.3 + C49.6
|
TOTAL
|
Limb amputation
|
4
|
4
|
4
|
17
|
420
|
157
|
16
|
3
|
625
|
Lymphadenectomy
|
10
|
55
|
19
|
140
|
10
|
10
|
117
|
27
|
388
|
Chemotherapy
|
742
|
1132
|
324
|
1931
|
1706
|
1410
|
1342
|
842
|
9429
|
Radiotherapy
|
505
|
1147
|
183
|
1157
|
1225
|
506
|
278
|
480
|
5481
|
Retroperitoneal resection
|
2
|
2
|
3
|
5
|
|
|
3656
|
|
3668
|
Wide tumoral excision
|
1240
|
8734
|
4094
|
6651
|
1792
|
1587
|
1185
|
1701
|
26984
|
Simple tumoral resection
|
764
|
4852
|
4546
|
804
|
3288
|
4772
|
74
|
1177
|
20277
|
TOTAL
|
3267
|
15926
|
9173
|
10705
|
8441
|
8442
|
6668
|
4230
|
66852
|
When first course treatment was analyzed, patients who underwent specific resection of their tumors had a better prognosis (Wide tumoral excision, HR= 0.6665; 95% CI =0.6449-0.6887 and Simple tumoral resection with an HR= 0.499; 95% CI =0.4799-0.5188) and, according to the Kaplan-Meier survival analysis (Figure 3), had a significant better survival rate than the other treatment modalities, with initial lymphadenectomy and limb amputation being the least performed procedures. These results go in accordance with the standard treatment of the STS, where an adequate (and wide if necessary) resection is indicated, with a predilection of limb-sparring surgeries, since 1985 (6, 7).
Regarding the use of chemotherapy and radiotherapy on the sarcoma patient, literature indicates the use of radiotherapy, currently, in neoadjuvant or in adjuvant settings in order de improve local control rate and decrease the recurrence rate (mainly in extremity STS), but has no improvement in overall survival. The ESMO recommendation favors adjuvant radiotherapy when tumors size is above 5 cm or deeply located or high grade and when not R0 resection occurs and NCCN recommends neoadjuvant radiation therapy with external beam for microscopic residual disease control and adjuvant treatment when insufficient margins, with local control rates of 95% with preoperative RT and negative margins, but reinforces that radiotherapy is not substitute for the definitive surgical resection(8, 9). The use of chemotherapy, both neoadjuvant or adjuvant, remains controversial with benefits described as the facilitation of surgery, when used perioperatively, or in a systemic modality, with anthracyclines with ifosfamides for high risk patients with thoracic or extremity STS (8).
Treatment wise, the Brazilian are, apparently, in resonance with European and American practices. When we correlate the data on clinical staging, type of first course procedure and combination of clinical and surgical approaches, we observed that the vast majority of patients who underwent only chemotherapy were, in its majority, clinically staged as 4. Neoadjuvant radiotherapy or neoadjuvant with adjuvant radiotherapy were mostly administered in patients staged 2 or 3. If we consider that the non-surgical treatment is reserved for patients with no possibility of surgical intervention, our study had 13.834 who underwent chemotherapy and radiotherapy exclusively or combined, with different proportions of clinical staging distributions, and not only to higher stages. It is important to reinforce that many different histological subtypes of STS have different recommendation of systemic treatment. The lack of information regarding the histological grading and clinical staging of a large number of patients (classified as “GX” and “undetermined clinical staging”) is presumed to occur because of sub registration. Due to the large number of patients treated with only surgery (without complementation with chemotherapy or radiotherapy) the filing of SIA forms, in which staging and tumor grading related information is mandatory, was – most likely - not performed. After correlation with all the clinical and surgical treatments analyzed, it is believed that due to the majority of them undergoing simple resection or wide resection and not going through clinical treatment afterwards, presumably, the surgical procedure performed is fully controlling the progression of the disease, and the patients are not being referred to adjuvant systemic treatment.
When comparing survival curves with another countries, it was observed a small difference in 1-year overall survival between the Brazilian an American STS patient. A further analysis of the survival by age shows a worst prognosis when long time survival is evaluated amongst men. After the first year of diagnosis, around 84% of male and 84.5% of female STS patients in United States are expected to have survived, compared to 79.5% and 84.9%, respectively, in Brazil, with the latter demonstrating a slight better result within the female population. The 5-year and 10-year survival data, however, show a rapid decrease in survival of patients from both countries. The worst results are seen with the Brazilian male population with, respectively 51% and 34,5% 5- and 10-year survival rates, compared to 64,9% and 59,2% 5- and 10-year survival rates of the American male population. And, regardless of a better overall outcome regarding survival risks, the female population still has a decrease of survival rates amongst American (with 66.5% and 61.1% 5- and 10-year survival rates, respectively) and Brazilian women (63.4% and 49%5- and 10-year survival rates, respectively). The SEERS database collects cancer incidence data from population-based cancer registries covering approximately 34.6 percent of the U.S. population, with an STS incidence valued less than 6 cases for 100,000. However, the annual incidence of the STS in Brazilian population remains unknown, and was not calculated in this study due to this cohort not being a representation of all sarcoma patients registered on the SUS databases (due to exclusion criteria) or the totality the patients treated for STS in Brazil, as a whole.
By comparing STS data from different populations, it was observed that British patient’s survival chance is approximately 7% lower than the Brazilian ones, and 9.2% lower when compared to American population within the first year of STS follow up (1-year survival rates of 75%, 82% and 84.2% respectively). And this order of, potentially, improved outcomes is maintained we compare the rates of 5-year survival data available (65.6% in United States, 55% in United Kingdom and 57% in Brazil). However, it is possible to identify a shift in long term survival comparison when we observe the 10-year survival rates, United Kingdom presenting a better survival rate (45%) than Brazil (42%) amongst the STS patients. The values for both countries remain, however, significantly lower than American 10-year survival rate, which reaches 60.1%. The progressive decrease in survival of the Brazilian STS patients might also be related to the fact that the majority of the evaluated patients underwent first treatment for their tumor after 65 years of age, with 33% of this cohort being constituted of elderly patients (HR= 1.61; 95% CI =1.561-1.66)(10-12).
This study is based on the gathering of information obtained from mandatory forms filled out by health care providers and provide the data for administrative databases. As in the many cohorts, several limitations related to the use of a secondary database can be found in this study, such as inconsistency, inadequacy of collected information, confounding factors and missing information. The difficulties to access this data reinforces the necessity of a unified platform. On account of the coverage of this study and its development based on databases generated by the performance of oncologic treatment for STS (surgical, systemic - with chemotherapy - or loco regional – with radiotherapy), information that is present on medical charts and medical files generated by standard follow up consultations were not available and neither these patients could be accurately identified for this investigation, after the elaboration of the cohort. The Brazilian government is currently working on a unified platform.
A major limitation of this study is the lack of direct access to histopathological, molecular, clinical and therapeutic variables or information of the sarcoma subtypes, making the diagnosis confirmed by the registry of the patient under C48, C48.0, C48.1, C48.2, C48.8, C49, C49.0, C49.1, C49.2, C49.3, C49.4, C49.5, C49.6, C49.8. C49.9) according to the tenth revision of the international classification of diseases (ICD-10), topographic localization associated with the therapeutic utilized (and depending on if the patient underwent systemic treatment) the only mean to infer over the possible subtype of the mass/tumor registered, and the significant number of missing data
Regardless of that, no other study performed by Brazilian researchers was able to provide data resulting in an estimate of the incidence, considering that the SUS databases available only contemplate about ¾ of the Brazilian population, or provided an evaluation of the survival of the STS patients (of all subtypes) in Brazil.