Oncological Outcome and Prognostic Factors of Surgery for Soft Tissue Sarcoma After Neoadjuvant or Adjuvant Radiation Therapy: A Retrospective Analysis over 15 Years

Discussion

In the current study, our working group retrospectively analysed a single-centre cohort treated in a national sarcoma centre. We determined the outcome and prognostic factors of STSs patients after surgical treatment and compared ART and NRT. To the best of our knowledge, this is the most up-to-date report providing a prognostic evaluation of STS with comparison of ART versus NRT.

Localization and overall survival. In the present study, the localization of STS was comparable to that noted in existing literature. Our cohort had an equal distribution of sexes, with a median age of 58.3 years. The most common tumour site was the thigh (approximately 60% tumours), followed by the lower leg and upper extremity, which is similar to results from the cohorts of Kikuta et al. and Bonvalot et al. (8, 9). The subtypes of STSs in our cohort are comparable to those of large epidemiologic studies with undifferentiated pleomorphic sarcoma as the most common subtype, followed by myxoid liposarcoma and MFS (3).

The overall survival rate in our cohort was 94.1% one year after initial diagnosis and dropped to 68.9% after 5 years. The 5-year survival rate in our cohort is slightly lower than that in some cohorts in the literature, e.g., Sanfillipo et al. (10), who found a rate of 80% in a homogenous cohort of mostly MFS patients. Our data confirm the results of Harati, who indicated a 5-year survival rate of 65.3% in a comparable cohort of STS patients (10, 11). The survival rate of STSs is multifactorial and depends on different parameters, such as grading, tumour size, surgical experience/resection margins, metastatic status, distribution of subtypes and local recurrence; therefore, the study cohorts are not easy to compare (1, 12, 13). Comparing the NRT and ART groups, the ART group seemed to have advantages in terms of 5-year survival, but the difference was not significant (62.6% vs. 77.8%; p=0.328).

Many patients in our cohort had subfascial tumour localization, slightly over 85%. We could not detect statistical significance for tumour localization as a prognostic parameter for overall survival. Pfister et al. have reported a significant difference between subfascial and epifascial localization in their cohort (5-year survival; 69.4% vs. 91.7%) (14). In the literature, there is no agreement concerning this prognostic factor; the results of Weitz et al. are comparable to our findings, but it must be stated that their cohort had many more patients with epifascial tumours (15).

The high number of subfascial tumours in our cohort can be explained by the study location being a national reference sarcoma centre treating complex and complicated cases. However, comparing the adjuvant vs. neoadjuvant radiation groups, a trend was detected; subfascial tumours had poorer survival rates in the NRT group, though the difference was not statistically significant (60.4% vs. 77.3%). This observation agrees with the surgical assessment of experienced tumour surgeon, as tumours with deep localization and neoadjuvant radiation tend to develop liquid tumour necrosis with the risk of bursting during resection, contaminating the surgical site. Despite the lack of statistical power, our study detects this trend.

However, tumour size is an important prognostic factor. Tumour size between 10-15 cm had a dramatic HR of 9.1 (95%CI=1.2-68.5; p=0.032), statistical significance (Reference < 5 cm) and indicated poor 5-year survival (Figure 4). These findings are in complete contrast to HR reported (1.64-2.54) by Eilber et al. comparing the tumour size <5 group with the >10 cm group (16). It should be mentioned that the working group of Eilber did not subclassify tumours larger than 10 cm as we did in our cohort (Table I). Additionally, their cohort included only approximately 50% high-grade sarcoma with overrepresentation of liposarcoma, whereas in our cohort, high-grade (G2+G3) tumours were overrepresented, and only myxoid and pleomorphic liposarcoma were included. This fact clearly demonstrated the problems of studies with rare entities and heterogeneous study designs. Other cohorts with homogenous tumour types, e.g., MFS, show comparable results to our study concerning tumour size (11, 17).

Comparing the tumour size groups divided into ART and NRT groups, again, the trend of lower 5-year survival in the NRT group can be observed. This trend was particularly clear in patients with tumour size 5-10 cm, which had a 5-year survival rate of 63.3% with NRT vs. 82.7% with ART.

In terms of histopathology, most of the tumours in our cohort were classified as high grade, as mentioned above. In total, 109 of 119 patients had histopathologic classification of G2 (n=41) or G3 (n=68). This fact could explain the lower overall survival rate compared to other cohorts (9). Grading of STSs correlated significantly with the 5-year survival of the patients (Figure 2), which decreased from 100% in the G1 group to 63% in the G3 group. According to Biau et al., patients with a histological G3 tumour have different negative predictors for long-term survival, such as a greater risk of local recurrence and metastasis (12). Different studies have investigated the probability of local recurrence comparing high-grade vs. low-grade STS. Coindre et al. and Eilber et al. have reported an HR of approximately 2 (16, 18), which at first glance seems to be relatively low. However, high-grade STS tend to have an even greater risk of metastasis; therefore, patients with high-grade sarcoma are more likely to die from systemic disease before local recurrence can occur (12). We detected equal results comparing NRT and ART in the G2 group but again detected a trend of poorer outcome in the G3 group (49.8 vs. 79.9%) among those who received NRT.

Despite being a rare disease, STS represents a heterogeneous group of tumour entities (4). Our cohort includes the most common tumour entities of STS. We detected highly variable 5-year survival rates among the different entities (Figure 3), with a low 5-year survival rate of approximately 60% for undifferentiated pleomorphic sarcoma and MFS and a high 5-year survival rate for synovial sarcoma and myxoid liposarcoma. However, in the statistical analysis, we could not state statistical significance (p=0.05-0.9). This trend stands in part in contrast to the findings of Weitz et al., who have reported a 5-year survival rate of 63% for synovial sarcoma and 87% for MFS (15). However, we confirmed their findings regarding the survival rate of undifferentiated pleomorphic sarcoma (formerly known as MFH) (15). This difference could be explained by the heterogeneous study design and lack of statistical power in our cohort.

Surgical margins are an ongoing and controversial issue in STS treatment. The literature is characterized by inconsistent findings regarding the prognostic value. Some authors state that surgical margins influence local recurrence but not overall survival (19, 20). On the other hand, some authors have stated the importance of negative margins for overall survival (14, 21). Our study lacks statistical power to give any further informative value to this pattern.

Our study proved local recurrence as a prognostic factor for the survival of STS patients. The 5-year survival rate decreased from 74% to 51% (p=0.036), and the HR increased to 2.2 in patients with and without local recurrence. Local recurrence occurred independent of the state of the margins; in fact, most of the patients with local recurrence had histologically negative margins. Local recurrence is a major problem for surgeons and patients. Reoperation is much more difficult due to neurovascular structures and scar tissue because most STSs are located deep in the thigh. This fact was examined by Kikuta et al. in their cohort of MFS patients with local recurrence, who had a 5-year re-recurrence-free survival rate with positive histopathological margins of 9.8% and those with negative margin of 62.3% (22).

Local recurrence of STS can be seen as a biological marker of the aggressiveness of the tumour (14, 20). In line to the findings of Albertsmeier et al., the local recurrence rate in our study was significantly higher in patients with ART compared to those with NRT (6).

In total, 54 patients (45.4%) developed distant metastases during the study period. Basically, the appearance of metastases indicates a transition from a local disease to a systemic disease accompanied by a dramatic decrease in 5-year survival, dropping to 37.2% (95%CI=22.5-51.9) compared to 98.0% (95%CI=94.1-100.0) in metastasis-free patients (p<0.001), as shown in Figure 6. We proved a strong relationship between distant metastasis and tumour-related mortality in our cohort. Metastasis formation is a statistically significant prognostic factor for poor outcome of STS. We confirmed the results of other working groups, such as Zagars et al. and Pisters et al., who have reported an even poorer outcome with a 5-year survival of 28% (14, 21). The HR of 31 is another parameter that reflects the dramatic rise in mortality when metastasis occurs.

Surgical complications are common after radiation and are well known. Patients suffer from wound complications, deep wound infections, seroma, and fractures that sometimes lead to amputation of the affected extremity. These complications are well described for adjuvant radiation therapy (23-25). Neoadjuvant radiation therapy could contribute to reducing these problems. The main problem we were facing was wound healing disorders (total of 36 patients/119 30%) followed by deep wound infections in 11/119 patients. We confirmed the findings of O’Sullivan et al. (5), who reported a 18% wound healing complication rate in their cohort. The significantly higher rate of wound healing problems in the NRT group compared to the ART group was not reproduced in our cohort. We had equal distribution in the NRT and ART groups (Table V). Several explanations for this are feasible. In the cohort of O’Sullivan (5) not all patients had primary wound closure and sometimes plastic surgery reconstruction was performed in the adjuvant group. In our cohort, patients had primary wound closure. Second, the radiation protocol varied in the two studies; some of the patients in their NRT group received a second dose of radiation after primary wound closure. However, NRT or ART, though an important step in the treatment of STS, is followed by important surgical complications that the patient and the surgeon must be aware of (1). Devastating complications such as limb amputation are rare but may occur.

Our study has certain limitations. The number of patients included in the study limits the statistical analysis. STS remains a rare disease with different histopathological subtypes that respond differently to radiation therapy. Therefore, a multicentre study with a detailed analysis of the histopathological subtypes and their response to radiation therapy would be desirable. Furthermore, no patients were included in our study who received additional chemotherapy that could possibly contribute to an improved outcome, but this would have led to a further subdivision of the total cohort. As a future outlook for individualized radiation therapy, it may be expected that models using clinical and radiomic features could improve therapy in patients with STS (26-28).