Treatment of Locally Advanced Merkel Cell Carcinoma-A Multi-Center Study.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a high risk of recurrence and poor prognosis. The treatment of locally advanced disease involves surgery and radiotherapy. To analyze real-life treatment patterns and clinical outcomes, we conducted a retrospective analysis of data from 161 MCC patients treated with curative intent in four oncological centers in Poland. The median age at diagnosis was 72 years (30-94); 49.7% were male. Lymph node (LN) involvement at diagnosis was found in 26.9% of patients. Sentinel lymph node biopsy (SLNB) was performed in 36.5% of patients (positive in 10.5%), and 51.9% of patients received perioperative treatment. The relapse rate was 38.3%. With the median follow-up of 2.3 years, the median disease-free survival (DFS) was not reached, and the 1-year rate was 65%. The negative independent risk factors for DFS were male gender, metastases in LN at diagnosis, no SLNB in patients without clinical nodal metastases, and no perioperative radiotherapy. The estimated median overall survival (OS) was 6.9 years (95% CI 4.64-9.15). The negative independent risk factors for OS were male gender, age above 70, metastases in LN at diagnosis, and no SLNB in patients without clinical nodal metastases. Our results confirm that the MCC treatment should be conducted in an experienced multidisciplinary team; however, the outcomes are still unsatisfactory.

Efficacy and Safety of Hypofractionated Preoperative Radiotherapy for Primary Locally Advanced Soft Tissue Sarcomas of Limbs or Trunk Wall.

BACKGROUND: The use of adjuvant radiotherapy (RT) shows a significantly decreased incidence of local recurrence (LR) in soft tissue sarcomas (STS). This study aimed to assess the treatment scheme's effect in patients with primary STS treated at one institution. METHODS: In this phase 2 trial, 311 patients aged ≥18 years with primary, locally advanced STS of the extremity or trunk wall were assigned to multimodal therapy conducted at one institution. The preoperative RT scheme consisted of 5 Gy per fraction for a total dose of 25 Gy. Surgery was performed within 2-4 days from the last day of RT. The primary endpoint was LR-free survival (LRFS). Adverse events of the treatment were assessed. RESULTS: We included 311 patients with primary locally advanced STS. The median tumor size was 11 cm. In total, 258 patients (83%) had high-grade tumors. In 260 patients (83.6%), clear surgical margins (R0) were obtained. Ninety-six patients (30.8%) had at least one type of treatment adverse event. LR was observed in 13.8% patients. The 5-year overall survival was 63%. CONCLUSION: In this group, with a significant percentage of patients with extensive, high-grade STS, hypofractionated preoperative RT was associated with good local control and tolerance.

What is the best front-line approach in patients with desmoid fibromatosis? - A retrospective analysis from a reference center.

INTRODUCTION: Desmoid fibromatosis (DF) is a locally aggressive, not metastasizing tumor associated with high local recurrence rates. Surgery was a standard-of-care for DF treatment; however, recently, conservative treatment and active surveillance are preferred. This study aimed to evaluate the real-life outcomes of DF treatment. MATERIALS AND METHODS: All consecutive patients diagnosed with DF and treated between 01.1999 and 12.2018 at one sarcoma reference institution were included in this retrospective analysis. Kaplan-Meier estimator, long-rank test, Cox regression model, and Chi2 tests were used for statistical analyses. RESULTS: The analyses included 363 patients (254 female, 109 male). 195 patients (53.7%) underwent surgical resection, and 139 (38.3%) experienced a watch-and-wait approach with or without concomitant therapy with nonsteroid anti-inflammatory drugs (NSAIDs) in the first line. Disease recurrence/progression occurred in 43.2% of patients treated with surgery and 42.6% in the watch-and-wait group, resulting in 5-year event-free survival (EFS) rates of 60% and 55%, respectively. There was no difference in EFS between both groups (HR1.28, 95%CI 0.91-1.79). Surgery without prior biopsy and extra-abdominal wall location was associated with inferior outcomes. CONCLUSIONS: Results of DF treatment in our center showed that watch-and-wait approach ± NSAIDs has similar efficacy to upfront surgery and allows to avoid unnecessary surgery in approximately half of the patients, primarily when tumors are located in unfavorable sites, like extremities.

The Long-Term Outcomes of Intensive Combined Therapy of Adult Patients with Localised Synovial Sarcoma.

INTRODUCTION: Synovial sarcoma (SaSy) is a high-grade, malignant soft tissue sarcoma (STS) accounting for 5-9% of STS. The aim of this study was to analyse outcomes of patients with localised SaSy treated in a single institution with a uniform neo- and adjuvant-combined therapy protocol. METHODS: 171 patients with stage II/III SaSy were treated between 1997 and 2014. Chemotherapy consisted of 4 cycles of ifosfamide 12 g/m2 and two cycles of a doxorubicin-based regimen 75 mg/m2. With the exception of patients who underwent amputation, all patients received neoadjuvant radiotherapy. RESULTS: Median age was 33 years (range 17-69). Tumours larger than 5 cm in size were found in 70% of patients. The 5-year overall survival (OS), local relapse-free survival (LRFS) and metastasis-free survival (MFS) rates were 75%, 80% and 60%, respectively. In multivariate Cox's regression, age > 35 years, male sex, larger tumour size and histology other than monophasic were associated with worse OS. CONCLUSIONS: In adult patients with localised SaSy, long-term survival can be achieved in a significant proportion of cases with intensive combined therapy. The multivariate analysis identified age, sex, disease stage and histology subtype as independent prognostic factors of OS.

Malignant peripheral nerve sheath tumors - Outcomes and prognostic factors based on the reference center experience.

INTRODUCTION: Malignant peripheral nerve sheath tumor (MPNST) accounts for about 5% of soft tissue sarcomas. It can occur as sporadic diseases or can be associated with type 1 neurofibromatosis. MPNST is usually associated with poor prognosis, mostly due to their aggressive behavior, high metastatic potential, and resistance to chemotherapy. Our study aimed to determine treatment outcomes and associated prognostic factors in a large cohort of patients with MPNSTs treated at the reference sarcoma center. METHODS: 239 consecutive patients (114 women and 125 men) diagnosed with MPNST between March 1998 and March 2018 who were treated with surgery with curative intent in the reference sarcoma center were included in the retrospective analysis. RESULTS: The mean age at diagnosis was 51 years (range 15-86). 28 (11.7%) patients had neurofibromatosis type 1 associated tumors (NF1 positive). Median OS was 126.5 months and 5-year survival rate was 61.9% in the group treated with curative intent. Median DFS, LRFS and DMFS were 91.6, 126.5 and 126.5 months, respectively. We identified tumor size, high tumor grade and positive surgical margins as independent negative predictors of DFS, LRFS, DMFS and OS. CONCLUSIONS: High-quality surgery remains a gold standard of MPNST treatment. High grade, size and quality of surgery are significant independent prognostic factors for overall survival. There is an unmet need for improvement, especially regarding the perioperative treatment and treatment of metastatic disease. Future studies on the biology of MPNST would lead to the development of novel treatment options and improvement of treatment outcomes.

Hypofractionated Radiotherapy in Locally Advanced Myxoid Liposarcomas of Extremities or Trunk Wall: Results of a Single-Arm Prospective Clinical Trial.

INTRODUCTION: Myxoid liposarcoma (MLPS) has been reported to be more radiosensitive compared with other soft tissue sarcomas. The main objective of the study was to assess the efficacy of hypofractionated radiotherapy (RT) in the preoperative setting in patients with locally advanced primary MLPS. METHODS: Single-arm prospective exploratory clinical trial enrolled MLPS patients for preoperative 5 × 5 Gy RT with delayed surgery. The endpoints of the study were the rate of early wound healing complications and 5-year local control rate. RESULTS: 29 patients (pts) were included, all had tumors located on the lower limb. The median maximum size of the tumor was 13 cm (IQR 10-15 cm). Early RT tolerance was good. Postoperative wound complications occurred in 11 pts (37.9%), late complications concerned 13.8% of patients. A total of 27 patients were included for the efficacy analyses. The pathological features of response to RT were detected in all analyzed surgical specimens. In 25 patients R0 margins were achieved, two patients had an R1 resection. None of the patients had local recurrence. CONCLUSION: Preoperative hypofractionated RT with a prolonged gap between RT and surgery is a feasible method of the management of MLPS, providing a good local control and low rates of treatment toxicity.

The clinical prognostic factors and treatment outcomes of adult patients with Ewing sarcoma.

BACKGROUND: The data about treatment results of Ewing sarcoma in adult patients are limited. The aim of our study was to analyze prognostic factors and outcomes of therapy in this group of patients. METHODS: Between 2000 and 2018, 180 patients at the age of > 18 years old diagnosed with Ewing sarcoma were treated in referral center according to multimodal protocols. In 50 patients (28%) treatment was initiated outside our hospital, and 23 of them had started recommended therapy after 3 months since the date of biopsy/unscheduled operation. We analyzed clinical prognostic factors and overall survival (OS). RESULTS: The median age was 28 years (18-67 years), primary tumor was localized axially in 114 patients (63%), metastases at presentation were detected in 51 pts (28%). 5-year OS rate was 65% for patients with localized disease, in metastatic disease it was 15%; the presence and the number of metastases was a prognostic factor. 5-year PFS was significantly better in patients treated at referral center (or when the patients were admitted to referral center within 3 months from the date of biopsy, which was performed outside referral center), comparing to patients treated initially outside referral center; 5-year PFS rates in total population were 28 and 13%, respectively. In terms of OS, unfavorable prognostic factor showing a statistical trend (p = 0.098) was lower dose density of neoadjuvant chemotherapy due to toxicity. CONCLUSIONS: Approximately two-third of adult patients with localized Ewing sarcoma survive 5 years. In order to improve survival of this patients the multidisciplinary treatment in referral center is mandatory.

Results of systemic treatment of cutaneous melanoma in inoperable stage III and IV.

AIM OF THE STUDY: The incidence of melanoma is increasing rapidly worldwide. Metastatic melanoma is still an incurable disease, although an era of new drugs is approaching. Current methods to predict outcomes in patients with advanced, metastatic melanoma are limited. A retrospective analysis of a contemporary large group of advanced melanomas was performed to determine clinical prognostic factors that accurately predict survival in patients with metastatic melanoma before the era of new targeted/immunological therapy. MATERIAL AND METHODS: The retrospective analysis of 427 patients with metastatic melanoma treated between 1995 and 2005 at two reference oncological centres. RESULTS: The median overall survival time (OS) was 7.1 months (95% CI: 6.7-7.9) and the 1-year, 2-year and 5-year survival rates were 32.3%; 12.5%; 3.9%, respectively. The median progression-free survival time (PFS) after the first line of treatment was 3.5 months (95% CI: 3.1-3.8). There were 19.1% objective responses (CR - 6.1%, PR - 13.0%) and SD - 45.5% after the first line of therapy. The most common adverse events were anaemia, neutropenia, thrombocytopenia, nausea and vomiting. IN MULTIVARIATE ANALYSES: PS (performance status) 0-1, normal serum levels of lactate dehydrogenase (LDH) and aspartate transaminase (AspAT), older age in women, palliative surgical treatment and palliative radiotherapy, type of the first line of therapy (DTIC), and metastatic melanoma of unknown primary site were independent positive predictors for survival. CONCLUSIONS: The survival rate of patients with metastatic melanoma has not changed significantly over the last years. We identified a set of independent positive predictors for OS treated with systemic therapy. DTIC still may be useful in treatment of patients in a good general condition and with normal serum levels of LDH. Because the results of treatment of metastatic melanoma are still not satisfactory, the majority of patients should be treated within prospective, randomized clinical trials.

Surgery combined with brachytherapy in patients with retroperitoneal sarcomas.

PURPOSE: The primary aim of this work was to analyze feasibility of combined treatment of retroperitoneal sarcomas (RS): surgery (S) and intraoperative brachytherapy (IOBRT). The secondary aim was to analyze results and complications after this treatment. MATERIAL AND METHODS: 84 patients with retroperitoneal sarcomas were qualified for combined treatment (S and IOBRT) between June 1998 and September 2006. 65 of the patients (77.4%) had local recurrences. Sarcomas with intermediate and high grade of histological malignancy (G2, G3 - 76.2%) were the most frequent within the all surgically treated patients. Resection ability (R0/R1) in analyzed group of patients was estimated as 85% (74 cases). After intraoperative evaluation, 57 (67.8%) patients were qualified for IOBRT. Since 2000, in 34 patients (60%) an adjuvant postoperative external beam radiation therapy (EBRT) in dose of 50 Gy was applied. Median follow-up of the surviving patients was 40 months. RESULTS: On the basis of the univariate analysis, relevant aspects negatively influencing overall survival rate within the RS group treated with IOBRT were as follows: surgery of sarcoma recurrence (p = 0.002), higher grade of histological malignancy (p = 0.05), histological type different than liposarcoma (p = 0.05) as well as no adjuvant EBRT (p = 0.05). On the basis of multivariate analysis one can ascertain that relevant factors negatively influencing LRFS in RS patients treated with IOBRT were: surgery due to recurrence of sarcoma (p = 0.008) and lack of EBRT (p = 0.01). CONCLUSIONS: Combined treatment (surgery and brachytherapy) was possible to be carried out on 68% of RS patients. The overall number of complications was quite high, however acceptable, taking into consideration the application of extensive, multi-organ treatments in case of sarcoma recurrences in this localization. The results suggest that the method of treatment will improve the final outcome when most of patients will be qualified for treatment of primary sarcomas in experienced centre.

The megavoltage radiation therapy in treatment of patients with advanced or difficult giant cell tumors of bone.

PURPOSE: To assess the outcomes of radiotherapy, in terms of local control and treatment complications, of advanced or difficult giant cell tumors of bone (GCTB) that could not be treated by surgery. METHODS AND MATERIALS: Among 122 consecutive patients with confirmed GCTB from 1985 to 2007, 77 patients were treated by megavoltage radiotherapy because they were inappropriate candidates for surgery. We have performed analysis of all data in terms of progression-free survival (PFS) and treatment morbidity. Median follow-up time was 58 months. RESULTS: In the irradiated group, maximal tumor size ranged from 5 to 18 cm (median, 8.5). Anatomic distribution was as follows: femur, 27 cases; tibia, 19; radial/ulnar bone, 12; sacrum, 9; pelvic bones, 5; other, 5. Twenty-one patients (27%) were referred for local recurrence after ≥1 other treatment procedures. The radiation doses ranged from 26 to 89 Gy (median, 56; administered 1.8-2.0 Gy/fraction with average total duration of treatment of 5-7 weeks); 8 patients (10%) received <50 Gy. All patients tolerated treatment well without acute or late complications. All patients except two are alive. Local control was achieved in 65 patients (84%; bone recalcification/restitution of joint functions), 12 patients showed signs of local progression, all within irradiated fields (9 were treated successfully with salvage surgery). Five- and 10-year local PFS were 83% and 73%, respectively. Three patients developed lungs metastases. Malignant transformation of GCTB occurred in two patients. CONCLUSIONS: GCTB can be safely and effectively treated with megavoltage radiotherapy with local control rate >80% at 5 years. Our study confirms that radiotherapy of GCTB offers an alternative to difficult or complex surgery and may be an option of choice in the treatment of inoperable patients.

Surgery combined with intraoperative brachytherapy in the treatment of retroperitoneal sarcomas.

BACKGROUND: The purpose of this study was to analyze the results of treatment of retroperitoneal soft tissue sarcomas (RSTS) by surgery combined with intraoperative brachytherapy (IOBRT). METHODS: Seventy adult patients with RSTS were considered for combined treatment (surgery plus IOBRT) between June 1998 and February 2004. There were 64 (91%) recurrent tumors, and 93% of tumors exceeded 5 cm. IOBRT was performed with high-dose-rate Gammamed 12 with iridium 192 (IOBRT time range, 20-87 minutes; median, 56 minutes). RESULTS: After intraoperative re-evaluation, 24 patients (34%) were found to be ineligible for IOBRT because of multiple intraperitoneal recurrences, macroscopically nonradical resection, poor general condition, and technical aspects. Thirty-seven patients underwent IOBRT immediately after surgery during the same general anesthesia procedure. Nine patients underwent delayed IOBRT within 1 to 3 days after the primary operation. Ten (21.5%) of 46 patients underwent reoperation because of surgical complications. One patient died in the postoperative period. After IOBRT, 24 patients (52%) underwent adjuvant external beam radiotherapy (EBRT) to a total dose of 50 Gy. Over a median follow-up time of 20 months, the estimated 5-year overall survival and local recurrence-free survival rates in IOBRT patients were 55% and 51%, respectively. Application of adjuvant EBRT showed a favorable local control rate. CONCLUSIONS: The scheduled combined treatment (surgery plus IOBRT) was possible to perform in 66% of RSTS cases that received surgical treatment. The complication rate was high, but we consider it acceptable because of the necessity for extensive aggressive surgical treatment in regionally advanced RSTS. EBRT seems to be an indispensable part of treatment that provides better local control.