The Effect of chemo- and radiotherapy on tumor necrosis in soft tissue sarcoma- does it influence prognosis?

BACKGROUND: Soft tissue sarcomas (STSs) are a heterogeneous group of tumors. Wide surgical resection is standard, often combined with neoadjuvant chemotherapy, radiotherapy, or both. Studies have shown the predictive value of tumor necrosis in bone sarcoma (BS); however, the role of necrosis in STS after neoadjuvant therapies is still unclear. This study aimed to investigate the role of chemo- and radiotherapy in the formation of tumor necrosis and to evaluate the influence of tumor necrosis on overall survival and local recurrence-free survival. Data from BS patients and patients who did not receive neoadjuvant therapy were compared. METHODS: A total of 779 patients with STS or BS were treated surgically. In all patients, tumor-specific factors such as type, size, or grading and the type of adjuvant therapy were documented. Local recurrence (LR), the diagnosis of metastatic disease, and survival during follow-up were evaluated. RESULTS: A total of 565 patients with STS and 214 with BS were investigated. In STS, 24.1% G1 lesions, 34.1% G2 lesions, and 41.8% G3 lesions were observed. Two hundred twenty-four of the patients with STS and neoadjuvant therapy had either radiotherapy (RTx) (n = 80), chemotherapy (CTx) (n = 93), or both (n = 51). Three hundred forty-one had no neoadjuvant therapy at all. In STS, tumor necrosis after neoadjuvant treatment was significantly higher (53.5%) than in patients without neoadjuvant therapy (15.7%) (p < 0.001). Patients with combined neoadjuvant chemo-/radiotherapy had substantially higher tumor necrosis than those with radiotherapy alone (p = 0.032). There was no difference in tumor necrosis in patients with combined chemo-/radiotherapy and chemotherapy alone (p = 0.4). The mean overall survival for patients with STS was 34.7 months. Tumor necrosis did not influence survival in a subgroup of G2/3 patients. In STS with no neoadjuvant therapy and grading of G2/3, the correlation between necrosis and overall survival was significant (p = 0.0248). There was no significant correlation between local recurrence (LR) and necrosis. CONCLUSION: STS shows a broad spectrum of necrosis even without neoadjuvant chemo- or radiotherapy. After CTx or/and RTx necrosis is enhanced and is significantly pronounced with a combination of both. There is a trend toward higher necrosis with CTx than with RTx. Grading substantially influences the necrosis rate, but necrosis in soft-tissue sarcoma following neoadjuvant therapy does not correlate with better survival or a lower local recurrence rate, as in bone sarcomas.

Refusal of Adjuvant Therapies and Its Impact on Local Control and Survival in Patients with Bone and Soft Tissue Sarcomas of the Extremities and Trunk.

BACKGROUND: In soft tissue or bone sarcomas, multimodal therapeutic concepts represent the standard of care. Some patients reject the therapeutic recommendations due to several reasons. The aim of this study was to assess the impact of that rejection on both prognosis and local recurrence. METHODS: Between 2012 and 2019, a total of 828 sarcoma patients were surgically treated. Chemotherapy was scheduled as a neoadjuvant, and adjuvant multi-agent therapy was performed following recommendations from an interdisciplinary tumor board. Radiotherapy, if deemed appropriate, was administered either in a neoadjuvant or an adjuvant manner. The recommended type of therapy, patient compliance, and the reasons for refusal were documented. Follow-ups included local recurrences, diagnosis of metastatic disease, and patient mortality. RESULTS: Radiotherapy was recommended in 407 (49%) patients. A total of 40 (10%) individuals did not receive radiation. A reduction in overall survival and local recurrence-free survival was evident in those patients who declined radiotherapy. Chemotherapy was advised for 334 (40%) patients, 250 (75%) of whom did receive all recommended cycles. A total of 25 (7%) individuals did receive a partial course while 59 (18%) did not receive any recommended chemotherapy. Overall survival and local recurrence-free survival were reduced in patients refusing chemotherapy. Overall survival was worst for the group of patients who received no chemotherapy due to medical reasons. Refusing chemotherapy for non-medical reasons was seen in 8.8% of patients, and refusal of radiotherapy for non-medical reasons was seen in 4.7% of patients. CONCLUSIONS: Divergence from the advised treatment modalities significantly impacted overall survival and local recurrence-free survival across both treatment modalities. There is an imperative need for enhanced physician-patient communication. Reducing treatment times, as achieved with hypofractionated radiotherapy and with therapy in a high-volume sarcoma center, might also have a positive effect on complying with the treatment recommendations.

Impact of postoperative baseline MRI on diagnostic confidence and performance in detecting local recurrence of soft-tissue sarcoma of the limb.

OBJECTIVE: To evaluate the impact of a postoperative baseline (PB) MRI on diagnostic confidence and performance in detecting local recurrence (LR) of soft-tissue sarcoma (STS) of the limb. MATERIALS AND METHODS: A total of 72 patients (8 with LR, 64 without LR) with primary STS of the limb were included. Routine follow-up MRI (1.5 T) at 6 and approximately 36 months (meanLR: 39.7 months; meanno LR: 34.9 months) after multimodal therapy or at time of LR were assessed by three independent readers using a 5-point Likert scale. Furthermore, the following imaging parameters were evaluated: presence of a mass, signal characteristics at T2- and T1-weighted imaging, contrast enhancement (CE), and in some of the cases signal intensity on the apparent diffusion coefficient (ADC). U-test, McNemar test, and ROC-analysis were applied. Interobserver reliability was calculated using Fleiss kappa statistics. A p value of 0.05 was considered statistically significant. RESULTS: The presence of a PB MRI significantly improved diagnostic confidence in detecting LR of STS (p < 0.001) and slightly increased specificity (mean specificity without PE 74.1% and with presence of PB MRI 81.2%); however, not to a significant level. The presence of a mass showed highest diagnostic performance and highest interreader agreement (AUC [%]; κ: 73.1-83.6; 0.34) followed by T2-hyperintensity (50.8-66.7; 0.08), CE (52.4-62.5; 0.13), and T1-hypointensity (54.7-77.3; 0.23). ADC showed an AUC of 65.6-96.6% and a κ of 0.55. CONCLUSION: The presence of a PB MRI increases diagnostic confidence in detecting LR of STS of the limb.

Post-Neoadjuvant Gemcitabine and Cisplatin with Regional Hyperthermia for Patients with Triple-Negative Breast Cancer and Non-pCR after Neoadjuvant Chemotherapy: A Single-Institute Experience.

BACKGROUND: Patients with triple-negative primary breast cancer (TNBC) who have residual invasive carcinoma after neoadjuvant chemotherapy have poor prognosis. Proven adjuvant approaches to reduce the risk of recurrence and improve outcome in patients with non-pathological complete response (non-pCR) are limited. METHODS: From our institutional registry, a consecutive case series of patients with operable, unilateral, primary invasive noninflammatory early TNBC of stage I-IIIB and pathologically verified residual cancer cells (no pathological complete response) after neoadjuvant chemotherapy underwent adjuvant treatment with gemcitabine plus cisplatin combined with regional hyperthermia. For quality assurance, we analyzed feasibility, efficacy, and toxicity of all treated patients. Outcome was evaluated for the entire group of patients as well as for the subgroups of patients with or without lymph node involvement at baseline (cN0/ cN+). RESULTS: From August 2012 to January 2019, we offered this treatment to 53 patients at our center as part of routine care. The median follow-up was 38 months. The majority of patients (64.2%) had cT2 tumors at baseline. Twenty-four patients (45%) were clinically node positive as evaluated by sonography. Thirty-nine patients (74%) had grade 3, and 14 patients (26%) had grade 2 tumors. Forty-one patients (76%) showed a regression grade 1 according to Sinn. Patients received a median of six treatment cycles of gemcitabine and cisplatin (range 1-6) combined with 12 applications of regional hyperthermia (median 12, range 2-12). Disease-free survival (DFS) at 3 years was 57.5%. In patients with no lymph node involvement at baseline (cN0), DFS at 3 years was significantly higher than in initially node-positive (cN+) patients (80 vs. 31%; p = 0.001). Overall survival (OS) at 3 years was 81.6%. In patients with no lymph node involvement at baseline (cN0), OS at 3 years was significantly higher than in node-positive (cN+) patients (93 vs. 70.4%; p = 0.02). Overall, grade 3/4 toxicities were leukopenia (38%), thrombocytopenia (4%), and anemia (4%). CONCLUSION: After standard neoadjuvant chemotherapy containing anthracycline plus cyclophosphamide followed by taxanes, addition of adjuvant gemcitabine plus cisplatin in combination with regional hyperthermia was safe and effective in TNBC patients with non-pCR.

External-beam radiation therapy combined with limb-sparing surgery in elderly patients (>70 years) with primary soft tissue sarcomas of the extremities : A retrospective analysis.

PURPOSE: To report our experience with EBRT combined with limb-sparing surgery in elderly patients (>70 years) with primary extremity soft tissue sarcomas (STS). METHODS: Retrospectively analyzed were 35 patients (m:f 18:17, median 78 years) who all presented in primary situation without nodal/distant metastases (Charlson score 0/1 in 18 patients; ≥2 in 17 patients). Median tumor size was 10 cm, mainly located in lower limb (83%). Stage at presentation (UICC7th) was Ib:3%, 2a:20%, 2b:20%, and 3:57%. Most lesions were high grade (97%), predominantly leiomyosarcoma (26%) and undifferentiated pleomorphic/malignant fibrous histiocytoma (23%). Limb-sparing surgery was preceded (median 50 Gy) or followed (median 66 Gy) by EBRT. RESULTS: Median follow-up was 37 months (range 1-128 months). Margins were free in 26 patients (74%) and microscopically positive in 9 (26%). Actuarial 3­ and 5­year local control rates were 88 and 81% (4 local recurrences). Corresponding rates for distant control, disease-specific survival, and overall survival were 57/52%, 76/60%, and 72/41%. The 30-day mortality was 0%. Severe postoperative complications were scored in 8 patients (23%). Severe acute radiation-related toxicity was observed in 2 patients (6%). Patients with Charlson score ≥2 had a significantly increased risk for severe postoperative complications and acute radiation-related side effects. Severe late toxicities were found in 7 patients (20%), including fractures in 3 (8.6%). Final limb preservation rate was 97%. CONCLUSION: Combination of EBRT and limb-sparing surgery is feasible in elderly patients with acceptable toxicities and encouraging but slightly inferior outcome compared to younger patients. Comorbidity correlated with postoperative complications and acute toxicities. Late fracture risk seems slightly increased.

Erufosine, a novel alkylphosphocholine, induces apoptosis in CLL through a caspase-dependent pathway.

The alkylphosphocholine (APC) erufosine is a synthetic phospholipid analogue with antineoplastic activity. APC are known to interact with lipid metabolism and modulate cellular signaling pathways, particularly the phosphorylation of Akt. Here, in primary CLL cells induction of apoptosis was detected with an IC50 of 22muM whereas healthy donor PBMC were less sensitive towards erufosine. Treatment with erufosine caused dose-dependent cleavage of PARP, co-incubation with caspase inhibitor z-VAD almost completely abrogated the cytotoxic effect of erufosine indicating a caspase-dependent mechanism of erufosine. Erufosine was shown to induce apoptosis in primary CLL cells and merits further investigation regarding therapeutic options in CLL.