Predictors of lung recurrence and disease-specific mortality after pulmonary metastasectomy for soft tissue sarcoma.

BACKGROUND: We identified prognostic factors in a 30-year series of STS treated at a single Institution, using an advanced statistical approach. METHODS: From June 1988 to July 2019, 164 patients were referred to Rizzoli Orthopedic Hospital, Bologna, Italy) for STS lung metastasectomy (LMTS). The endpoints were lung metastasis recurrence (LMR) and lung metastasis-specific mortality (LMSM). The analysis included directed acyclic graphs, cubic splines, and a competing risk model in order to minimize bias. RESULTS: The 10- and 15- year LMR cumulative incidence were 0.77 (0.76-0.78) whereas 10- and 15- year freedom from LMSM were 0.60 [0.51-0.70] and 0.56 [0.47-0.67], respectively. The malignant peripheral nerve sheath tumor (MPNST) histotype (SHR 4.12 [2.05-8.27]), a disease-free interval (DFI) up to 68 months (HR from 2 [1.7-2.2] to 1.5 [1.1-1.9]) and a LM size ≥4 mm (3.1 [2.1-4.4]) predicted LMR. Myxofibrosarcoma (HR 2.52[1.64-3.86]), synovial sarcoma (2.53[1.22-5.23]), adjuvant chemotherapy (2.01[1.11-3.61]), DFI between 2 months and 20 months (HR from 1.5 [1.1-2.3] to 1.3 [1.1-1.7] and primary tumor size a primary tumor size comprised between 3.6 cm and 10 cm predicted LMSM. A sharp increase in LMSM was observed with a tumor size from ≥20 cm. CONCLUSIONS: Our analysis corrected by potential confounders allowed us to identify specific histotypes and DFI intervals as predictors of both LMR and LMSM. Tumor size adjuvant chemotherapy adversely affected LM-related survival. Our findings need to be confirmed by larger randomized studies.

Primary lung adenocarcinoma in three adolescent patients affected by bone sarcomas.

Pediatric primary lung carcinomas are extremely rare. Apart from known associations with congenital adenomatoid malformations, cases of primary lung adenocarcinomas after prolonged treatments of pediatric malignancy have been reported. We describe the morphological and molecular features of three cases of lung adenocarcinoma developed in adolescents aged 8 to 17 years during progression of their bone osteosarcoma or Ewing sarcomas. The morphological features overlapped those of adult lung adenocarcinoma including in situ, minimally invasive, and invasive forms. EGFR gene mutations were found in all three cases by targeted next-generation sequencing. The two patients with Ewing sarcoma had no progression of their lung cancer and no further progression of the metastatic bone tumor after additional chemo- and radio-therapy. Conversely, the osteosarcoma patient refused further treatments after thoracic surgery for metastatic osteosarcoma and locally advanced adenocarcinoma and died 2 years later of widespread distant metastases. Our results indicate that primary lung cancer might originate in pediatric patients during prolonged adjuvant therapies for primary bone neoplasm, and this possibility should be considered in the presence of suspected lung disease progression to correctly monitor the primary tumor evolution and define the appropriate therapeutic strategy at each time point. If appropriately treated, second primary lung cancer may not affect the patients' prognosis. The pathogenetic mechanisms of these rare lung adenocarcinomas are not clear, but the presence of EGFR mutations in all three cases indicates an oncogene addiction of the lung tumor, rather than a direct cancerogenic effect of the sarcoma-related treatment.

Stereotactic Radiotherapy in the Treatment of Lung Metastases from Bone and Soft-tissue Sarcomas.

BACKGROUND: The purpose of this study was to evaluate local control and toxicity in a group of patients treated with stereotactic body radiotherapy (SBRT) for lung metastases (LM) from bone and soft tissue sarcomas. PATIENTS AND METHODS: From October 2010 to July 2014, patients with LM from sarcomas not suitable for surgery were treated with daily cone-beam computed tomography-guided SBRT. The dose administered ranged from 30 to 60 Gy in 3-8 fractions. Acute and late toxicity were scored according to Common Terminology Criteria for Adverse Events version 4.0. RESULTS: A total of 24 patients with 68 LM from sarcomas were treated with SBRT. The median follow-up after SBRT was 17 months (range=11-51 months). Two-year actuarial lesion local control and overall survival were 85.9% and 66.4%, respectively. No G3 or greater acute and late toxicities were observed. CONCLUSION: SBRT is a safe and effective treatment for LM from sarcoma and might be used as an alternative option in patients unfit for surgery.

High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005.

BACKGROUND: Approximately one-third of patients with localized osteosarcoma at presentation relapse as well as about three-fourths of the patients with metastases at diagnosis, about 90% of relapses are lung metastases. The role of lung metastasectomy remains to be determined. PATIENTS: and methods: Three hundred and twenty three patients, 88 with resectable lung metastases at diagnosis and 235 with localized disease at presentation who relapsed with lung metastases were treated. RESULTS: A total of 498 lung surgeries and 607 thoracotomies were performed. The 5 year overall survival was 37%. Final outcome was significantly related to presence or absence of metastasis, time of first relapse and presence of local recurrences. According to stage of the disease, the rate of a 5 year event-free survival (EFS) was 36% for patients with localized disease who later relapsed and 9% for patients with resectable lung metastases at presentation (p<0.0001). However, there were no differences in EFS between patients who underwent two or three thoracotomies and patients who had four or five thoracotomies (7.5 vs 18.7%, p=0.29). CONCLUSIONS: In patients with recurrent resectable pulmonary metastases from high grade osteosarcoma treated with adjuvant or neoadjuvant chemotherapy, thoracotomy should always be considered regardless the number of previous lung relapses and the number of secondary pulmonary lesions.

Local and systemic control of Ewing's bone sarcoma family tumors of the ribs.

BACKGROUND: A retrospective analysis of the results and relapse pattern was evaluated in 34 patients with Ewing's family bone tumors (EFBT) treated at Rizzoli Institute with neoadjuvant chemotherapy between 1983 and 2003. OBJECTIVES: The aim of the study was to evaluate treatment strategy and compare our results with those obtained in other studies. METHODS: Local treatment in these patients was radiotherapy alone in 4 cases, surgery alone in 13 and surgery followed by radiotherapy in 17. RESULTS: Five-year event-free survival (EFS) was 44%, no different from that observed in another 558 patients with EFBT located in other sites treated in the same period with neoadjuvant chemotherapy protocols. Eighteen patients had a systemic relapse, followed by local relapse in two and one patient had a local relapse alone. EFS was significantly correlated to the time interval between onset symptoms and beginning of treatment and, in operated patients to histologic response to preoperative treatment. CONCLUSIONS: We conclude that EFBT of the ribs, when treated with neoadjuvant chemotherapy, have an outcome similar to that of patients with EFBT located in other sites.

High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions.

BACKGROUND AND METHODS: Between 1986 and 2001, 162 patients with extremity osteosarcoma and lung metastases at presentation, were treated by neoadjuvant chemotherapy, simultaneous resection of primary and, when feasible, secondary lesions followed by chemotherapy. RESULTS: After neoadjuvant chemotherapy, metastases disappeared in 14 patients, 16 were judged unresectable by both our thoracic surgeons, 132 had primary tumors and lung metastases removed simultaneously. Removal of lung metastases was complete in 123 and incomplete in 9. Histologically lesions were benign in 32 patients. For the 100 patients simultaneously operated with histologically proven lung metastases, 5-year event-free survival (EFS) was 18.9%; 27.4% for the 91 who had a complete resection of pulmonary lesions and entered remission as opposed to none for 9 patients who had incomplete removal of lung nodules. Among these 91, 5-year EFS was significantly higher for patients with monolateral compared to bilateral lesions (27.1% vs. 7.9%, P < 0.02) and when only one to three metastatic nodules were present (40.0% vs. 13.3%, P < 0.0001). CONCLUSIONS: These different results, demonstrate that our treatment had a reasonable survival outcome whereas other groups continue to have dismal prognosis. More efforts should be made to improve survival by identifying new active agents or novel approaches with cellular molecular targets.

Ultrasonography is superior to computed tomography and magnetic resonance imaging in determining superficial resection margins of malignant chest wall tumors.

OBJECTIVE: The purpose of this study was to retrospectively analyze results obtained in 22 patients affected by malignant high-grade chest wall tumors evaluated preoperatively by ultrasonography as well as other imaging techniques. METHODS: Twenty-two patients with chest wall high-grade sarcomas routinely underwent computed tomography, magnetic resonance imaging, total body scintigraphy, and ultrasonography. Ultrasonography was always performed by the same person using an ultrasonography system with a 5- to 13-MHz probe and with color Doppler evaluation of the lesion. Scans were done with the patient positioned as during surgery. Tumor lateral margins were identified, and a line was marked at 4 cm. In 8 patients with local recurrence, the presence of micronodules was also studied. Results of computed tomography, magnetic resonance imaging, and ultrasonography were compared with the surgical specimens. RESULTS: Histologically, all surgical specimens excised according to ultrasonographic margins showed wide margins. Ultrasonography showed micronodules in 6 of 8 patients with local recurrence; histologically, they were all identified as sarcoma nodules. Ultrasonography failed in particular with cervical-mediastinal vessels. CONCLUSIONS: Our results confirm that ultrasonography is feasible and reliable in the study of superficial margins and for detection of micronodules of less than 0.5 cm in diameter.

Resection of recurrent pulmonary metastases in patients with osteosarcoma.

BACKGROUND: Surgical resection of lung metastases is widely accepted in osteosarcoma patients. Few data exist on treatment of recurrent pulmonary metastases. The authors of the current study retrospectively analyzed patients with osteosarcoma who received surgery for recurrent lung metastases. METHODS: From 1980 to 2001, 127 metastasectomies were performed on 94 patients. Criteria of eligibility were no metastases beyond the lung, no local recurrence, possibility of achieving complete resection of metastases without causing respiratory insufficiency, acceptable operative risk. Data were statistically elaborated with survival analysis according to Kaplan-Meier method of univariate analysis, life tables and Gehan statistic model, and multivariate analysis using Cox regression test. Results were considered in terms of time from first (DFI1) and second (DFI2) metastasectomy. RESULTS: Of 94 patients operated upon twice, 59 (62.7%) died. Thirty-five (37.3%) are alive; 31 (32.9%) of these are continuously disease-free. The 3- and 5-year event-free actuarial survival curve from first metastasectomy was 45%, and 38%, respectively, whereas from the second metastasectomy, it was 33% and 32%, respectively. According to a Cox regression model, DFI1 has a risk of death of 0.974 times and DFI2 of 0.972 times for every additional month of survival. In multivariate analysis, Cox regression test showed the best predictive model of local recurrence and number of metastases (P = 0.0014). CONCLUSIONS: The authors concluded that patients persistently free of the primary osteosarcoma who developed recurrent resectable metastatic disease of the lung should be considered for reoperation a second, third, or fourth time, as these patients had similar DFI curves after five-years.

Liver metastases from colorectal cancer: present surgical approach.

BACKGROUND/AIMS: New developments in surgical techniques and strategies are modifying the indications to resection of liver metastases. METHODOLOGY: From January 1986 to December 2000, 246 consecutive patients with colorectal liver metastases underwent curative hepatic resection. Surgical strategies included simultaneous resection of primary and metastatic colorectal tumor, re-resection of colorectal liver recurrences, two-stage resection and resection of the inferior vena cava when involved by the tumor. Disease-free survival in relation to clinical, pathological and surgical factors was retrospectively assessed with univariate and multivariate analyses. RESULTS: The overall operative mortality was 0.8%. The 1-, 3- and 5-year disease-free survival rates were 75%, 47% and 40%, respectively. Tumors larger than 7 centimeters, multiple lesions, tumors involving more than 2 segments and those requiring major hepatectomy had a worse prognosis at univariate analysis. A size of the tumor above 7 centimeters was the only independent prognostic factors at multivariate analysis. Two-stage and inferior vena cava resection increased operability; re-resection of recurrent colorectal secondaries prolonged survival. CONCLUSIONS: Resection of colorectal liver metastases is safe and effective; it should be considered the treatment of choice for this disease and proposed even for advanced lesions. Counseling of the hepatobilary surgeon should be asked for once a liver secondary is detected in the preoperative work-up of a colorectal cancer.