June 2010

Research Corner

An ESUN Resource

Long-term results after resection for bone sarcoma pulmonary metastases

European Journal of Cardio-thoracic Surgery 37 (2010) 1205—1208

About 40% of bone sarcoma patients are found to have metastases to the lungs.  Pulmonary metastases are treated using a combination of radiation and chemotherapy.  The authors of this study “aim to study the influence of different prognostic factors on long-term survival”.   Data was collected for 52 patients that had received treatment at the Universidad de Navarra in Pamplona, Spain during the 10 year interval between 1996 and 2005.  Each had received chemotherapy and removal of pulmonary metastases.  The selected patients had been treated for the following types of tumors:  Osteosarcoma, Ewing’s Sarcoma, Chondrosarcoma, Undifferentiated sarcoma, Fibrosarcoma, Neuroectodermic tumor, Leiomyosarcoma, Adamantinoma and Fusocellular tumor.

According to the study, the following patient characteristics were taken into consideration,

  1. age
  2. gender
  3. primary site
  4. histopathologic type
  5. disease-free interval between treatment of the primary bone tumour and first lung metastasectomy (DFI)
  6. disease-free interval between first and second lung surgery (DFI2)
  7. thoracic approach and type of lung resection
  8. number of lung metastases
  9. complete resection of lung metastases and
  10. re-do surgery for oncological purposes.

Regarding repeated lung surgeries, it is interesting to note that the authors find that repeat surgeries are beneficial.  The authors state, “Lung metastasectomies have low morbidity and mortality rates. This is basically because (1) patients with bone sarcoma lung metastases usually have normal cardiopulmonary function tests and (2) lung resections are conservative operations, being re-do lung surgery for recurrent disease, quite frequent in these patients (31% of patients in our series). Various studies have demonstrated that repeated pulmonary resections enable controlling the disease for an extended period [16, 18].

Following extensive analysis, the authors conclude, “Long-term survival is encouraging after bone sarcoma lung metastasectomy, with a 5-year survival rate of 31%. In our series, DFI and DF2 showed to be prognostic factors, none of the other variables studied had an influence on survival. Redo surgery, although not found to be a key prognostic factor, was highly significant in long-term survivors.”

References
[16] McCarville MB, Kaste SC, Cain AM, Gouloubeva O, Rao BN, Pratt CB. Prognostic factors and imaging patterns of recurrent pulmonary nodules after thoracotomy in children with osteosarcoma. Cancer 2001;91: 1170—6.

[18] Bricolli A, Ferrari S, Picci P, Mercuri M, Bacci G, Guernelli N. Surgical treatment of pulmonary metastases of osteosarcoma. Apropos of 206 operated cases. Ann Chir 1999;53:207—14.

 
Sarcomas Across the Age Spectrum

Semin Radiat Oncol 20:45.51 © 2010 Elsevier Inc, All rights reserved.

In this paper, researchers Suzanne Wolden and Kaled Alektiar of the MSK Cancer Center in New York discuss the incidence of sarcoma at different patient ages.  They begin by noting that sarcoma is known for occurring in infants, the elderly and all ages in between.  Treatment for sarcomas differs based on the whether they primarily affect children vs. adults.  The authors state, “In general, the pediatric-type sarcomas tend to be relatively sensitive to chemotherapy and radiotherapy, whereas the adult sarcomas are less so. These distinctions have led to different treatment algorithms for pediatric and adult sarcomas. In addition, the long-term risk to benefit ratio of different treatment modalities differs between children and adults. This also influences our approach to treating sarcomas across the age spectrum.”

They go on to note that, despite the histological differences between sarcomas, scientific advances made through research into one type of sarcoma can result in findings that relate to other sarcomas.  “For example”, the authors state, “advances at the molecular level in Ewing sarcoma, a disease that affects predominantly children, helped spearhead the uncovering of several signature translocations in adult sarcomas, such as synovial sarcoma and myxoid liposarcomas.

The success of chemotherapy in pediatric sarcomas continues to be a benchmark for adult sarcomas to emulate.”   Advances in treatment of adult sarcomas have also enhanced pediatric treatments.  For example, limb-sparing surgery in combination with radiation therapy was pioneered with adult patients having extremity sarcomas, but is now used more frequently for pediatric sarcomas as well. 

The authors define their approach to this discussion, saying, “To illustrate some of these concepts and to enhance our understanding of sarcomas across the age spectrum, 4 types of sarcoma are discussed. The first 2 are Ewing sarcoma and rhabdomyosarcoma seen mainly, but not exclusively, in children. The other 2 are synovial sarcoma, which can be looked at as a bridge between pediatric and adult sarcomas as it affects mainly young adults, and liposarcoma that is almost exclusively an adult sarcoma.”

Some interesting snippets from the discussion of treatment therapies for these 4 sarcomas and findings based on age:

Regarding RMS, “A recent article confirms that adults with RMS have significantly worse outcomes than children.  Part of the difference may be attributed to a higher percentage of adult patients having poor prognostic features, such as unfavorable site or histology (Table 1). However, the explanation for this is not known ..... Regional and distant metastases were not more common in adults. Given the dramatic difference in 5-year survival for localized disease, ~7% for adults versus 82% for children (P < 0.0001), it is clear that age itself is a strong prognostic factor.”

Regarding Ewing's sarcoma, “When deciding whether to use radiotherapy for a child with ES, one must consider a variety of potential late effects that may not be a significant consideration in the older adult patient.   Growth of bone and soft tissue can be severely impaired when treating young patients. This problem is much less of concern for a mature teen than for the younger child, but even muscle development seems more impaired in teens than in adults.”

Following extensive analysis of the data, the authors summarize their findings, saying, “Much progress has been made treating pediatric sarcomas in children and adult sarcomas in adults, but we do not yet understand how to optimally treat these tumors when they occur at uncharacteristic ages. The COG is currently conducting a trial (ARST 0332) for non-RMS soft-tissue sarcomas in an effort to meet this clinical challenge. Likewise, additional work is needed in adult oncology to understand and potentially narrow the gap in survival for adults with pediatric-type tumors, such as RMS. Our hope for future progress will depend on collaboration of pediatric and adult oncologists to study sarcomas across the age spectrum.”

 

CD117 and Stro-1 Identify Osteosarcoma Tumor-Initiating Cells Associated with Metastasis and Drug Resistance

Emerging evidence indicates the presence of tumor-initiating cells (TIC) or cancer stem cells in osteosarcoma. However, no study has shown specific markers to identify osteosarcoma TICs with in vivo tumor formation ability. Additionally, there has been a lack of investigations gauging the contribution of osteosarcoma TICs to metastatic and drug-resistant properties. In this study, the investigators have identified mouse and human osteosarcoma TICs using mesenchymal stem cell markers CD117 and Stro-1. These markers were preferentially expressed in spheres and doxorubicin-resistant cells. Both mouse and human cells expressing these markers were sorted and analyzed for their abilities of tumor formation with as few as 200 cells, self-renewability, multipotency, drug resistance, metastatic potential, and enrichment of a metastasis-associated marker (CXCR4) and a drug resistance marker (ABCG2). CD117+Stro-1+ cells efficiently formed serially transplantable tumors, whereas CD117–Stro-1– cells rarely initiated tumors. On orthotopic injections, CD117+Stro-1+ cell-derived tumors metastasized at a high frequency. Further, CD117+Stro-1+ cells showed high invasive and drug-resistant properties and were efficiently enriched for CXCR4 (20–90%) and ABCG2 (60–90%). The investigators conclude: These results suggest possible mechanisms for the high metastatic and drug-resistant properties of osteosarcoma TICs. In summary, CD117 and Stro-1 identify osteosarcoma TICs associated with the most lethal characteristics of the disease—metastasis and drug resistance—and these markers offer candidates for TIC-targeted drug delivery aimed at eradicating osteosarcoma.

 

Improved Survival With Radiation Therapy in High-Grade Soft Tissue Sarcomas of the Extremities: A SEER Analysis

The benefit of radiation therapy in extremity soft tissue sarcomas remains controversial. The purpose of this study was to determine the effect of radiation therapy on overall survival among patients with primary soft tissue sarcomas of the extremity who underwent limb-sparing surgery. This was a retrospective study from the Surveillance, Epidemiology, and End Results (SEER) database that included data from January 1, 1988, to December 31, 2005. A total of 6,960 patients constituted the study population. Overall survival curves were constructed using the Kaplan-Meir method and for patients with low- and high-grade tumors. Hazard ratios were calculated based on multivariable Cox proportional hazards models. The results were as follows: Of the cohort, 47% received radiation therapy. There was no significant difference in overall survival among patients with low-grade tumors by radiation therapy. In high-grade tumors, the 3-year overall survival was 73% in patients who received radiation therapy vs. 63% for those who did not receive radiation therapy (p < 0.001). On multivariate analysis, patients with high-grade tumors who received radiation therapy had an improved overall survival (hazard ratio 0.67, 95% confidence interval 0.57-0.79). In patients receiving radiation therapy, 13.5% received it in a neoadjuvant setting. The incidence of patients receiving neoadjuvant radiation did not change significantly between 1988 and 2005. The authors conclude: To our knowledge, this is the largest population-based study reported in patients undergoing limb-sparing surgery for soft tissue sarcomas of the extremities. It reports that radiation was associated with improved survival in patients with high-grade tumors.

 

Abdominal soft tissue sarcoma: a multicenter retrospective study

Soft tissue sarcomas (STS) are rare mesenchymal neoplasms with a variety of histological subtypes. However, in Japan, data on the clinical characteristics and prognostic profiles of these tumors are lacking. The purpose of this study was to clarify the clinical features and outcomes of Japanese patients with retroperitoneal and abdominal STS. The authors reviewed and analyzed retrospectively the data for 82 patients who underwent surgery for retroperitoneal and abdominal STS at Osaka University and affiliated hospitals from 2000 to 2007. The factors analyzed included patient demographics and clinical features. The results were as follows: The histological subtypes included leiomyosarcoma in 32 patients (39.0%), liposarcoma in 30 (36.6%), malignant fibrous histiocytoma in 10 (12.2%), and other miscellaneous subtypes in 10 (12.2%). The overall survivals were 92, 69, and 62%, respectively, at 1, 3, and 5 years after primary surgery. The overall survival of patients with low-grade sarcoma was significantly better than that of patients with high-grade sarcoma. Complete resection was done in 63 patients (77%) and their recurrence-free survivals were 73, 34, and 23%, respectively, at 1, 3, and 5 years after the surgery. Subgroup analysis of differences between leiomyosarcoma and liposarcoma revealed that liposarcomas were mainly located in the retroperitoneum and leiomyosarcomas were located equally in the retroperitoneum and abdominal cavity. The tumor size of liposarcomas was larger than that of leiomyosarcomas; however, the recurrence-free survival was better in patients with liposarcoma than in those with leiomyosarcoma. The authors conclude: Results showed the clinical features and prognoses of retroperitoneal and abdominal STS in Japan. Further large-scale nationwide studies are required to clarify the detailed clinical behavior of retroperitoneal and abdominal STS in Japan.

 

Clinical outcome of children and adults with localized Ewing sarcoma

Ewing’s sarcoma (EWS) can affect children and adults.  Patients can be treated at either a pediatric or an adult institution. This study investigated whether differences in therapeutic strategy undertaken in pediatric and adult specialty sarcoma centers correlated with clinical outcome. Data from patients with localized EWS treated between 1990 and 2005 at tertiary care pediatric and adult institutions were reviewed. The results were as follows: Fifty-three patients (24 adult and 29 pediatric) were treated. Pediatric patients received a median of 16 cycles of chemotherapy comprised of doxorubicin, vincristine, cyclophosphamide, ifosfamide, and etoposide. Adult patients received a median of 10 cycles of treatment, and a significantly lower total cumulative dose of ifosfamide and cyclophosphamide (P < .0001). There was no difference noted with regard to the total dose of doxorubicin, or in the type of local therapy offered (surgery or radiotherapy, vs. both). However, local therapy occurred earlier in pediatric patients compared with adults (3.7 months vs. 7.4 months; P = .0003). The 3-year event-free survival (EFS) rate in pediatric and adult patients was 70% ± 9% and 43% ± 13% (P = 0.1), respectively. The 3-year overall survival rate was 81% ± 7.7% and 59% ± 12% (P = .02) for pediatric and adult patients, respectively. Factors found to be significantly associated with EFS on univariate analysis included pelvic site, cyclophosphamide dose, and time to local therapy. On multivariate analysis, only pelvic disease (hazard ratio [HR] 4.26; P = .018) and time to local therapy (HR, 1.19; P = .002) were found to be significant. The authors conclude: Adults with localized EWS have an inferior outcome compared with pediatric patients. This difference may be related to lower doses of alkylating agents and the timing of local therapy.

 

Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells

The purpose of this study was to better understand the mechanisms of cytotoxicity and cell death induced by HDACI PCI-24781 in bone sarcoma cells. Four bone sarcoma cell lines were treated with PCI-24781, and the cytotoxicity was investigated. Further, accumulation of acetylated histones, p21, and PARP cleavage were evaluated in PCI-24781-treated cells. The synergistic effect of PCI-24781 to doxorubicin and its mechanism was investigated in bone sarcoma cells. The results were as follows: MTT assay demonstrated that the growth of bone sarcoma cells was inhibited after treatment with PCI-24781. Accumulation of acetylated histones, p21, and PARP cleavage were found in PCI-24781-treated cells. Expression of DNA repair protein RAD51 was inhibited, and the expression of apoptosis protein GADD45α was induced by PCI-24781 in bone sarcoma cells. Bone sarcoma cells treated with PCI-24781 become more sensitive to doxorubicin. The caspase-3/7 activity was increased with doxorubicin and PCI-24781 treatment in these cells. The investigators conclude: HDACI PCI-24781 has a synergistic effect on doxorubicin-induced apoptosis in bone sarcoma cells.

 

Sox9 Expression Is Not Limited to Chondroid Neoplasms: Variable Occurrence in Other Soft Tissue and Bone Tumors With Frequent Expression by Synovial Sarcomas

The transcription factor Sox9 is known to play a crucial role in normal chondrogenesis, and antibodies against Sox9 have been proposed as a diagnostic tool for neoplasms with chondroid differentiation. However, the pattern of Sox9 immunohistochemical expression by other bone and soft tissue neoplasms, as well as its diagnostic specificity, remain unexplored. The authors in this study have performed immunohistochemistry with antibodies against Sox9 in 106 chondroid and nonchondroid bone and soft tissue neoplasms. Moderate to intense Sox9 nuclear staining was observed in 14/20 chondrosarcomas (70%), and in 24/81 (29.6%) cases from a multitumor tissue microarray, which included 16/18 synovial sarcomas, 4/15 osteosarcomas, 2/5 peripheral primitive neuroectodermal tumor (PNET)/Ewing sarcomas, 1/1 mesenchymal chondrosarcoma, and 1/1 chondroblastoma. The results suggest that Sox9 usefulness in the diagnosis of chondroid tumors may be limited because of low sensitivity and specificity. The finding of Sox9 expression by 88.9% of synovial sarcomas represents a novel and striking observation, which deserves further investigation.

 

Distinct roles for miR-1 and miR-133a in the proliferation and differentiation of rhambomyosarcoma cells

Rhabdomyosarcoma is the most common soft tissue sarcoma in the pediatric population. As this tumor has an undifferentiated myogenic phenotype, agents that promote differentiation hold particular promise as part of a novel therapeutic approach to combat this type of cancer. In this report, the investigators focus on the contribution of two microRNAs (miRNAs) in rhabdomyosarcomas. Levels of miR-1 and miR-133a are drastically reduced in representative cell lines from each major rhabdomyosarcoma subtype (embryonal and alveolar). Introduction of miR-1 and miR-133a into an embryonal rhabdomyosarcoma-derived cell line is cytostatic, thereby suggesting a tumor suppressor-like role for these myogenic miRNAs. Transcriptional profiling of cells after miR-1 and miR-133a expression reveals that miR-1 (but not miR-133a) exerts a strong promyogenic influence on these poorly differentiated tumor cells. They identify mRNAs that are down-regulated by these miRNAs and propose roles for miR-1 and miR-133a in repressing isoforms of genes that are normally not expressed in muscle. Finally, they show that mRNA targets of miR-1 and miR-133a are up-regulated in rhabdomyosarcomas, suggesting a causative role for these miRNAs in the development of rhabdomyosarcomas. More important, these results point to the promise of enhancing rhabdomyosarcoma therapy using miRNAs as agents that mediate cytostasis and promote muscle differentiation.

 

Surgery and Radiotherapy for Retroperitoneal and Abdominal Sarcoma

The purpose of this study was to evaluate the effect of surgical resection and radiotherapy (RT) in retroperitoneal or abdominal sarcoma. It was a retrospective study of patients 18 years or older with initial diagnosis of primary retroperitoneal and nonvisceral abdominal sarcoma between 1988-2005. Main outcome measures were survival for 2 years after diagnosis. Kaplan-Meier survival was stratified based on surgery and RT status. Cox proportional hazards model was used to assess adjusted effects of surgery and RT on survival in patients with locoregional disease. The results were as follows: Of 1901 patients with locoregional disease, 1547 (81.8%) underwent resection; 447 (23.5%) received RT. Overall, patients who received both surgery and RT demonstrated improved survival compared with patients who underwent either therapy alone; patients undergoing monotherapy in turn had more favorable survival compared with patients who received neither therapy (P < .001, log rank). Cox analysis demonstrated that surgical resection (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.21-0.29; P < .001) and RT (0.78; 0.63-0.95; P = .01) independently predicted improved survival in locoregional disease only. In adjusted analyses stratified for American Joint Commission on Cancer (AJCC) stage, for stage I disease (n = 694), RT provided an additional benefit (HR, 0.49; 95% CI, 0.25-0.96; P = .04) independent of that from resection (0.35; 0.21-0.58; P < .001). For stage II/III (n = 552), resection remained protective (HR, 0.24; 95% CI, 0.18-0.32; P < .001); however, RT was no longer associated with a significant benefit (0.78; 0.58-1.06; P = .11). The authors conclude: Surgical resection was associated with significant survival benefits for AJCC disease stages I to III. Radiotherapy provided additional benefit for patients with stage I disease. Resection should be offered to reasonable surgical candidates with nonmetastatic retroperitoneal/abdominal sarcomas; radiotherapy may most benefit patients with early-stage disease.

 

Primary Bone Malignancy: Effective Treatment with High-Intensity Focused Ultrasound Ablation

The purpose of this study was to evaluate the long-term follow-up results of ultrasonographically (US)-guided high-intensity focused ultrasound ablation in patients with primary bone malignancy. From December 1997 to November 2004, 80 patients with a primary bone malignancy—60 with stage IIb disease and 20 with stage III disease (Enneking staging system)—were treated with US-guided high-intensity focused ultrasound ablation. High-intensity focused ultrasound ablation combined with chemotherapy was performed in 62 patients with osteosarcoma, one patient with periosteal osteosarcoma, and three patients with Ewing sarcoma. The remaining 14 patients had chondrosarcoma, giant cell bone cancer, periosteal sarcoma, or an unknown malignancy and were treated with high-intensity focused ultrasound ablation only. Magnetic resonance (MR) imaging or computed tomography (CT), and single photon emission computed tomography (SPECT) were used to assess tumor response. Cumulative survival rates were calculated by using the Kaplan-Meier method. Adverse effects were recorded. The results were as follows: High-intensity focused ultrasound ablation guided by real-time US was performed. Follow-up images demonstrated completely ablated malignant bone tumors in 69 patients and greater than 50% tumor ablation in the remaining 11 patients. Overall survival rates at 1, 2, 3, 4, and 5 years were 89.8%, 72.3%, 60.5%, 50.5%, and 50.5%, respectively. Survival rates at 1, 2, 3, 4, and 5 years were 93.3%, 82.4%, 75.0%, 63.7%, and 63.7%, respectively, in the patients with stage IIb cancer and 79.2%, 42.2%, 21.1%, 15.8%, and 15.8%, respectively, in those with stage III disease. Among the patients with stage IIb disease, long-term survival rates were substantially improved in the 30 patients who received the full treatment—that is, complete high-intensity focused ultrasound and full cycles of chemotherapy—compared with the survival rates for the 24 patients who did not finish the chemotherapy cycles and the six patients who underwent partial ablation only. Only five (7%) of the 69 patients who underwent complete ablation had local cancer recurrence during the follow-up period. Forty adverse events were recorded, with 14 patients requiring surgical intervention. The investigators conclude: US-guided high-intensity focused ultrasound ablation of malignant bone tumors is feasible and effective and eventually may be a component of limb-sparing techniques for patients with these cancers.

 

V7N3 ESUN Copyright © 2010 Liddy Shriver Sarcoma Initiative.