Conditional survival of extremity soft-tissue sarcoma: results beyond the staging system

BACKGROUND:

With increasing interest in adult cancer survivorship, currently available prognostic estimates for long‐term survivors of extremity soft‐tissue sarcoma (ESTS) are limited. We assessed determinants of survival in adults surgically treated for nonmetastatic ESTS, conditional on specific survival periods.

Methods:

We identified 6215 persons aged >18 in the Surveillance Epidemiology and End Results program who were surgically treated for nonmetastatic ESTS from 1991 to 2006. We used Cox proportional hazards regression to assess demographic, tumor, and treatment factors associated with 10‐year sarcoma‐specific survival (SSS) at diagnosis and conditional on surviving 3 and 5 years postdiagnosis.

RESULTS:

At the time of diagnosis, age, tumor, and treatment factors predicted SSS. Although older age significantly predicted worse SSS for all age groups at diagnosis (HR 3.78 for age >81 vs 18‐35; P < .05 for all), the effect of age became nonsignificant as survival time increased, except for the oldest group (>80 years). Tumor size, grade, and histologic subtypes continued to be important predictors of SSS for all periods of conditional survival. Persons who underwent limb amputation were at 3 times the risk of mortality for all conditional survival periods.

CONCLUSIONS:

In this large population‐based experience of ESTS survivors, age >80, tumor, and treatment factors continued to affect long‐term survival, whereas the effect of age dampened over time. These estimates provide important counseling information for changing risk factors as survival time increases, help to streamline future surveillance programs, and provide insights into the design of adult survivorship care. Cancer 2011. © 2010 American Cancer Society.     

Prognosis following locally recurrent soft-tissue sarcoma. A staging system based on primary and recurrent tumour characteristics

We have shown that the clinical growth rate of local recurrence from soft-tissue sarcoma could be expressed as a growthrate index (GRI) which was predictive for metastasis, and which was able to identify 2 equal populations of good (80% 2-year MFS) and poor survivors (33%). We now report the associations between characteristics of the primary and GRI, and combine primary and locally recurrent tumour characteristics in a staging system. We studied 460 adult patients with soft-tissue sarcomas of the extremities and trunk wall who were diagnosed and treated between 1964 and 1990, of whom 134 developed local recurrences and 151 metastases. The association of primary tumour size, histologic malignancy grade, depth, spontaneous necrosis, intratumoral vascular invasion and S-phase fraction with local recurrence, GRI and metastasis were examined. High GRI was associated with primary tumours that were larger, deeper, more malignant, underwent spontaneous tumour necrosis, demonstrated intravascular invasion and had a higher S-phase fraction. The same factors were also strongly associated with the incidence of metastasis. A multivariate analysis found GRI and primary tumour necrosis to be the strongest and most significant prognostic factors. GRI and tumour necrosis were combined in a staging system that identified groups with good survival (79 to 94% 2-year MFS), intermediate survival (61% 2-year MFS) and exceptionally poor survival (6% 2-year MFS). These findings validate our earlier assertion that high GRI reflects highly malignant tumours. A staging system composed of primary tumour necrosis and GRI can identify patients who may be suitable candidates for trials of adjuvant chemotherapy. © 1995 Wiley-Liss, Inc.     

Patient surveillance after treatment for soft-tissue sarcoma

About 1% of all cancers are soft tissue sarcomas (STS); about 60% of these occur in the extremities. Post-treatment surveillance programs are designed to identify recurrence, new primary cancers, and complications of therapy early enough to increase survival duration and quality of life. The intensity of surveillance varies among surgeons. We hypothesized that geographic factors would account for much of this variation. The 1,592 members of the Society of Surgical Oncology were surveyed regarding their personal postoperative STS surveillance strategy using standardized clinical vignettes and a questionnaire based on the vignettes. Practice patterns were analyzed by US Census Region, Metropolitan Statistical Area (MSA), and managed care organization (MCO) penetration rate, using repeated measures analysis of variance. The study end-point was surveillance intensity. Mean follow-up intensity for the 12 surveillance modalities on the questionnaire was highly correlated with tumor size, grade, and year post surgery. Controlling for tumor stage, grade, and year post surgery, the practice location of the surgeon infrequently impacted surveillance intensity. MSA was a significant (p<0.05) predictor only of office visit frequency. MCO penetration rate significantly predicted only the frequency of urinalysis and tumor-site MRI. US Census Region significantly predicted only the frequency of LFTs. Geographic factors do not generally predict self-reported surveillance practice patterns for patients after curative-intent STS surgery. The overall variation in follow-up intensity appears to reflect factors not evaluated, such as the absence of high-quality evidence supporting any particular strategy and the quality of patients' insurance.     

PET-CT staging affects time to treatment in sarcoma

Background and objectivesPET-CTs are being increasingly utilized in sarcoma care. This study sought to investigate the impact of PET-CT acquisition on time to treatment initiation.MethodsThe records of bone and soft tissue sarcoma patients treated at our institution were reviewed. Dates of initial presentation to a sarcoma-treating physician and dates of treatment initiation were recorded.ResultsTime to treatment was greater in patients (p < 0.001) with median time to treatment of 26 days (IQR 17, 36) and 20 days (IQR 12, 29) for those who did and did not undergo PET-CT, respectively. Those who underwent PET-CT in addition to a plain chest CT also had significantly increased time to treatment (p < 0.001) with median time to treatment of 27 days (IQR 17, 36) and 20 days (IQR 13, 28) for those who underwent both studies and those who underwent plain CT alone, respectively.ConclusionsDespite a statistically significant increase in time to treatment with the acquisition of a PET-CT scan, the added time is likely clinically insignificant. Additionally, PET-CT may offer additional benefits in potentially more accurate staging.     

Amputation for soft-tissue sarcoma

Soft-tissue sarcomas are a group of rare malignant tumours, many of which arise in the limbs. Most are treated with a combination of wide local excision and radiotherapy, but a small number--including proximal, large, high-grade, or recurrent tumours, or those involving major neurovascular structures--necessitate major amputation including forequarter or hindquarter amputation. These uncommon operations should remain in the surgical armamentarium for carefully selected patients. Those being considered for amputation should be referred to a tertiary sarcoma unit for examination of all other options, such as limb-salvage surgery, tumour downstaging with chemotherapy or radiotherapy (perhaps with subsequent limb-salvage surgery), or novel techniques such as isolated limb perfusion. Only after careful assessment should amputation be carried out. Outcomes after major amputation are highly variable, but such procedures can confer useful palliation to patients with distressing symptoms (pain, bleeding, fungation), long-term disease-free survival with reasonable function in carefully selected patients, and cure in some.     

Trabectedin (ET-743): evaluation of its use in advanced soft-tissue sarcoma

Trabectedin (ET-743; Yondelis) is a novel DNA-binding agent, originally derived from the marine tunicate, Ecteinascidia turbinata, and now produced synthetically. The efficacy of trabectedin in patients with advanced soft-tissue sarcoma has been demonstrated in three Phase II studies involving 189 previously treated patients. A pooled analysis of data from these studies showed that trabectedin induced tumor control (objective responses plus disease stabilization) in approximately 50% of patients; median overall survival was 10.3 months and progression-free survival at 6 months was 19.8%, with 29.3% of patients alive at 2 years. Responses were achieved in patients who were resistant to both doxorubicin and ifosfamide. Trabectedin is generally well tolerated, with adverse events being non cumulative, reversible and manageable. Unlike other commonly used cytotoxic agents, trabectedin is not associated with cardiotoxicity or neurotoxicity and alopecia is rare. Trabectedin is an interesting new anticancer agent that offers much promise for the treatment of advanced soft-tissue sarcoma.     

Surgical treatment of metastatic pulmonary soft-tissue sarcoma

The lung is the most frequent site of metastasis from soft-tissue sarcomas. Due to the relative resistance of sarcoma to either chemotherapy or radiotherapy, compared to other solid tumors, surgical management of pulmonary metastases has been a pivotal therapy in this disease. With decades of experience in numerous centers, criteria for patient selection have been ascertained and documented. We review the current literature on the use of pulmonary metastasectomy in patients with soft-tissue sarcoma, as well as survival data after such treatment. Osteogenic sarcoma is not included in this discussion.     

Initial McGill experience with fluorodeoxyglucose pet/ct staging of soft-tissue sarcoma

Background

Soft-tissue sarcoma spreads predominantly to the lung. The frequency with which positron-emission tomography (pet) detects metastases not already obvious by chest computed tomography (ct) or clinical examination is currently unclear.

Methods

We retrospectively identified cases of soft-tissue sarcoma. Ewing sarcoma, rhabdomyosarcoma, and gastrointestinal stromal tumour were excluded, as were cases in which patients underwent imaging for follow-up, response assessment, or recurrence. Patients all had undergone diagnostic chest ct as part of their staging. Directed studies were requested to follow up on abnormal findings in the clinical history or physical examination. All charts and pre-treatment imaging were reviewed retrospectively.

Results

From 2004 to 2008, 75 patients met the criteria for the present review. Their median age was 51 years. In 21% of cases, the primary tumour had been removed (by excisional biopsy or unplanned excision) before staging. Of the previously unresected primary tumours, 97% were avid for fluorodeoxyglucose. Of all tumours, 81% were intermediate or high grade (Fédération Nationale des Centres de Lutte Contre le Cancer grades 2–3). The primary tumour was stage T2b in 69% of cases. The most common primary site was a lower extremity (55%). The most common pathologic diagnoses were leiomyosarcoma (21%), liposarcoma (19%), and synovial sarcoma (17%). At the end of staging, 17% of patients were considered to have metastatic disease.Imaging by pet was negative for distant disease in 64 of the 75 cases. In 7 of the 64 cases, metastatic disease was evident on chest ct (negative predictive value: 88%). Imaging by pet was positive in 8 cases, with 5 of those already known to have metastases, 2 having pathologically proven false positives, and 1 being a new finding of a pulmonary metastasis (positive predictive value: 75%). The pet imaging was indeterminate in 3 patients (none of whom subsequently developed metastatic disease). Two incidental benign parotid tumours were found. Overall, only 1 patient was upstaged as a result of pet imaging (1.3%). In addition, pet did not alter the management of patients already know to have M1 disease (no new organ sites identified).

Conclusions

Although pet may be helpful in specific circumstances, routine use of fluorodeoxyglucose pet imaging for detection of metastatic disease as part of the initial staging of soft-tissue sarcoma added little to imaging by chest ct and was unlikely to alter management in our series.     

New medical treatment options and strategies to assess clinical outcome in soft-tissue sarcoma

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignant tumors predominantly arising from the embryonic mesoderm. The mainstay of curative therapy is the complete surgical resection of all tumor manifestations with negative histological margins. However, up to 50% of patients will develop distant metastases during the course of their disease. The prognosis for those patients is grim with a 5-year overall survival of less than 10%. First-line systemic therapy with ifosfamide and doxorubicin results in overall response rates of only 20% by conventional response evaluation criteria in solid tumors (RECIST). However, stabilization of disease can be seen in a greater proportion. Therefore, the role of the RECIST criteria has been questioned and the implementation of new imaging studies (e.g., FDG-PET) has shown promising results in assessing early tumor response to therapy. Furthermore, a broader insight into the molecular pathways of sarcomagenesis has been gained in recent years, revealing intriguing targets for new therapeutic approaches (e.g., VEGF, VEGF receptor, IGF receptor, EGF receptor, mTOR and cyclin-dependent kinases). In addition, a growing body of evidence is linking specific genetic aberrations with clinical outcome (e.g., SYT–SXX translocation in synovial sarcoma). With further insight into the biology of STS and the combination of new treatment options with modern imaging techniques, we will most certainly be able to improve clinical outcome in patients with STS in the upcoming years.     

Brachytherapy for pediatric soft-tissue sarcoma

PURPOSE: To review the use of brachytherapy (BRT) to treat soft-tissue sarcoma (STS) in pediatric patients at St. Jude Children's Research Hospital. METHODS AND MATERIALS: Thirty-one patients, median age 11 years (range 1-21 years) with Pediatric Oncology Group (POG) Grade 2-3 soft-tissue sarcoma (excluding rhabdomyosarcoma and Ewing's sarcoma) were treated with BRT initially (n = 27) or at the time of recurrence (n = 4) using I-125 or Ir-192 in a temporary (n = 29) or permanent implant (n = 2). Twelve patients were treated with BRT alone and the remaining 19 were treated with a combination of BRT and external beam irradiation (EBRT). The majority of patients had involved margins of resection (n = 20) and tumors less than 5 cm (n = 17). RESULTS: Twenty-seven patients were treated with BRT at the time of presentation. Among the 10 patients treated with BRT alone, one patient developed metastases (4 months) and died of metastatic disease (12 months after presentation); there were no local or regional failures among the remaining 9 patients. Among the 17 patients treated with a combination of BRT and EBRT, there was one local (17 months), two regional (both at 8 months), and 3 distant failures (12, 15, 66 months). The median survival for the surviving 25 patients was 34 months. Wound dehiscence, fibrosis/telangectasia, pigment changes, and cellulitis were the most common side effects. CONCLUSIONS: BRT is an excellent treatment option for pediatric patients with STS. Disease control may be achieved with a high rate of success when BRT is used alone or in combination with EBRT. BRT should be considered for patients with STS who require radiation therapy with the objective of reducing the dose to normal tissues and shortening the overall treatment time. Limb preservation, functional outcome, and toxicity assessment require careful assessment in a prospective study.     

Recent advances in radiotherapy for soft-tissue sarcoma

The use of radiotherapy in soft-tissue sarcoma continues to evolve. This review focuses on how current management is influenced by the most recent publications in the field. In particular, experience of patients treated without radiotherapy permits guidelines to be established that define a subset of patients who do not need radiotherapy to achieve sarcoma cure with good function. Strategies for radiotherapy delivery are discussed, including the most recent prospective results from a trial of preoperative and postoperative radiotherapy, with particular emphasis on randomized data. Also, the definitions for adequacy of surgical excision and the ability to achieve high rates of local control when margins are minimally positive are integrated into a planned approach. The difficult problem of retroperitoneal sarcoma is discussed, as are chemoradiotherapy protocols that may enhance local and systemic outcome. Finally, the potential for image-guided radiotherapy, enhanced targeting, and better radiotherapy delivery in the contemporary era is addressed.     

Brachytherapy for locally recurrent soft-tissue sarcoma

Radiation is used to reduce potential risk of local recurrence from microscopic residual disease after surgical resection. Brachytherapy is a clinically established means of providing radiation for soft-tissue sarcomas that recur after surgical resection alone or surgical resection and radiation. Although the total dose of radiation that is prescribed is approximately the same for patients undergoing external beam radiation or brachytherapy, the radiobiologic characteristics of brachytherapy, based on the inverse-square law, provide higher doses of radiation to the surgical bed. This provides a theoretical advantage for the use of brachytherapy as compared with external beam radiation among patients with recurrence after surgical resection. When soft-tissue sarcomas recur in a previously irradiated area, further external beam radiation generally is not possible; therefore, brachytherapy allows a radiotherapeutic alternative in an attempt to reduce the risk of further local recurrence. Recommendations for patient selection, the total dose of radiation, and the radiation dose-rate are outlined. Standard grading systems for response, symptoms, and severity of complications should be used.     

Costs of follow-up after potentially curative treatment for extremity soft-tissue sarcoma

Soft-tissue sarcoma is an uncommon cancer with the potential for high rates of recurrence after initial therapy. Multiple surveillance strategies have been developed to follow patients after primary treatment. The purpose of this study was to quantify the costs associated with various published post-treatment surveillance strategies. A literature review covering the years 1982-2003 was performed to find all modern published surveillance methods for extremity soft-tissue sarcoma. Only articles describing an explicit 5-year follow-up strategy were included. Total costs of 5-year follow-up were calculated for each strategy using Medicare-allowed charges as a proxy. Thirty-four articles depicting 54 strategies were identified. Total Medicare-allowed charges in year 2003 dollars ranged from 485 dollars for follow-up of low-grade sarcoma to 21,235 dollars for follow-up of high-grade sarcoma, a 42.8-fold cost differential. The average charge for these 54 strategies was 6,401 dollars. Physical examination and chest x-ray were the most commonly used screening modalities. Several guidelines have been proposed for extremity soft-tissue sarcoma patient follow-up, most prominently those of the National Comprehensive Cancer Network. The literature has yet to reflect the consensus these guidelines suggest. This study shows wide disparity in the costs of 54 specific methods of following soft-tissue sarcoma patients. Clinical trials are needed to identify an optimal surveillance strategy, one balancing gains in survival, quality of life, costs, and societal willingness to expend resources. Such trials have not been conducted due to the rarity of extremity soft-tissue sarcomas and the costs associated with conducting long-term trials. Alternatively, prospective evaluation of imaging modalities used in follow-up should be assessed as part of other trials. Computer simulation analysis also holds great promise as an assessment tool for surveillance strategies because patient participation is not required.     

Ewing's sarcoma of bone: relation between clinical characteristics and staging

Patients with metastatic Ewing's sarcoma of bone have a poor prognosis. A relation between clinical characteristics and presence of metastatic disease at diagnosis in patients with Ewing's sarcoma of bone was investigated. Data from 618 patients [136 (22%) with metastases at diagnosis] registered at the authors' institution between April 1972 and December 1997 were collected. The distribution of several clinical and hematologic parameters in patients with metastases and those without metastases was analyzed, and clinical risk factors of metastatic disease at presentation were analyzed by means of multivariate logistic regression analysis. All the variables significant at the univariate analysis (age, fever, site, volume, lactic dehydrogenase, anemia, and interval between onset of symptoms and diagnosis) were considered in the multivariate analysis. Pelvic location of the tumor, high level of lactic dehydrogenase, presence of fever, an interval between onset of symptoms and diagnosis less than 3 months, and age older than 12 years were found to be risk factors of clinically evident metastatic disease. In the subset of patients with no risk factors the rate of metastatic disease at presentation was only 4%; in case of contemporary presence of two factors it was 23%, although it was almost double (44%) if three or four factors were present. Only six patients were positive for five factors and all of them had metastases at presentation. The parameters identified are clinical markers of Ewing's sarcoma having a particularly aggressive metastatic behavior.     

Periosteal margin in soft-tissue sarcoma

BACKGROUND: Soft-tissue sarcomas frequently rest in contact with bone. The purpose of the study was to evaluate the risk of local recurrence for sarcomas adjacent to bone and to determine whether the periosteum provides an adequate margin of resection. METHODS: Fifty patients with soft-tissue sarcomas abutting bone were treated at a single institution between 1990 and 2004. All patients had high-grade, T2 (>5 cm), nonmetastatic disease in the lower extremity. Bone contact was verified by preoperative magnetic resonance imaging (MRI) and/or computed tomography (CT) scans. Forty-three of 50 patients received preoperative radiation with a mean dose of 50 Gy. In 11 cases a composite resection of bone and soft tissue was performed. In 39 cases the excision involved only soft tissue. RESULTS: True bone invasion was verified by histopathologic examination in 3 of 50 cases (6%). Local recurrence in the soft tissues developed in 8 of 50 (16%) patients. In no case did the recurrence involve destruction of cortical bone or erosion into bone. The recurrent tumor resided against the region of previous bone contact in 1 of 8 cases. There was no statistically significant difference in local recurrence between patients who had composite bone resection and patients who had soft-tissue resection only (P = .87). CONCLUSIONS: Relatively few sarcomas are able to penetrate cortical bone. Composite bone and soft-tissue resections are indicated primarily for frank bone invasion. In the absence of this, the periosteum is an adequate surgical margin for sarcomas treated with wide excision and radiation.