Clinical question 1. Does radiotherapy at a specialised sarcoma centre improve outcomes?

 

  • Population: Adult and Paediatric patients with bone and soft tissue sarcoma 
  • Intervention: Multidisciplinary team, radiotherapy
  • Comparison: Treatment at non-specialised centre
  • Outcomes: local control, overall survival, wound complication/toxicity

Author: Angela Hong, and Sarcoma Guidelines Working Party

Topic 1 addresses the role for management of patients with sarcoma at a specialised sarcoma centre. Due to nature of the clinical question, it is not possible to conduct a randomised trial and therefore evidence is from analysis of patient series treated within and outside specialised sarcoma centres.  There is a large volume of retrospective studies from the cancer registries from the United States and Europe, and large specialised sarcoma centres around the world addressing this important question. Most studies report on overall survival with multivariate analysis of the impact of treatment at specialised centres on outcomes. Most studies also report on surgical endpoints such as local recurrence, immediate postoperative mortality, and overall survival.

In the curative setting, the role of radiotherapy (RT) is for improvement in local control before or after appropriate surgical resection of soft tissue sarcoma or as definitive treatment in unresectable primary bone tumour such Ewing sarcoma, chordoma or chondrosarcoma. Given the vast variation in tumour size and location, RT for sarcoma is associated with significant technical demands in target delineation and treatment planning. In the STRASS trial of preoperative RT for retroperitoneal sarcoma, a non-compliant RT plan was associated with worse abdominal relapse free survival and a trend towards worse overall survival (5).  The systematic review identified 21 studies for this question. Nine studies utilise the United States National Cancer Data Base (NCDB) which captures >70% of all cancers reported in the United States.  The NCBD captures the overall survival endpoint but not local recurrence which is the main endpoint for RT in sarcoma. The NCDB also does not collect the granular RT data such as dose, fractionation, timing, technique, and target volume delineation. Hence, despite several studies from the United States NCDB with a large number of patients examining the effect of treatment at specialized sarcoma centre, the potential benefit of improvement in local control by delivering RT at specialised sarcoma centre could not be determined from these NCDB studies. It is also impossible to account for all unknown confounders that may exist in large databases.

There were various definitions of a specialised sarcoma centre in these studies. Some were defined by case number per year (6-12), some by percentile of the total case diagnosed in the region (13-16) and two studies by the facility of the hospital including number of speciality, case number and postgraduate speciality training program (17, 18). Overall most studies showed higher RT use in soft tissue sarcoma at specialised sarcoma centres.

Local Control

There are four studies reporting the local recurrence endpoint including RT as part of the limb salvage treatment (19-22). All are retrospective studies from Europe and Australia of adult patients with soft tissue sarcoma. Critical appraisal of these studies by the party member reached the conclusion that it was not possible to determine the specific effect of RT at specialised sarcoma centres as these studies reported the outcome of the overall treatment at specialised sarcoma centres.  One study described the outcome by conformity to the French clinical practice guidelines which included a multidisciplinary team discussion of the management (20). In the multivariate analysis, pre-surgery multidisciplinary discussion and management in reference centre within cancer network independently predicted conformity to clinical practice guidelines. Sampo et al. reported a significant difference in RT utilisation by number of sarcoma case per year (high volume centre compared with intermediate and low volume centres, 75.2% vs 56.3% vs 31.6%, p<0.001) (21). The local recurrence free rate at five years was significantly higher at high volume centres than at intermediate and low volume centres, 82% vs 61% and 69% (p=0.046). In the Australian study, the location of initial surgical management was a predictor for local recurrence, distant metastasis and disease specific survival (22). All patients in this study had further surgery at the specialised sarcoma centres with or without RT. It must be noted that in these studies, patients were classified as managed in a sarcoma centre by location of surgery, not necessarily by location of radiotherapy. 

Toxicity

Ellison et al. is the only identified study which specifically compared RT toxicity between treatment at a specialised sarcoma centre with non-specialised centres (23). This is a retrospective study of 191 patients with localised, resectable soft tissue sarcoma of the extremity or trunk treated with preoperative RT followed by resection.  All resections were performed at one specialised sarcoma centre (Medical College of Wisconsin, USA).  One hundred seventeen patients received preoperative RT at the specialised sarcoma centre (61.3%) and 74 patients (38.7%) received RT at community cancer centres. There was a significant reduction in postoperative major wound complication rate when the preoperative RT was performed at the specialised sarcoma centre compared with community cancer centres (21% vs 39%, P=0.009). The use of advanced RT technique (intensity modulated radiotherapy, IMRT) did not significantly impact the rate of postoperative wound complications at the specialised sarcoma centre (p= 0.08).  However, in the community cancer centre setting, the use of IMRT significantly decreased the rate of postoperative wound complication from 59% to 7% (P<0.0001). In the multivariate analysis, patients receiving RT at community centres were 2.25 times more likely to develop a major wound complication (OR: 2.25, 95% CI: 1.13-4.48, P= 0.02) than those who received RT in the specialised sarcoma centre. 

Overall Survival

Most studies analysed the overall survival by classifying patients treated in specialised sarcoma centres or not. Fourteen studies reported the overall survival endpoints. Twelve studies showed a significantly better 5-year overall survival for patients managed at a specialised sarcoma centre (6, 8-18). Three of the 12 studies also showed a consistently better overall survival at 10 years. Two studies reported no difference in 5-year overall survival between hospital categories  (7, 24).  However, the direct benefit of RT at a specialised sarcoma centre on the overall survival could not be determined in most of these studies as the patient cohorts were grouped into management by multidisciplinary team or not. Treatment of patients with sarcoma requires close collaboration between surgeons, radiation oncologists, medical oncologists, radiologists, and pathologists. Each member of this complex team contributes to timely diagnosis, optimal staging, sequencing of therapy, and post treatment surveillance. High-volume centres are more likely to have closer collaboration and workflows between these disciplines, including a specific sarcoma multidisciplinary team discussion. Staff, including clinicians, nurses, and allied health members, at high-volume centres have more experience with managing toxicity associated with extensive surgery and radiation therapy, and therefore adherence to treatment completion may be higher.

Tchelebi et al. is the only publication which analysed the overall survival by RT facility location (24). The study utilized the US NCDB to determine 5-year overall survival for patients with solid malignancy treated by RT with curative intent.  745 of the 6231 patients treated by preoperative RT and 1933 of  147,980 patients treated with postoperative RT had a soft tissue sarcoma diagnosis.  In multivariate analysis adjusted by age, gender, comorbidity score, race, insurance status, clinical stage, geographic location income and facility type (community, comprehensive, academic, integrated network cancer program), surgery (yes or no), systemic therapy (yes or no), there was no impact on the overall survival by facility for the soft tissue sarcoma subgroup. However, the multivariate analysis did not adjust for grade of the sarcoma, and surgery location (specialised sarcoma surgeon or not).

Therefore the working party concluded that is insufficient information in the literature to provide a recommendation on the overall survival endpoint in the PICO model by RT at a specialised sarcoma centre. However, evidence from this systematic review supports overall treatment at specialised sarcoma centre to improve the overall survival.

Evidence summary

  Level

  Reference

The rate of local recurrence after radiotherapy as part of the limb salvage treatment for soft tissue sarcoma is lower in adult population treated in specialist sarcoma centre. It is not possible to determine from the available evidence which component of the sarcoma centre multi-disciplinary care is predominantly responsible for this benefit and specifically whether radiotherapy delivered at a specialised sarcoma centre will improve local control.

  III-3, IV

  (19-22)

Major wound complication is higher when patients with localised soft tissue sarcoma received preoperative radiation therapy in a non-specialised sarcoma centre.

  III-3

  (23)

Evidence-based recommendation

Grade*

Patients with soft tissue sarcoma requiring radiotherapy to be managed through a specialised sarcoma centre to reduce local recurrence and rate of major wound complication.

B

*National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for developers of guidelines. Canberra: NHMRC; 2009. (https://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/developers/nhmrc_levels_grades_evidence_120423.pdf)

To view the administrative report click here

To view the techinical report click here