An Assessment of Factors Affecting Outcome in Patients Presenting with Metastatic Soft Tissue Sarcoma Peter Ferguson MD1,2, Benjamin Deheshi MD1,2, Anthony Griffin MSc1, Robert Bell MD1,2, Brian O’Sullivan MD3, Charles Catton MD3, Peter Chung MD3, Jay Wunder MD1,2 1 Musculoskeletal Oncology Unit, Mount Sinai Hospital 2 Department of Surgery, University of Toronto 3 Department of Radiation Oncology, Princess Margaret Hospital

44 year old woman Painful mass in paraspinal region 2 small pulmonary nodules Bx – grade 3 leiomyosarcoma Preop radiation

Mass grew on radiation Patient unable to lie supine due to large mass and severe pain requiring narcotics Chest x-ray at time of surgery…

Post op wound infection Patient dead of progressive metastatic disease within 2 months

60 year old male Early onset Alzheimer’s, otherwise healthy Rapidly growing mass left proximal thigh Bedridden due to severe pain Bx – grade 3 MFH

CT chest after radiation shows small pulmonary nodules Patient underwent resection, free latissimus dorsi flap Never regained ambulatory status Dead of progressive metastatic disease within 3 months

62 year old male Rapidly growing right chest wall mass Patient bedridden in severe pain Required dressing changes several times per day Repeated transfusions for anemia

Preop radiation Resection and TRAM flap Partial flap necrosis requiring dressing changes Patient did not regain ambulatory status Dead of progressive metastatic disease 2 months later

Rationale What role does surgery play in treating patients presenting with primary metastatic STS? Attempt at cure? Prolong life? Palliation of symptoms?

Rationale 5 year disease specific survival of AJCC stage IV STS – 6% Can surgical resection be withheld from patients presenting with stage IV disease on this basis? Is it possible to predict which patients are more likely to be cured and therefore benefit from aggressive surgical resection? Is it possible to determine factors associated with longer survival?

Billingsley et al, Ann Surg, 229(5): p 602. 719 patients who either presented with or developed pulmonary mets Predictors of outcome on Cox modelling – complete resection of pulmonary mets, disease free interval > 12 months, low grade sarcoma No differentiation between those who presented with or developed mets

Casson et al, Cancer 69(3): p. 662. Group of STS patients undergoing pulmonary metastasectomy Predictors of outcome – 3 or fewer pulmonary mets, long disease free interval Bilaterality of disease not significant

Billingsley et al, Cancer, 82(2): p. 389. 230 patients with metastatic STS Predictors of outcome after multivariate analysis – complete resection of metastatic disease, disease free interval> 12 months, absence of preceeding LR, age < 50 Factors in long term survivors (> 36 months) – complete resection of metastatic disease, tumor size < 5cm

Zagars et al, Int J Rad Onc Biol Phys 57(3): p. 739. 402 patients with localized STS who developed recurrent or metastatic disease Of those with metastatic disease, factors for survival included – complete resection of metastases, disease free interval > 1 year, absence of prior chemotherapy Site of metastasis (lung vs. other) not a significant factor

Purpose To investigate predictors of outcome of patients who present with primary AJCC stage IV soft tissue sarcoma who are treated with surgical resection of their primary tumor.

Methods REB approval Retrospective review of prospectively collected database at Mount Sinai Hospital from years 1986 – 2006 Inclusion – resection of primary tumor (either limb salvage or amputation)

Methods Survival analysis – Kaplan-Meier – log rank Cox proportional hazards analysis for factors found to be significant on univariate analysis

Results 1537 patients 130 presented with AJCC stage IV (8.5%) Mean age 56 years (range 15-93 years) 75 male, 55 female Median survival 11 months (range 0-226 months)

Presenting Status Presentation # of patients (%) Lung mets only 81 (62) Lymph node mets only 20 (10) Lung & lymph node mets 13 (15) Presentation as metastasis 16 (12)

Tumor Factors # of patients (%) Depth Superficial 14 (11) Deep 116 (89) Size < 5cm 21 (16) > 5cm 109 (84) Grade 1 5 (4) 2 20 (15) 3 105 (81)

Treatment Factors # of patients (%) Type of Surgery Limb Salvage 115 (88) Amputation 15 (12) Chemotherapy Yes 48 (37) No 82 (63) Radiation 78 (60) 52 (40)

Univariate Analysis for Overall Survival (log rank) Factor Significance (p-value) Anatomic location 0.5 Depth 0.11 Gender 0.35 Histologic subtype 0.15 Bilateral vs. unilateral lung mets 0.62 Pulmonary metastasectomy 0.32 Use of chemo 0.53

p=0.0006

p=0.02

p=0.05

p=0.04

Cox model Factor Significance Hazard Ratio # of lung mets (<=3 vs. >3) 0.09 0.6 Lymph node vs. lung mets 0.008 2.7 Grade 0.8 0.9 Size 0.15

Survival > 3 or >6 months We dichotomized outcome into survival of < 3 months or > 3 months, or < 6 months or > 6 months The same factors maintained prognostic significance No other factors demonstrated significance Therefore the same factors can be used to predict longer survival

Discussion Patients presenting with stage IV STS have dismal prognosis Patients with lymph node mets rather than lung mets can occasionally be cured by aggressive surgical management

Discussion Other factors including small primary tumor size, low grade and fewer than 4 pulmonary metastases may suggest more indolent course These may also benefit from aggressive treatment to prolong survival

Is survival the best outcome in deciding on correct treatment? Obviously not Patients must be told from the outset that their prognosis is poor However other outcome measures may be useful in evaluating effectiveness of what should be considered palliative surgery

Quality of life measures Symptom specific McGill Pain Index Generic functional assessment Karnofsky performance status Secific quality of life assessments Function assessment of cancer therapy (FACT) Edmonton symptom assessment system

Future studies Prospective evaluation of effectiveness of surgery in improving quality of life in patients undergoing palliative resection of STS Development of disease-specific quality of life outcome measure for palliative sarcoma surgery

Conclusions Patients presenting with metastatic soft tissue sarcoma with isolated lymph node metastases, fewer than 4 lung metastases, low grade tumours or tumours less then 5 cm have better survival on univariate analysis Isolated lymph nodes mets only significant prognostic factor on multivariate analysis Aggressive surgical treatment of the primary and metastasis with curative intent may be warranted in small group of patients