An Assessment of Factors An Assessment of Factors Affecting Outcome in Patients Affecting Outcome in Patients

Presenting with Metastatic Presenting with Metastatic Soft Tissue Sarcoma Soft Tissue Sarcoma

Peter Ferguson MDPeter Ferguson MD1,21,2, Benjamin Deheshi MD, Benjamin Deheshi MD1,21,2, , Anthony Griffin MScAnthony Griffin MSc11, Robert Bell MD, Robert Bell MD1,21,2, Brian , Brian

O’Sullivan MDO’Sullivan MD33, Charles Catton MD, Charles Catton MD33, Peter Chung , Peter Chung MDMD33, Jay Wunder MD, Jay Wunder MD1,21,2

1 Musculoskeletal Oncology Unit, Mount Sinai Hospital1 Musculoskeletal Oncology Unit, Mount Sinai Hospital2 Department of Surgery, University of Toronto2 Department of Surgery, University of Toronto3 Department of Radiation Oncology, Princess 3 Department of Radiation Oncology, Princess

Margaret HospitalMargaret Hospital

44 year old woman44 year old woman

Painful mass in Painful mass in paraspinal regionparaspinal region

2 small pulmonary 2 small pulmonary nodulesnodules

Bx – grade 3 Bx – grade 3 leiomyosarcomaleiomyosarcoma

Preop radiationPreop radiation

Mass grew on Mass grew on radiationradiation

Patient unable to lie Patient unable to lie supine due to large supine due to large mass and severe pain mass and severe pain requiring narcoticsrequiring narcotics

Chest x-ray at time of Chest x-ray at time of surgery…surgery…

Post op wound Post op wound infectioninfection

Patient dead of Patient dead of progressive progressive metastatic disease metastatic disease within 2 monthswithin 2 months

60 year old male60 year old male

Early onset Early onset Alzheimer’s, Alzheimer’s, otherwise healthyotherwise healthy

Rapidly growing mass Rapidly growing mass left proximal thighleft proximal thigh

Bedridden due to Bedridden due to severe painsevere pain

Bx – grade 3 MFHBx – grade 3 MFH

CT chest after radiation CT chest after radiation shows small pulmonary shows small pulmonary nodulesnodules

Patient underwent Patient underwent resection, free latissimus resection, free latissimus dorsi flapdorsi flap

Never regained Never regained ambulatory statusambulatory status

Dead of progressive Dead of progressive metastatic disease within metastatic disease within 3 months3 months

62 year old male62 year old male

Rapidly growing right Rapidly growing right chest wall masschest wall mass

Patient bedridden in Patient bedridden in severe painsevere pain

Required dressing Required dressing changes several times changes several times per dayper day

Repeated transfusions for Repeated transfusions for anemiaanemia

Preop radiationPreop radiation

Resection and TRAM flapResection and TRAM flap

Partial flap necrosis Partial flap necrosis requiring dressing requiring dressing changeschanges

Patient did not regain Patient did not regain ambulatory statusambulatory status

Dead of progressive Dead of progressive metastatic disease 2 metastatic disease 2 months latermonths later

RationaleRationale

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

symptoms?symptoms?

RationaleRationale

5 year disease specific survival of AJCC stage 5 year disease specific survival of AJCC stage IV STS – 6%IV STS – 6%

Can surgical resection be withheld from patients Can surgical resection be withheld from patients presenting with stage IV disease on this basis?presenting with stage IV disease on this basis?

Is it possible to predict which patients are more Is it possible to predict which patients are more likely to be cured and therefore benefit from likely to be cured and therefore benefit from aggressive surgical resection?aggressive surgical resection?

Is it possible to determine factors associated Is it possible to determine factors associated with longer survival?with longer survival?

Billingsley et al, Ann Surg, 229(5): p 602.Billingsley et al, Ann Surg, 229(5): p 602.

719 patients who either presented with or 719 patients who either presented with or developed pulmonary metsdeveloped pulmonary mets

Predictors of outcome on Cox modelling – Predictors of outcome on Cox modelling – complete resection of pulmonary mets, complete resection of pulmonary mets, disease free interval > 12 months, low disease free interval > 12 months, low grade sarcomagrade sarcoma

No differentiation between those who No differentiation between those who presented with or developed metspresented with or developed mets

Casson et al, Cancer 69(3): p. 662.Casson et al, Cancer 69(3): p. 662.

Group of STS patients undergoing Group of STS patients undergoing pulmonary metastasectomypulmonary metastasectomy

Predictors of outcome – 3 or fewer Predictors of outcome – 3 or fewer pulmonary mets, long disease free intervalpulmonary mets, long disease free interval

Bilaterality of disease not significantBilaterality of disease not significant

Billingsley et al, Cancer, 82(2): p. 389.Billingsley et al, Cancer, 82(2): p. 389.

230 patients with metastatic STS230 patients with metastatic STSPredictors of outcome after multivariate Predictors of outcome after multivariate analysis – complete resection of analysis – complete resection of metastatic disease, disease free interval> metastatic disease, disease free interval> 12 months, absence of preceeding LR, 12 months, absence of preceeding LR, age < 50age < 50Factors in long term survivors (> 36 Factors in long term survivors (> 36 months) – complete resection of months) – complete resection of metastatic disease, tumor size < 5cmmetastatic disease, tumor size < 5cm

Zagars et al, Int J Rad Onc Biol Phys 57(3): Zagars et al, Int J Rad Onc Biol Phys 57(3): p. 739.p. 739.

402 patients with localized STS who 402 patients with localized STS who developed recurrent or metastatic diseasedeveloped recurrent or metastatic disease

Of those with metastatic disease, factors Of those with metastatic disease, factors for survival included – complete resection for survival included – complete resection of metastases, disease free interval > 1 of metastases, disease free interval > 1 year, absence of prior chemotherapyyear, absence of prior chemotherapy

Site of metastasis (lung vs. other) not a Site of metastasis (lung vs. other) not a significant factorsignificant factor

PurposePurpose

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

MethodsMethods

REB approvalREB approval

Retrospective review of prospectively Retrospective review of prospectively collected database at Mount Sinai Hospital collected database at Mount Sinai Hospital from years 1986 – 2006from years 1986 – 2006

Inclusion – resection of primary tumor Inclusion – resection of primary tumor (either limb salvage or amputation)(either limb salvage or amputation)

MethodsMethods

Survival analysis – Survival analysis – Kaplan-Meier – log Kaplan-Meier – log rankrank

Cox proportional Cox proportional hazards analysis for hazards analysis for factors found to be factors found to be significant on significant on univariate analysisunivariate analysis

ResultsResults

1537 patients1537 patients

130 presented with 130 presented with AJCC stage IV (8.5%)AJCC stage IV (8.5%)

Mean age 56 years Mean age 56 years (range 15-93 years)(range 15-93 years)

75 male, 55 female75 male, 55 female

Median survival 11 Median survival 11 months (range 0-226 months (range 0-226 months)months)

Presenting StatusPresenting Status

PresentationPresentation # of patients (%)# of patients (%)

Lung mets onlyLung mets only 81 (62)81 (62)

Lymph node mets onlyLymph node mets only 20 (10)20 (10)

Lung & lymph node Lung & lymph node metsmets

13 (15)13 (15)

Presentation as Presentation as metastasismetastasis

16 (12)16 (12)

STS subtype

8 6.2 6.2 6.2

32 24.6 24.6 30.8

14 10.8 10.8 41.5

4 3.1 3.1 44.6

6 4.6 4.6 49.2

8 6.2 6.2 55.4

21 16.2 16.2 71.5

5 3.8 3.8 75.4

4 3.1 3.1 78.5

5 3.8 3.8 82.3

2 1.5 1.5 83.8

2 1.5 1.5 85.4

3 2.3 2.3 87.7

8 6.2 6.2 93.8

4 3.1 3.1 96.9

4 3.1 3.1 100.0

130 100.0 100.0

Liposarcoma

MFH

Synovial sarcoma

Fibrosarcoma

MPNST

Rhabdomyosarcoma

Leiomyosarcoma

Epitheliod sarcoma

Neurofibrosarcoma

Alveolar soft partssarcoma

ST CSA

PNET/ Ewing's

Clear cell sarcoma

STS NOS

ST OSA

Angiosarcoma

Total

ValidFrequency Percent Valid Percent

CumulativePercent

Tumor location

21 16.2 16.2 16.2

13 10.0 10.0 26.2

4 3.1 3.1 29.2

7 5.4 5.4 34.6

36 27.7 27.7 62.3

31 23.8 23.8 86.2

11 8.5 8.5 94.6

4 3.1 3.1 97.7

3 2.3 2.3 100.0

130 100.0 100.0

Shoulder

Elbow

Wrist/ hand

Pelvic girdle

Hip

Knee

Ankle/ foot

Paraspinal

Chest wall

Total

ValidFrequency Percent Valid Percent

CumulativePercent

Tumor FactorsTumor Factors

# of patients (%)# of patients (%)

DepthDepth SuperficialSuperficial 14 (11)14 (11)

DeepDeep 116 (89)116 (89)

SizeSize < 5cm< 5cm 21 (16)21 (16)

> 5cm> 5cm 109 (84)109 (84)

GradeGrade 11 5 (4)5 (4)

22 20 (15)20 (15)

33 105 (81)105 (81)

Treatment FactorsTreatment Factors

# of patients (%)# of patients (%)

Type of SurgeryType of Surgery Limb SalvageLimb Salvage 115 (88)115 (88)

AmputationAmputation 15 (12)15 (12)

ChemotherapyChemotherapy YesYes 48 (37)48 (37)

NoNo 82 (63)82 (63)

RadiationRadiation YesYes 78 (60)78 (60)

NoNo 52 (40)52 (40)

Current status

17 13.1 13.1 13.1

11 8.5 8.5 21.5

3 2.3 2.3 23.8

99 76.2 76.2 100.0

130 100.0 100.0

ANED

AWED

Deceased

DOD

Total

ValidFrequency Percent Valid Percent

CumulativePercent

Univariate Analysis for Overall Univariate Analysis for Overall Survival (log rank)Survival (log rank)

FactorFactor Significance (p-value)Significance (p-value)

Anatomic locationAnatomic location 0.50.5

DepthDepth 0.110.11

GenderGender 0.350.35

Histologic subtypeHistologic subtype 0.150.15

Bilateral vs. unilateral lung Bilateral vs. unilateral lung metsmets

0.620.62

Pulmonary metastasectomyPulmonary metastasectomy 0.320.32

Use of chemoUse of chemo 0.530.53

0 50 100 150 200 250

Overall survival (months)_

0.0

0.2

0.4

0.6

0.8

1.0 combined

presenting status

Lung mets

lymph node mets

Lung mets-censored

lymph node mets-censored

Overall Survival by Presenting Status

p=0.0006

0 50 100 150 200 250

Overall survival (months)_

0.0

0.2

0.4

0.6

0.8

1.0 sizecode

1

2

1-censored

2-censored

Overall Survival by Size

p=0.02

0 50 100 150 200 250

Overall survival (months)_

0.0

0.2

0.4

0.6

0.8

1.0 GRADE_

1

2

3

1-censored

2-censored

3-censored

Overall Survival by Grade

p=0.05

0 50 100 150 200 250

Overall survival (months)_

0.0

0.2

0.4

0.6

0.8

1.0 Mets dichotomized

3 or fewer mets

4 or more mets

3 or fewer mets-censored

4 or more mets-censored

Overall Survival by Number of Lung Mets

p=0.04

Cox modelCox model

FactorFactor SignificanceSignificance Hazard RatioHazard Ratio

# of lung mets # of lung mets (<=3 vs. >3)(<=3 vs. >3)

0.090.09 0.60.6

Lymph node vs. Lymph node vs. lung metslung mets

0.0080.008 2.72.7

GradeGrade 0.80.8 0.90.9

SizeSize 0.150.15 0.60.6

Survival > 3 or >6 monthsSurvival > 3 or >6 months

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

DiscussionDiscussion

Patients presenting Patients presenting with stage IV STS with stage IV STS have dismal have dismal prognosisprognosis

Patients with lymph Patients with lymph node mets rather than node mets rather than lung mets can lung mets can occasionally be cured occasionally be cured by aggressive by aggressive surgical managementsurgical management

DiscussionDiscussion

Other factors including Other factors including small primary tumor size, small primary tumor size, low grade and fewer than low grade and fewer than 4 pulmonary metastases 4 pulmonary metastases may suggest more may suggest more indolent courseindolent course

These may also benefit These may also benefit from aggressive from aggressive treatment to prolong treatment to prolong survivalsurvival

Is survival the best outcome in Is survival the best outcome in deciding on correct treatment?deciding on correct treatment?

Obviously notObviously notPatients must be told Patients must be told from the outset that from the outset that their prognosis is poor their prognosis is poor However other However other outcome measures outcome measures may be useful in may be useful in evaluating evaluating effectiveness of what effectiveness of what should be considered should be considered palliative surgerypalliative surgery

Quality of life measuresQuality of life measures

Symptom specificSymptom specific– McGill Pain IndexMcGill Pain Index

Generic functional assessmentGeneric functional assessment– Karnofsky performance statusKarnofsky performance status

Secific quality of life assessmentsSecific quality of life assessments– Function assessment of cancer therapy Function assessment of cancer therapy

(FACT)(FACT)– Edmonton symptom assessment systemEdmonton symptom assessment system

Future studiesFuture studies

Prospective evaluation of effectiveness of Prospective evaluation of effectiveness of surgery in improving quality of life in surgery in improving quality of life in patients undergoing palliative resection of patients undergoing palliative resection of STSSTS

Development of disease-specific quality of Development of disease-specific quality of life outcome measure for palliative life outcome measure for palliative sarcoma surgerysarcoma surgery

ConclusionsConclusions

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