Thomas J. Wood, MD1,2, Kathleen M. Quinn, MD1,5, Theresa J.C. Pazionis1,2, Forough Farrokhyar, PhD2,3, Ben Deheshi, MD, FRCSC1,2 Tom Corbett MD, FRCPC1,4, Michelle A. Ghert, MD, FRCSC1,2

1Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada2Department of Surgery, McMaster University, Hamilton, Ontario, Canada3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada4Department of Oncology - Division of Radiation Oncology, McMaster University, Hamilton, Ontario, Canada5Department of Medicine, McMaster University, Hamilton, Ontario, Canada

November 14, 2012

There are no financial interests to disclose

Extra-abdominal desmoid tumors, although benign, are frequently

aggressive, with a poorly circumscribed local infiltrative pattern and have a marked propensity for recurrence (7, 8).

Aggressive wide local excision: recurrence rates are reported well above 40% (9, 3, 10, 11, 12).

Radiation (13,14) and chemotherapy (5) have also been used resulting in improved local control and recurrence rates.

There is little consensus regarding the role of radiation therapy, surgery and chemotherapy in the clinical management of extra-abdominal desmoid tumors.

The purpose of this study was to perform a systematic review and meta-analysis in order to crystalize the evidence available regarding local control of extra-abdominal desmoid tumor.

A literature search was conducted of the following electronic databases: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE (January 1950 to January 2011), CINAHL (January 1982 to January 2011, and EMBASE (January 1980 to January 2011).

The key words used were a combination of : “fibromatosis” “extra-abdominal tumour” “desmoid tumour” “therapy”

Papers published in English Human subjuects

1. Treatment of extra-abdominal desmoid tumours

2. Different modalities for treatment of extra-abdominal desmoid tumours

3. Use of a clinical outcome marker (i.e. recurrence rate) to evaluate differences in modalities

4. unpublished data from studies fulfilling criteria 1) or 2).

1. articles exclusively examining non-living populations or animal studies

2. articles examining intra-abdominal desmoid tumours.

3. case reports.

4. articles that studied other variables outside of the treatment of extra-abdominal desmoid tumours.

Primary Local Failure Rates

Secondary Response Rate for Systemic Therapy

Newcastle-Ottawa Quality Assessment Scale (NOQAS) for cohort studies

Evaluates papers on three key areas selection of studies comparability of the groups assessment of exposure (for case control)

or outcome (for cohort studies)

The level of reviewer agreement, mean, & standard deviation of the NOQAS scores for study quality were assessed

Heterogeneity among studies was tested using the Cochrane Q test with a P-value set at 0.1 for significance

Alpha was set at 0.05 for statistical significance

Review Manager 5.0 (Cochran Library for Systematic Reviews) and StatsDirect 2.7. (StatsDirect Ltd, UK) was used for data analysis.

35 studies selected for study inclusion Assessed to be high quality by NOQAS

Papers characterized by treatment modality 7 Radiation Therapy (all retrospective design) 18 Surgical Therapy (2 prospective; 16

retrospective) 14 Combination Therapy 9 Systemic Therapy

▪ 4 non cytotoxic (3 prospective; 1 retrospective design) ▪ 5 cytotoxic (3 prospective; 2 retrospective design)

The weighted pooled proportion for local failure rate FOR ALL STUDIES:

Radiation alone: 0.22 (95% CI: [0.16- 0.28]) with between study heterogeneity of I2=15% (p= .315)

Surgery alone : 0.35 (95% CI: [0.26-0.44]) with between study , with between study heterogeneity of I2 =90%, (p<.001)

Combination of surgery + radiation: 0.28 (95% CI: [0.18-0.39]) with between study heterogeneity of I2=84% (p<.001)

Study or Subgroup

Ballo et al 1998Ballo et al 1999Guadagnolo et al 2008Spear et al 1998

Total (95% CI)

Total eventsHeterogeneity: Chi² = 3.76, df = 3 (P = 0.29); I² = 20%Test for overall effect: Z = 1.27 (P = 0.20)

Events

9101510

44

Total

52467441

213

Events

75

131

26

Total

23214115

100

Weight

25.7%22.4%44.6%7.3%

100.0%

IV, Fixed, 95% CI

0.48 [0.15, 1.50]0.89 [0.26, 3.02]0.55 [0.23, 1.30]

4.52 [0.53, 38.78]

0.69 [0.38, 1.23]

Surgery plus radiation Radiation Odds Ratio Odds RatioIV, Fixed, 95% CI

0.02 0.1 1 10 50Surgery plus radiation Radiation

Study or Subgroup

Ballo et al 1999Baumert et al 2007Duggal et al 2004Merchant et al 1999Pignatti et al 2000Pritchard et al 1996Rock et al 1984Spear et al 1998

Total (95% CI)

Total eventsHeterogeneity: Chi² = 1.94, df = 7 (P = 0.96); I² = 0%Test for overall effect: Z = 1.94 (P = 0.05)

Events

101727726

10

61

Total

46688

3117101041

231

Events

43127

172812

11815

252

Total

1223827746334

15551

564

Weight

22.4%18.3%4.3%

14.0%11.9%4.9%8.1%

16.2%

100.0%

IV, Fixed, 95% CI

0.51 [0.23, 1.13]0.72 [0.30, 1.74]0.95 [0.15, 5.86]0.98 [0.36, 2.66]0.88 [0.30, 2.59]0.46 [0.08, 2.51]0.47 [0.13, 1.76]0.77 [0.30, 1.97]

0.69 [0.47, 1.00]

Surgery plus radiation Surgery Odds Ratio Odds RatioIV, Fixed, 95% CI

0.02 0.1 1 10 50Surgery plus radiation Surgery

Surgery + radiation in combination had lower local failure rates than radiation alone and surgery alone (when examining comparative

studies)

The weighted pooled proportion response rates were 0.91 (95% CI: [0.86-0.96]) for studies that evaluated non cytotoxic therapies (I2 = 0%, p=.581) and 0.52 (95% CI: [0.39-0.65]) for studies that evaluated cytotoxic therapies (I2 =29%, p=.228).

Surgery alone had a higher local failure rate compared to radiation alone or surgery combined with radiation.

The combination of surgery and radiation outperformed either surgery alone (p=0.05) or radiation alone (p=0.20).

Potential for successful outcomes using radiation alone (for stable disease) and in combination with surgery

Consider treating extra-abdominal desmoid tumours with either radiation alone or radiation + surgery to achieve local control, but not with surgery alone (7, 19, 4, 11).

Many patients often had many rounds of chemotherapy and extensive local management including surgery and radiation prior to the published result.

Difficult to determine the isolated effect of chemotherapy

There is a role for systemic therapy, more specifically non-cytotoxic chemotherapy, in treating extra-abdominal desmoid tumours having reported stable disease rates >80% (33, 34, 35, 36).

Lack of large scale, well-controlled clinical trials.

Genotypic status (including beta-catenin mutational status) and specific tumour characteristics were not adequately reported (confounding variables)

▪ There is evidence to support combined radiation and surgery, but not surgery alone in the local management

▪ Systemic treatment, particularly with non cytotoxic agents, appears to be a promising approach and should be evaluated in randomized prospective trials.

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