Treatment and follow-up strategies in desmoid tumours: a practice guideline

Abstract

Objectives

We set out to

• determine the optimal treatment options—surgery, radiation therapy (rt), systemic therapy, or any combinations thereof—for patients with desmoid tumours once the decision to undergo active treatment has been made (that is, monitoring and observation have been determined to be inadequate).

• provide clinical-expert consensus opinions on follow-up strategies in patients with desmoid tumours after primary interventional management.

Methods

This guideline was developed by Cancer Care Ontario’s Program in Evidence-Based Care and the Sarcoma Disease Site Group. The medline, embase, and Cochrane Library databases, main guideline Web sites, and abstracts of relevant annual meetings (1990 to September 2012) were searched. Internal and external reviews were conducted, with final approval by the Program in Evidence-Based Care and the Sarcoma Disease Site Group.

Recommendations

Treatments

• Surgery with or without rt can be a reasonable treatment option for patients with desmoid tumours whose surgical morbidity is deemed to be low.

• The decision about whether rt should be offered in conjunction with surgery should be made by clinicians and patients after weighing the potential benefit of improved local control against the potential harms and toxicity associated with rt.

• Depending on individual patient preferences, systemic therapy alone or rt alone might also be reasonable treatment options, regardless of whether the desmoid umours are deemed to be resectable.

Follow-Up Strategies

• Undergo evaluation for rehabilitation (occupational therapy or physical therapy, or both).

• Continue with rehabilitation until maximal function is achieved.

• Undergo history and physical examinations with appropriate imaging every 3–6 months for 2–3 years, and then annually.

1. INTRODUCTION

Desmoid tumours, also known as aggressive fibromatoses, are rare neoplasms. The global incidence of desmoid tumours is 2–4 new cases per million population per year^1,2. Although desmoid tumours are non-malignant and non-metastasizing, and seldom cause death, they are locally invasive and exhibit a high risk for recurrence². Generally, they are asymptomatic, but they can cause significant local and neuropathic pain, can compress local structures, and might limit function. Some tumours can grow to a large size; others remain stable without intervention. Clinical observation is therefore a preferable management option in patients without symptoms.

Several treatments are available for patients with desmoid tumour when the decision has been made to pursue active (non-observational) treatment such as surgery, radiotherapy (rt), systemic therapy, or a combination of those options. However, there is little consensus about which treatment strategy leads to a lower recurrence rate and less long-term toxicity. Thus, the Sarcoma Disease Site Group (dsg), in association with the Program in Evidence-Based Care (pebc) of Cancer Care Ontario, decided to develop a clinical guideline for Ontario addressing two research questions.

2. QUESTIONS

• When the decision has been made to pursue active treatment for a patient with desmoid tumour, what is the optimal treatment option—considering surgery, rt, systemic therapy, and any combinations thereof—for improving clinical outcomes (that is, rates of relapse-free survival, local control, progression-free survival, response, and toxicity, and patient-reported outcomes, among others)?

• After primary treatment, what are reasonable follow-up strategies for patients with desmoid tumours?

3. METHODS

This guideline, developed by Cancer Care Ontario’s pebc and the Sarcoma dsg, used the methods of the practice guidelines development cycle³. For this project, the core methodology used to develop the evidentiary base was the systematic review. The pebc is mandated to post its approved practice guidelines on the Cancer Care Ontario Web site (http://www.cancer care.on.ca/) for dissemination to Ontario oncologists⁴.

3.1. Literature Search

For the second research question of this guideline, the authors agreed at the project planning stage that few or no original studies in the literature compared various follow-up strategies or intervals, and that the Sarcoma dsg would make final recommendations based on existing clinical practice guidelines and the clinical experience of experts in Ontario. The systematic review for the first research question is published separately⁵. Briefly, the medline and embase databases, and the Cochrane Library (January 1990 to September 2012); guideline Web sites; and the American Society of Clinical Oncology and Connective Tissue Oncology Society annual meeting abstracts (January 2009 to September 2012) were searched. Preplanned study selection criteria were used to screen the literature retrieved.

3.2. Internal Review

Before this draft report was submitted for external review, it was reviewed and approved by the Sarcoma dsg members and by the pebc Report Approval Panel (rap), which has a membership of three: two oncologists with expertise in clinical and methodology issues and one methodologist.

3.3. External Review

The pebc external review process is two-pronged: a targeted peer review obtains direct feedback on the draft report from a small number of specified content experts, and a professional consultation facilitates dissemination of the final guidance report to Ontario practitioners.

3.3.1. Targeted Peer Review

During the guideline development process, the Sarcoma dsg identified 9 targeted international peer reviewers considered to be clinical or methodology experts on the topic. Several weeks before completion of the draft report, the nominees were contacted by e-mail and asked to serve as reviewers. The draft report and a questionnaire were sent by e-mail to the 5 reviewers who consented to participate. The questionnaire consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a guideline. Written comments were invited. Follow-up reminders were sent at 2 weeks (e-mail) and at 4 weeks (telephone call).

3.3.2. Professional Consultation

Feedback was obtained through a brief online survey of health care professionals who are the intended users of the guideline in Ontario. Clinicians in the pebc database who were identified using the key word “sarcoma” (n = 51) were asked to rate the overall quality of the guideline and to indicate whether they would use or recommend it. Written comments were invited. Participants were contacted by e-mail and directed to the survey Web site, where they were provided with access to the survey, the guideline recommendations, and the evidentiary base.

4. RESULTS

4.1. Literature Search Results

For the first research question, 3791 citations were identified in the searches of medline, embase, and the Cochrane Central Register of Controlled Trials. A search of abstracts from the American Society of Clinical Oncology and the Connective Tissue Oncology Society annual meetings yielded no abstracts that met the study selection criteria. The reference lists of the included articles were hand-searched, and no further eligible papers were found. The quality of the evidence in the forty-six full-text articles^6–51 and one systematic review⁵² that met the preplanned study selection criteria was poor to moderate⁴.

For the second research question, one consensus guideline was identified. That guideline—Soft Tissue Sarcoma, from the U.S. National Comprehensive Cancer Network (version 2.2012)⁵³—provided recommendations on follow-up strategies in patients with desmoid tumours. The quality of the guideline was assessed using the agree ii instrument (Table i)⁵⁴.

TABLE I.

Results ofagree ii quality rating for the U.S. National Comprehensive Cancer Network guideline^a on soft tissue sarcoma, version 2.2012

agree ii domain score (%)
Scope and purpose	Stakeholder involvement	Rigour of development	Clarity and presentation	Applicability	Editorial independence
64.8	40.7	25.7	87.0	22.2	61.1

^aAdopted from the Standards and Guidelines Evidence Inventory of Cancer Guidelines developed by the Canadian Partnership Against Cancer (http://cancerguidelines.ca/Guidelines/inventory/index.php).

4.2. Internal Review

The draft guideline prepared by the authors was circulated to the Sarcoma dsg members for review and discussion. The authors incorporated the comments from the dsg members into the draft guideline and forwarded the resulting document to the pebc’s rap.

The following key issues were raised by the rap:

• The reference for “wide margin” appears only in the recommendation. It is not referred to in the introduction, evidence, or discussion.

• Is overall survival not an important outcome?

• Studies that compare surgery with surgery plus rt, rt with surgery, and rt with surgery plus rt are addressing different questions.

• Where does drug treatment fit in sequentially? Is it always after surgery and rt having failed, or are there patients for whom drug treatment would be a primary option?

• There may be improvement in local regional control. Is this a good enough outcome?

4.3. Consensus Process

Feedback received from the rap was addressed by the authors⁴. On July 9, 2013, the revised guideline was sent to the Sarcoma dsg members for final approval. Of the 13 members of the Sarcoma dsg, 10 cast votes and 3 abstained (77% response rate). Of the 10 who cast votes, all approved the document (100%).

4.4. External Review

After approval of the document at the internal review, the authors circulated the draft document to external review participants on September 5, 2013, for review and feedback.

4.4.1. Targeted Peer Review

Responses were received from 4 reviewers by October 17, 2013. Table ii summarizes key results of the feedback survey. Main concerns expressed in the written comments were these:

• We must be careful in emphasizing even “microscopically negative margins” for not a metastasizing tumour. At times surgery is indicated to palliate, knowing that positive margins will result. This is acceptable when decided about by an experienced sarcoma board.

• Under Introduction in section 2, desmoids are rarely truly asymptomatic and most patients find them at least annoying. Experts understand the subtlety, but given that these are guidelines for potentially less experienced providers, it might be better to clarify that unless the mass is growing, causing true pain, or easy to remove, observation is not only acceptable but may be preferable, even if mildly “symptomatic.”

• Combinations of a nonsteroidal anti-inflammatory drug (often sulindac) and tamoxifen are commonly used as primary treatment of desmoids. Is the evidence entirely anecdotal (that is, the studies do not meet the criteria for inclusion in the guideline)? If so, it may be important to mention this. Similarly for the use of doxorubicin (and liposomal forms) and/or dacarbazine.

• Some places are not very clear. In bullet 2 under Key Evidence, “Goy et al. showed a similar result” is confusing (intended to mean similar results to Spear et al., but could be read as not difference between groups); on page 3, the second paragraph under Justification for Recommendation does not seem to fit there.

TABLE II.

Responses to eight items on the targeted peer reviewer questionnaire

Item	Reviewer ratings (n=4)
	Lowest quality				Highest quality
	1	2	3	4	5
Rate the guideline development methods.	0	0	0	0	4
Rate the guideline presentation.	0	0	0	1	3
Rate the guideline recommendations.	0	0	0	2	2
Rate the completeness of reporting.	0	0	0	1	3
Does this document provide sufficient information to inform your decisions? If not, what areas are missing?	0	0	1	2	1
Rate the overall quality of the guideline report.	0	0	0	3	1
	Strongly disagree				Strongly agree
	1	2	3	4	5
I would make use of this guideline in my professional decisions.	0	0	1	1	2
I would recommend this guideline for use in practice.	0	0	0	2	2

4.4.2. Professional Consultation

The notification e-mail was sent on September 5, 2013, and the consultation period ended on October 17, 2013. Among the 14 responders (27%), 7 indicated that they had no interest in this area or were currently unavailable to review the guideline. Table iii summarizes the key results of the feedback survey from the other 7 clinicians. The main written comments were these:

• One shortcoming: there is no definition of a “microscopically negative margin.”

• Who would be recommended to follow up the patients?

TABLE III.

Responses to three items on the professional consultation survey

Item	Ratings
	Lowest quality				Highest quality
	1	2	3	4	5
Rate the overall quality of the guideline report.	0	0	14	57	29
	Strongly disagree				Strongly agree
	1	2	3	4	5
I would make use of this guideline in my professional decisions.	0	14	0	43	43
I would recommend this guideline for use in practice.	0	0	0	43	57

5. PRACTICE GUIDELINE

The present report integrates the feedback obtained through the external review process with the final approval given by the Sarcoma dsg and the pebc rap⁴.

5.1. Recommendation 1: Optimal Treatment Options

• Surgery with or without rt can be a reasonable treatment option for patients with desmoid tumours whose surgical morbidity is deemed to be low.

• The decision about whether rt should be offered in conjunction with surgery should be made by clinicians and patients after weighing the potential benefit of improved local control against the potential harms and toxicity associated with rt.

• Depending on individual patient preferences, systemic therapy alone or rt alone might also be reasonable treatment options, regardless of whether the desmoid tumours are deemed to be resectable.

5.1.1. Qualifying Statements

• Given the variability of the clinical course of desmoid tumours and the potential for complications that can arise as a result of therapy, the cases of all patients with desmoid tumours who will undergo active treatment should be discussed by an experienced multidisciplinary sarcoma team, and the treatment plan should take into consideration patient preferences.

• Negative margin status (defined as surgical re-section with microscopically negative margins) should be achieved, if possible, for a patient who is managed surgically.

• Young patients might have a higher risk for local relapse.

• The optimal dose of rt, used as a surgical adjuvant or as primary therapy, has not been defined. Reported radiation doses have ranged from 10 Gy to 75 Gy for rt used alone, and from 9 Gy to 72 Gy for rt used as an adjuvant to surgery. Complication rates have been reported to increase significantly with doses exceeding 56 Gy¹².

• Imatinib and the cytotoxic combination of vinblastine and methotrexate are associated with manageable toxicities. Results are considered reasonable enough to merit discussion as an option for previously untreated patients or after failure of surgery or rt (or both). However, other combinations of nonsteroidal anti-inflammatory drugs (often sulindac); tamoxifen or doxorubicin (and its liposomal forms), with or without dacarbazine; and dacarbazine alone have, among other agents, occasionally been used as primary treatment of desmoids in some clinical centres. Because of small patient numbers, studies of these latter chemotherapy options did not meet our criteria for inclusion in the guideline.

5.1.2. Key Evidence

Of five retrospective comparative studies that conducted a multivariate analysis^{10–12,18,23}, one did not find a significant difference in patient characteristics at baseline²⁶. Three single-arm phase ii studies of systemic therapy^16,24,29 serve as the primary evidence base for the recommendations.

Spear et al.¹¹ reported that, compared with surgery alone, surgery plus rt led to a higher local control rate at 5 years (72% vs. 69%, p = 0.03). At 6 years in patients with microscopically positive margins, Goy et al.¹⁰ reported results similar to those of the Spear et al. study (78% vs. 32%, p = 0.02). Ballo et al.¹² reported that, compared with surgery alone, surgery plus rt or rt alone both led to a higher local control rate at 10 years (75% vs. 76% vs. 62%, p = 0.04).

In a comparison of surgery plus rt with surgery alone for patients with primary desmoid tumours, Sorensen et al.¹⁸ did not find a significant difference at 5 years in the rate of relapse-free survival (78% vs. 69%, p = 0.10) or of local control (82% vs. 68%, p > 0.05).

When surgery plus rt was compared with rt alone, Guadagnolo et al.²³ (primary desmoid tumours) and Rϋdiger et al.²⁶ (recurrent desmoid tumours) found no statistically significant differences in local control between the two groups at 4 or 10 years. The main complications of surgery included the need for reconstructive surgery, above-the-knee amputation, permanent disability, and chronic pain. The main radiation-related complications included healing problems, fibrosis, fracture, cellulitis, and secondary malignancy, among others.

In the five studies that conducted a multivariate analysis, three^10,11,18 included margin status in the model, and all three showed that positive margin status led to a worse rate of local control. Four studies indicated that younger age (≤30 years in three studies^12,18,23, ≤18 in one study¹¹) was predictive of a higher local failure rate.

In three single-arm phase ii studies, imatinib alone led to a progression-free survival rate of 58% at 3 years²⁴ and 55% at 2 years, with some grade 3–4 toxicities including rash, neutropenia, myalgia, asthenia, or a secondary cancer (clear cell renal carcinoma)²⁹; and methotrexate plus vinblastine led to a progression-free survival rate of 67% at 10 years, with 93% of patients developing grade 3 or 4 leukopenia¹⁶.

5.1.3. Justification for Recommendation 1

Despite the large number of publications reporting outcomes in patients treated for desmoid tumours, the data are of poor-to-moderate quality, and no studies with a multivariate analysis compared the effectiveness of surgery with that of chemotherapy or the effectiveness of rt compared with that of chemotherapy. Because of the absence of good-quality evidence, little consensus has developed among clinicians about the optimal treatment for patients with desmoid tumours. Because desmoid tumours are non-malignant and non-metastasizing, and seldom cause death², local relapse is the main concern. Surgery, rt, systemic therapy, and the combination of surgery and rt have all shown moderate success in achieving local control in these patients. Therefore, in the authors’ judgment, all of these modalities can be considered reasonable options, and the decision to use one modality over another should be made in conjunction with experts on a multidisciplinary sarcoma team. Given the trade-offs between the possible benefits and the potential harms of the various treatment options, patients should, as a part of the treatment decision-making process, be informed of the absence of definitive data favouring a particular type of treatment plan, and patient preferences should be taken into consideration.

5.2. Recommendation 2: Optimal Follow-Up Strategies

Cancer Care Ontario supports adoption of the follow-up strategy recommendations of the National Comprehensive Cancer Network’s Soft Tissue Sarcoma guideline (version 2.2012). Specifically, it is recommended that patients with desmoid tumours who have received primary treatment in Ontario

• undergo evaluation for rehabilitation (occupational therapy or physical therapy, or both).

• continue with rehabilitation until maximal function is achieved.

• undergo history and physical examinations with appropriate imaging every 3–6 months for 2–3 years, and then annually.

5.2.1. Qualifying Statement

If active treatment is not pursued, it is acceptable for patients to be followed annually by a sarcoma surgeon or any other member of the sarcoma team. Patients who are asymptomatic and who have clinically stable lesions can be discharged with the option of returning for treatment if symptoms or growth develop.

5.2.2. Justification for Recommendation 2

For the second objective of this guideline, the authors agreed at the project planning stage that the literature contained few or no original studies comparing various follow-up strategies or intervals. After discussion, the members of the Sarcoma dsg agreed that the follow-up strategies from the National Comprehensive Cancer Network’s Soft Tissue Sarcoma guideline (version 2.2012)⁵³ were reasonable, given standard clinical practice in the Ontario context.

6. FUTURE RESEARCH

By January 21, 2013, only four ongoing single-arm phase ii trials in the U.S. National Cancer Institute clinical trials database met our study selection criteria. Those four studies are investigating the effects of imatinib alone, toremifene alone, sulindac plus tamoxifen, and rt in patients with desmoid tumours⁴. Well-designed, high-quality randomized controlled trials, phase ii trials, or prospective comparative studies are needed to compare various treatment options, the efficacy of various rt and systemic therapy strategies (including varying doses), and specific follow-up protocols in the target patients.

7. UPDATING

All pebc documents are maintained and updated as described in the pebc document assessment and review protocol.

9. CONFLICT OF INTEREST DISCLOSURES

The pebc is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the pebc is editorially independent from its funding source. MG declared that she has published a systematic review on local control in patients with extra-abdominal desmoid tumours in Rare Tumours⁵⁵. The remaining authors declared they had no financial or professional conflicts of interest.