Percutaneous Cryoablation Provides Disease Control for Extra-Abdominal Desmoid-Type Fibromatosis Comparable with Surgical Resection

Abstract

Purpose.

The aim of this study was to determine outcomes and prognostic factors for patients with primary and locally recurrent extraabdominal desmoid tumors who underwent percutaneous cryoablation, and to compare with patients treated with surgery.

Methods.

Group characteristics were compared using Fisher’s exact test, and propensity score matching was performed using the nearest-neighbor approach. Kaplan–Meier and log-rank analyses were used to evaluate the variation in first local recurrence and disease control, while multivariate Cox regression was used to identify factors associated with first local recurrence. All statistical tests were two-sided and a p-value of 0.05 was considered statistically significant.

Results.

Twenty-two cryoablation patients were matched with 33 surgical patients (n = 55). Median follow-up after cryoablation was 16.3 months versus 14.9 months after surgery. Two-year local recurrence-free survival (LRFS) was 59% after cryoablation and 71% after surgery, and median LRFS was 26.6 months after cryoablation but was not reached after surgery. Two-year disease control for all patients was 85%, however median disease control was not reached in either the cryoablation or surgery groups. There was no significant difference in LRFS or disease control between matched cryoablation and surgical patients. No local recurrences occurred after the first cryoablation in patients with zero or one of the following risk factors: tumor size > 5 cm, age ≤ 25 years, or locally recurrent disease. All patients with two or more of these risk factors recurred locally after the first cryoablation.

Conclusion.

Percutaneous cryoablation of primary and locally recurrent extra-abdominal desmoid tumors provides freedom from first local recurrence and long-term disease control comparable with surgery.

Standardizing the management of desmoid-type fibromatoses, also referred to as desmoid tumors, is a challenge due to their unpredictable biologic behavior.^1–6 Active surveillance is often considered at initial presentation since desmoid tumors have no metastatic potential, and rarely is extent or morbidity of subsequent therapy affected if ultimately necessary.⁷ In patients with progressive or symptomatic disease, or with tumors in whom progression would lead to significant morbidity, intervention is considered. Although surgical resection was previously considered the gold standard for treatment, radiation, systemic chemotherapy, and targeted therapies can be primary therapies for desmoid patients given the potential morbidity of operative procedures; less invasive forms of therapy are preferred over more invasive options to minimize treatment-related toxicities in this indolent disease.^1,3,8–15 This has led to an investigation to define the role of minimally invasive ablative interventions such as cryotherapy in carefully selected patients with desmoids that require treatment.^16–20

Pilot studies exploring whether percutaneous cryoablation leads to local control of desmoid tumors have shown favorable results.^21,22 Until recently, the use of cryoablation has been limited to patients whose disease recurred following other forms of treatment or to patients who were poor surgical candidates.²² Although previous studies highlighted the efficacy of cryoablation as salvage therapy, its effectiveness compared with surgical resection, and its appropriateness in the management of desmoid tumors that have progressed following active surveillance, remains unknown.^23,24 The purpose of this study was to determine outcomes and prognostic factors for patients with primary and locally recurrent extra-abdominal desmoid tumors who underwent percutaneous cryoablation. Results are directly compared with treated patients undergoing surgical resection to provide evidence regarding the relative efficacy of the treatments, which may have a very different morbidity risk.

MATERIALS AND METHODS

Patient Cohort

After receiving Institutional Review Board approval, we conducted a Health Insurance Portability and Accountability Act-compliant review of soft tissue sarcoma and desmoid-type fibromatosis databases to identify all patients with biopsy-confirmed desmoid-type fibromatosis who were treated with cryoablation or surgery between February 2008 and October 2017.

Cohort Demographics and Clinicopathologic Characteristics

Clinicopathologic and outcomes data from surgically resected specimens were obtained from a prospectively maintained institutional soft tissue sarcoma database. Clinicopathologic and outcomes data from those undergoing cryoablation were collected retrospectively by chart review. Age was defined as age at diagnosis, and presentation status was defined as either primary desmoid tumor or locally recurrent desmoid tumor. Axilla, shoulder joint, buttock, groin, and head and neck lesions were grouped as extremity lesions,³ and intra-abdominal and retroperitoneal lesions were considered collectively. Size was defined according to the longest axis of the tumor. All cryoablation patients included in the cohort had complete ablation that included tumor margins (A0), and all surgical patients included in the cohort had negative gross resection margins (R0/R1). Since there were no patients treated with cryoablation who were > 65 years of age, had retroperitoneal or intra-abdominal tumors, or who had tumors ≥ 10 cm, surgical patients with these characteristics were excluded from the study.

Percutaneous Cryoablation Technique and Procedure Information

After administering general anesthesia, cryoablation was performed using either the Visual-ICE cryoablation system (Galil, Arden Hills, MN, USA) or the Endocare cryoablation system (Healthtronics, Austin, TX, USA). Cryoablation applicators (cryoprobes) were placed under computed tomography (CT) or magnetic resonance (MR) guidance. When necessary, a 40:1 mixture of normal saline and Omnipaque 300 (GE Healthcare, France) was used for hydrodissection. Two freeze-thaw cycles were completed during every treatment session.²⁵ Patients were admitted for post-procedure monitoring.

Data including radiologic guidance modality (CT or MR), number of cryoprobes used, freeze-thaw cycle settings, and the use of hydrodissection were collected. Indications for treatment, length of hospitalization, immediate post-procedure complications, post-procedure pain assessment scores, symptomatic benefit at first follow-up, and delayed complications at first follow-up were recorded. Patients were monitored with clinical examinations and by MR imaging at 3–12 months post-procedure depending on time from treatment. Imaging reports were provided by board-certified diagnostic radiologists.

Clinical Endpoints

Local recurrence-free survival (LRFS, in months) after the initial treatment, and disease control (in months) after one or more treatments, were the primary endpoints for both cryoablation and surgery. Events represent instances of local recurrence, which were defined as follow-up imaging demonstrating new tumor enhancement or interval tumor enlargement not attributable to post-treatment inflammatory changes. LRFS was defined as the time from initial cryoablation or surgery to first local recurrence. Since non-A0 and non-R0/R1 patients were excluded, the first local recurrence was considered an event when calculating LRFS. Patients were censored if the most recent follow-up imaging demonstrated no evidence of local recurrence.

Disease control was defined as the time from first cryoablation or surgery to the first local recurrence that was uncontrollable. The first local recurrence (or any subsequent local recurrence) was considered controllable and hence not an event if repeat cryoablation or surgery deemed the patient free of radiographically detectable disease. Patients were censored if the most recent follow-up imaging demonstrated no evidence of local recurrence.

Statistical Analysis

Patient demographics and clinicopathologic characteristics were compared using Fisher’s exact test. Patients treated with cryoablation were matched with surgical patients by propensity score matching using the nearest-neighbor approach in order to account for differences between groups. Kaplan–Meier curves were used to estimate event–time distributions for first local recurrence and disease control endpoints, and log-rank tests were used to compare differences between treatment groups. Cox proportional hazards models were used to evaluate independent risk factors associated with first local recurrence and disease control. A separate descriptive analysis was then performed using the cryoablation cohort in order to evaluate factors predictive of first local recurrence specifically following cryoablation. All statistical tests were two-sided, and a p-value of 0.05 was considered statistically significant.

RESULTS

Patient Demographics and Clinicopathologic Characteristics

Between 2008 and 2017, 146 patients underwent percutaneous cryoablation (n = 22, 15%) or surgical resection (n = 124, 85%) for a desmoid tumor. Of the 124 surgical patients, 13 were older than 65 years of age, 46 had retroperitoneal or intra-abdominal desmoids, and 30 had tumors ≥10 cm. Overall, 67 surgery patients who had any one of these characteristics were excluded from the analysis, for a total of 79 included surgical resection patients (Table 1).

TABLE 1.

Patient demographics and clinicopathologic characteristics prior to propensity score matching

	Treatment
Characteristic	Overall	Cryoablation	Surgery	p-Valuea
No. of patients	79	22	57
Age, years				0.500
≤25	13 (16)	5 (23)	8 (14)
> 25 and ≤65	66 (84)	17 (77)	49 (86)
Sex				0.400
Male	21 (27)	4 (18)	17 (30)
Female	58 (73)	18 (82)	40 (70)
Presentation status				0.004
Primary	62 (78)	12 (55)	50 (88)
Locally recurrent	17 (22)	10 (45)	7 (12)
Tumor site				0.019
Abdominal wall	25 (32)	11 (50)	14 (25)
Chest wall	17 (22)	6 (27)	11 (19)
Extremity	26 (33)	2 (9)	24 (42)
Other	11 (14)	3 (14)	8 (14)
Tumor size, cm				0.300
≤ 5	35 (44)	12 (55)	23 (40)
> 5 and < 10	44 (56)	10 (45)	34 (60)

Data are expressed as n (%)

^aStatistical tests performed: Fisher’s exact test

Overall, 13 patients (16%) were ≤ 25 years of age and 66 patients (84%) were > 25 and ≤ 65 years of age. Patients were more commonly female (n = 58, 73%) and more commonly presented for the treatment of a primary tumor (n = 62, 78%). Thirty-five patients (44%) had tumors ≤ 5 cm and 44 patients (56%) had tumors > 5 and < 10 cm. Twenty-five tumors (32%) were located in the abdominal wall, 17 (22%) in the chest wall, 26 (33%) in the extremities, and 11 (14%) were located elsewhere.

Prior to propensity score matching, treatment groups significantly differed on several clinical characteristics. A greater proportion of patients treated with cryoablation presented with locally recurrent disease compared with patients treated with surgery (n = 10 [45%] vs. n = 7 [12%], p = 0.004). There was also a significant difference in tumor site between the cryoablation and surgery groups (p = 0.019) prior to propensity score matching; however, there were no significant differences between groups after propensity score matching.

Percutaneous Cryoablation Procedures

All cryoablation procedures were performed by a board-certified interventional radiologist using general anesthesia (electronic supplementary Fig. S1 and Table S1), and were performed under CT (n = 19, 86%) or MR (n = 3, 14%) guidance.

An average of 5.1 cryoprobes were used per treatment (range 2–9). Mean freeze-thaw cycle settings were freeze-thaw cycle, 29.1 min; first freeze, 10.1 min; first thaw, 8.8 min; second freeze, 9.6 min; and active thaw, untimed. Hydrodissection was performed in 14 cases (64%) and was used more for primary tumors than for locally recurrent tumors (83% vs. 40%, p = 0.035).

Indications for cryoablation included pain (shooting pain, discomfort or tenderness at the tumor site; n = 19) or a palpable mass (n = 3), while immediate post-procedure complications following initial cryoablation included the following. One patient with a chest wall desmoid experienced an expected pneumothorax immediately post-procedure, which resolved following chest tube placement; the patient was discharged without further complications 3 days post-procedure. No other immediate post-procedure complications were observed following initial cryoablation, with the exception of pain at the tumor/treatment site, which occurred in all patients. The mean post-procedure pain score was 5.8 out of 10. Patients were admitted for an average of 1.3 nights in the hospital after cryoablation, with only three patients spending more than one night in the hospital.

Patients underwent first follow-up at 3 or 6 months post-cryoablation with an interventional radiologist and/or surgical oncologist (mean 4.0 months). At first follow-up, nine patients (41%) had no symptoms, five patients (23%) had persistent mild pain or discomfort at the tumor site that was improved when compared with their pre-procedure pain, four patients (18%) had pain or discomfort at the tumor site that resolved within 2 weeks post-procedure, two patients (9%) had persistent numbness at the tumor site, and one patient (4.5%) had progressive severe pain at the tumor site that required repeat cryoablation. A single patient (4.5%) who developed an expected immediate post-procedure pneumothorax after chest wall tumor ablation had complete resolution of pneumothorax-related pleuritic chest pain at first follow-up. All patients had resumed activities of daily living by first follow-up.

Clinicopathologic Characteristics Associated with First Local Recurrence

Prior to propensity score matching, univariate analysis was performed in order to identify clinicopathologic characteristics associated with first local recurrence following treatment. Clinicopathologic characteristics found to be significantly associated with first local recurrence were age > 25 and ≤ 65 years (ref = age ≤ 25 years; hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.12–0.90, p = 0.030), presenting with locally recurrent tumor (ref = primary tumor; HR 3.27, 95% CI 1.24–8.60, p = 0.017), and extremity tumor site (ref = abdominal wall; HR 3.71, 95% CI 1.11–12.40, p = 0.034) [Table 2]. Sex, tumor size, and treatment modality were not found to be univariately associated with first local recurrence. Presenting with a locally recurrent tumor remained significantly associated with first local recurrence when incorporated into a multivariate model with treatment modality (HR 1.10, 95% CI 0.04–2.10, p = 0.043).

TABLE 2.

Clinicopathologic characteristics predictive of local recurrence prior to propensity score matching

	Univariate		Multivariate
Variable	HR (95% CI)	p-Value	HR (95% CI)	p-Value
Sex (vs. male)
Female	2.65 (0.61–11.6)	0.200
Age, years (vs. ≤ 25 years)
> 25 and ≤ 65	0.33 (0.12–0.90)	0.030
Treatment modality (vs. surgery)
Cryoablation	2.08 (0.79–5.48)	0.140	−0.46 (−1.5–0.56)	0.400
Presentation status (vs. primary)
Locally recurrent	3.27 (1.24–8.60)	0.017	1.10 (0.04–2.10)	0.043
Tumor site (vs. abdominal wall)
Chest wall/othera	1.23 (0.33–4.59)	0.800
Extremity	3.71 (1.11–12.40)	0.034
Treated tumor size, cm (vs. ≤ 5)
> 5 and <10	1.20 (0.45–3.16)	0.7

HR hazard ratio, CI confidence interval

^aChest wall and other tumors were grouped together due to the low incidence of local recurrence events in those groups

Local Recurrence-Free Survival and Disease Control Following Treatment

Using the nearest-neighbor approach, 22 cryoablation patients were matched with 33 surgical patients, for a total of 55 patients; 15 of these 55 patients experienced a local recurrence during follow-up time (7 cryoablation patients, 8 surgery patients). Median follow-up of the entire matched cohort was 15.5 months, and median follow-up for patients treated with cryoablation was 16.3 months versus 14.9 months for surgical patients.

Median LRFS for the entire matched cohort was not reached, while median LRFS was 26.6 months after cryoablation and was not reached after surgical resection. Two-year LRFS was 67% (54–83%) for the entire matched cohort, 59% (37–94%) after cryoablation, and 71% (55–90%) after surgical resection. There was no significant difference in LRFS between matched patients who underwent cryoablation or surgical resection (p = 0.300) (Fig. 1a).

FIG. 1.

Comparison of a local recurrence-free survival and b proportion of patients in whom disease was controlled between cryoablation and surgery

Nine patients had an uncontrollable local recurrence during follow-up (two cryoablation patients and seven surgery patients). Median disease control was not reached for the entire matched cohort and was not reached for cryoablation or surgery when considered separately. There was no significant difference in disease control between matched patients who underwent cryoablation or surgical resection (p = 0.380) (Fig. 1b).

Salvage Therapy for Local Recurrence Following Cryoablation for Desmoids

Of the 22 patients treated with cryoablation, 2 of 12 patients (16%) treated for primary disease and 5 of 10 patients (50%) treated for locally recurrent disease recurred after one treatment. After repeat cryoablation of local recurrences, disease was ultimately controlled in 20 of 22 patients (91%), including 12 of 12 patients (100%) who presented with primary disease. The two patients with primary disease who were treated with repeat cryoablation remained free of recurrence 3 and 15 months following treatment. Of the five patients who presented with locally recurrent desmoids who again had local recurrence after the first cryoablation, one regressed spontaneously and four were treated with repeat cryoablation. Of the four patients treated with repeat cryoablation, one experienced another local recurrence that was treated with systemic therapy, while the other three underwent repeat cryoablation and are now without evidence of local recurrence 24, 55, and 91 months since their last cryoablation procedure (electronic supplementary Fig. S2).

Factors Predictive of Local Recurrence Following Cryoablation

In the cryoablation cohort, patients whose tumors recurred tended to have tumors >5 cm in diameter (n = 5, p = 0.033), be ≤ 25 years of age (n = 4, p = 0.010), and have been treated for locally recurrent disease (n = 5, p = 0.053) [Fig. 2]. There was no association between local recurrence and tumor site or patient sex. All patients with tumors > 5 cm or who were diagnosed before age 25 years had local recurrences diagnosed by 27 months post-procedure, while 3-year LRFS was 82% and 68% in patients with tumors ≤ 5 cm and in patients older than 25 years of age, respectively. Two-year LRFS in patients with primary disease was 89%, versus 29% for patients who presented with locally recurrent disease (p = 0.050). After one cryoablation, no local recurrences were observed in patients who had zero or one of the following risk factors: tumor size >5 cm, age ≤ 25 years, or locally recurrent disease. All patients with two or more of these risk factors experienced local recurrence after one cryoablation (Fig. 3).

FIG. 2.

First local recurrence-free survival following cryoablation according to clinicopathologic characteristics. a Tumor size, b patient age, and c primary versus recurrent disease

FIG. 3.

Local recurrence-free survival according to number of risk factors

DISCUSSION

Active observation and medical therapy are becoming first-line therapy for desmoid tumors; however, in a subset of patients with progressive disease, local interventions may be appropriate. We sought to examine whether percutaneous cryoablation, which is potentially associated with a reduced risk of morbidity compared with surgery, has the potential to provide disease control in this population. Our findings suggest that percutaneous cryoablation is an effective alternative to surgical resection in the management of primary and locally recurrent abdominal wall, chest wall, and extremity desmoid tumors. Given that percutaneous cryoablation, with or without repeat intervention, provides freedom from first local recurrence and long-term disease control comparable with surgical resection, cryoablation is an appropriate treatment consideration for select patients with primary and locally recurrent extra-abdominal desmoid-type fibromatosis.

This study identified several risk factors that increase the risk of local recurrence after the first cryoablation, including tumor size > 5 cm, age ≤ 25 years, and presenting with locally recurrent disease. All patients with zero or one risk factor had their disease controlled after one cryoablation, while patients with two or more risk factors universally recurred. These results can help to guide patient selection for cryoablation, as older patients with small to moderately sized primary tumors have a higher likelihood of having their disease controlled with one cryoablation. Younger patients with large, recurrent tumors should be advised that they are at greater risk of developing a local recurrence, but that additional cryoablation procedures can be safely employed to provide lasting disease control.

The implications of this study are limited to the treatment of abdominal wall, chest wall, and extremity desmoids. Most intra-abdominal desmoids arise from the small bowel mesentery and grow in obscure patterns, making it challenging to create safe, accurate cryoablation zones that encompass the entire tumor while avoiding non-target structures.^3,26 Although visualization of the ice ball under image guidance is an advantage of cryoablation over other ablation techniques, surgical resection remains the standard of care as it permits direct visualization of disease extent and allows for a greater opportunity for complete tumor removal.²⁷

The current study identified extremity tumors as having a markedly elevated risk of local recurrence after any treatment (HR 3.71, p = 0.034) compared with abdominal wall desmoids. Although this study only included two cases of extremity desmoids treated with cryoablation, other groups have reported that these lesions are difficult to treat percutaneously.²³ Desmoid tumors of the extremities can cause significant morbidity, including neuropathy, immobility, and disfigurement. Unresectable lesions are best treated with targeted medical therapy (sorafenib) or doxil chemotherapy. While surgery or medical therapy is currently preferred for extremity desmoids, cryoablation could be beneficial for a select group of extremity desmoids that are ≤ 5 cm, relatively well-circumscribed within muscle, and have not yet involved vital neurovascular structures.

Several studies have shown large tumor size to be a predictor of desmoid progression after surgery and some authors have postulated that cryoablation may be ineffective for controlling large lesions.^1,3,28,29 The majority of tumors included in this cohort were small to moderately sized, but cryoablation of larger desmoid tumors is becoming more common.^4,22,26 At other institutions, cryoablation has been used to treat lesions up to 13.2 cm in diameter.^23,30 While the findings of this study suggest that desmoids > 5 cm may be associated with a greater risk of local recurrence after cryoablation, repeat intervention can be safely used to achieve disease control and does not preclude future surgical resection. Although tumor size was reported in greatest axial dimension, it may be interesting, in future studies, to perform multivariate analyses using tumor volumetric data.

When dealing with massive abdominal wall desmoid tumors, post-surgical defects prompting abdominal wall reconstruction are problematic for patients and surgeons alike.^31,32 Complication rates of up to 42% have been described after abdominal wall reconstruction, including wound infection, ventral herniation, bowel erosion, and evisceration.^32,33 Patients often experience long-term discomfort and mesh sensation after large abdominal wall surgical repairs.³⁴ Radical excision of chest wall desmoids presents its own unique challenges as extension into adjacent structures may require resection of muscle, ribs, the sternum, or even neurovascular structures to obtain negative surgical margins.^35,36 In contrast, although none were observed in the current study, reported complications following cryoablation of desmoids included pain, emesis, infection, and neuropathy.^21,23,24 Cryoshock, a systemic inflammatory response to cryoablation, could theoretically occur.²⁷ The differing complication profile between cryoablation and surgery should prompt physicians to carefully assess patient goals of care in order to choose the optimal treatment modality.

This study has several limitations. As with all other desmoid-type fibromatosis investigations, this was a retrospective study, and, given alterations in therapeutic algorithms over time, does not represent patients consecutively managed at our institution. Due to the small sample size and limited number of outcome events, only one additional variable was included in the multivariate analysis, limiting assessment for confounding variables. The findings of the current study cannot be generalized to patients with familial adenomatous polyposis-associated desmoid-type fibromatosis, patients > 65 years of age, patients with retroperitoneal or intra-abdominal tumors, or patients with tumors ≥ 10 cm, as such patients were excluded from this study. The follow-up protocol for cryoablation and surgical patients was not necessarily the same. Cryoablation patients typically had more frequent MR follow-up, which could create a lead time bias since recurrences would be detected sooner. Longer follow-up is needed to more accurately evaluate the durability of disease control by cryoablation.

CONCLUSION

Percutaneous cryoablation is an effective alternative to surgical resection in the management of primary and locally recurrent desmoid tumors in the abdominal wall, chest wall, and extremities when local interventions are required. With regular monitoring and repeat intervention to treat local recurrence, cryoablation can provide freedom from first local recurrence and long-term disease control of primary and locally recurrent extra-abdominal desmoid tumors comparable with surgical resection.