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Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp. 1785-1791 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.5015 Optimizing Treatment of Desmoid Tumors
From the Departments of Cancer Biology, Radiation Oncology, Surgical Oncology, Pathology, and Sarcoma Medical Oncology, and the Division of Quantitative Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Dina Lev, MD, Department of Cancer Biology, Unit 1104, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: dlev{at}mdanderson.org
Purpose: This study compared a large series of desmoid patients treated at a single institution to a previously published series from the same institution to determine if patient population characteristics, treatment approaches, and clinical outcomes had undergone change over the two study periods. Materials and Methods: Data from a prospective soft tissue tumor database was used to analyze clinical courses of 189 desmoid patients treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) from 1995 to 2005 as compared with 189 UTMDACC desmoid patients treated between 1965 and 1994. Results: A nearly three-fold increase in annualized UTMDACC desmoid referral volume with significantly higher percentages and numbers of primary desmoid tumor referrals to UTMDACC was observed in the most recent study period. Significantly increased systemic therapy use and decreased reliance on surgery alone was observed more recently. While the recent series patients had higher rates of macroscopic residual disease and equivalent rates of positive microscopic margins after definitive surgery, the estimated 5-year local recurrence rate of 20% was improved compared with the 30% rate observed in the earlier series. Conclusion: Increased awareness of the complex multidisciplinary management needed for desmoid tumor control may underlie significantly increased numbers of referrals to UTMDACC, especially primary untreated desmoids. Increased neoadjuvant treatments may be associated with improved desmoid patient outcomes. These trends should be supported, particularly if personalized molecular-based therapies are to be rapidly and effectively deployed for the benefit of those afflicted by this rare and potentially debilitating disease.
Desmoid tumors are mesenchymal monoclonal proliferations that locally infiltrate but lack metastatic potential.1,2 Therapy consists of surgery, radiotherapy, and/or systemic approaches in various nonstandardized combinations,3-12 rendering direct comparison of treatment results problematic. Consequently, we examined the results of The University of Texas M.D. Anderson Cancer Center's (UTMDACC) two large desmoid experiences: 189 patients treated between 1965 and 199413 and a recent group of 189 (numerically coincident) desmoid patients treated from 1995 to 2005. We considered whether UTMDACC desmoid populations and treatment approaches had changed over time, perhaps providing an improved basis for therapeutic decisions. Our results demonstrate markedly increased desmoid patient referral, as well as increased reliance on multimodality therapies, including systemic approaches in the later time period. Moreover, 5-year local recurrence rates decreased remarkably from 30% (1965 to 1994) to an estimated 20% (1995 to 2005), suggesting that individualized, carefully planned, and executed multidisciplinary treatment approaches are optimal for desmoid patients confronting this rare and devastating disease.
This study was approved by the UTMDACC institutional review board, and a waiver of consent was granted for the patient record review. Desmoid patients who presented at UTMDACC from January 1, 1995, through December 31, 2005, were selected from a prospective soft tissue tumor database containing 150 data fields, as well as from radiation oncology and pathology archives. Desmoid histology was confirmed for all patients by a UTMDACC pathologist (A.A.L.) as part of the initial evaluation. All study patients remain in active or telephone follow-up through the UTMDACC Sarcoma Center. Patient age was defined as the age at presentation to UTMDACC, and it was categorized  30 years or > 30 years for analysis. Tumor size was determined by radiology/pathology reports and was split into 5 cm or > 5 cm for analysis. Tumor sites were categorized as extremity, superficial trunk, head and neck, or visceral.
Microscopic margin status was retrieved from final pathology reports. Radiotherapy targeting gross disease was delivered by megavoltage or electron beam at doses from Kaplan-Meier curves were used to determine relapse-free survival times. All Kaplan-Meier–derived P values were based on log-rank tests. Unpaired Student's t tests were used for comparisons of several clinical parameters, and Fisher's exact test was used to assess significance of the differences between proportions. A P value of < .05 was considered significant for all analyses.
Patient Characteristics From January 1, 1995, to December 31, 2005, 233 desmoid patients presented at UTMDACC. Forty-four patients who only received consultation or did not return for follow-up after definitive treatment were not further considered. Table 1 depicts patient and treatment factors for the 189 study patients. Ages ranged from 4 to 88 years, and 57 patients were 30 years, whereas 132 patients were > 30 years old. In 142 patients, the tumor was extra-abdominal, whereas 47 patients were intra-abdominal. Tumor size ranged from 1 to 35 cm ( 5 cm in 56 patients, 10 cm in 74, 15 cm in 43, and > 15 cm in 45). The median size of primary tumors was 8 cm, whereas the median size of recurrent tumors was 5 cm (P < .01). Size  5 cm was significantly more frequent in visceral locations versus all other desmoid sites (P < .05). Forty-nine patients (26%) presented at the time of first (n = 28) or after one or more recurrences (n = 21). There were no significant differences between primary versus recurrent tumors regarding site, patient age, or any other descriptive clinical criteria, other than size. Seventeen patients had Gardner syndrome. Interestingly, only seven had mesenteric tumors; the other 10 had superficial trunk or extremity lesions.
Therapeutic Considerations All 189 patients were evaluated in the UTMDACC bi-weekly multidisciplinary sarcoma conference before initiating therapy. Feasibility of nonmorbid negative-margin resection, radiotherapy's potential impact on adjacent normal tissues, Gardner syndrome status, and so on were used to select specific patient therapies (Fig 1). Interventions were grouped as surgery alone, radiation alone, systemic therapy alone (doxorubicin-based chemotherapy, and/or tamoxifen, and/or imatinib mesylate), and combined therapy.
Surgery was offered for all resectable tumors, and 146 patients had surgery as a component of their treatment. Operations performed included incomplete resection (residual macroscopic tumor; n = 15); wide local excision (n = 70); radical resection with immediate reconstruction (autologous tissue and/or prosthetic implants; n = 34), and laparotomy with visceral resection (n = 27). No patients received amputation as their initial surgical procedure. Surgical complications, defined as problems requiring additional operation(s) and/or prolonging hospitalization, occurred in 18 patients (12%): one amputation, three re-exploratory laparotomies, six incisional hernias, four complex-wound complications, and four significant neurological deficits. In 130 patients, surgery was performed for gross disease. In 16 patients, it was performed for residual disease after incomplete resection elsewhere. Of the 146 patients undergoing surgical resection, 16 (20%) of 78 with negative margins and 36 (53%) of 68 with positive margins received adjuvant therapy. Final pathology margins in the 93 surgery-alone patients were negative in 61 patients (66%) and microscopically positive in 32 (34%). All of these latter patients were offered (but they didn't choose to receive) postoperative radiotherapy. Thirty-two of the 58 who received combined therapy (group 4) were offered and received postoperative radiotherapy (n = 10 margin-negative and n = 22 margin-positive resections). Adjuvant therapy indications in margin-negative patients included multifocal disease or anatomically constrained tumor locations with who had macroscopic residual disease in the aftermath of attempted definitive resection, usually performed after neoadjuvant therapy. Nine patients were treated with radiotherapy alone because the tumor abutted unresectable anatomic constraints. Definitive radiotherapy was administered as previously described.13 All nine patients responded to radiotherapy—seven demonstrated significant (> 50%; partial regression [PR]) response, and two manifested complete regression (CR). Twenty-nine patients received systemic therapy alone. This management was mainly offered to patients with deep-seated visceral tumors deemed to be unresectable; 16 of 29 had Gardner syndrome. Of the chemotherapy-alone patients, there was one CR, 11 with PR, two with stable disease (SD), and two with progressive disease with first-line chemotherapy, but subsequently stabilized with second-line chemotherapeutics. Ten of the 13 tamoxifen patients achieved a PR, whereas three manifested progressive disease. The combined therapy group consisted of 53 patients who had surgery in combination with other therapies and five patients who received systemic therapy and radiotherapy without surgery. Thirty-two patients received postoperative radiation, and three patients received preoperative radiotherapy. Nine patients received systemic therapy in addition to surgery (six neoadjuvant and three adjuvant), and nine patients received systemic therapy, radiotherapy, and surgery in various sequences. An important subset of group 4 patients consisted of 15 individuals who had macroscopic residual disease in the aftermath of attempted definitive resection, usually performed after neoadjuvant therapy. Seven of these patients received postoperative radiotherapy—four achieved SD, two had PR, and one had CR. Eight of these 15 patients were treated using one or more systemic approach (multidrug chemotherapy, hormonal therapy, or imatinib mesylate). Three patients achieved SD, three had PR, and two had CR.
Patient Outcomes
Time to relapse ranged from 3 to 65 months (median 24 months); only one patient relapsed after more than 60 months (Fig 2B). Univariate analysis identified only extremity site and age 30 years as approaching significant correlation with outcome (P < .053 and .052; Figs 2C and 2D), and they were also the only factors prognostic for recurrence when the 140 primary tumor patients were analyzed separately (P < .03). All systemic therapy–alone patients who were partial responders or who progressed under initial systemic therapy are currently alive with stable disease and performance status. This subset excludes two Gardner syndrome patients who died of colon carcinoma after receiving systemic therapy alone. In the surgery-alone group, 10 recurrences were in patients with margin-negative resection (10 [16%] of 61), whereas six recurrences were in the 32 patients with margin-positive resections (19%). These 16 recurrences were treated either by surgery alone (n = 7), surgery combined with an additional modality (n = 7), or by observation (n = 2). Seven of these are free of disease after a median 40-month follow-up. Three patients suffered a second recurrence and were treated with surgery alone (n = 2) or surgery and radiotherapy (n = 1). All are free of disease after 18, 24, and 27 months of follow-up. Two patients have had four or more recurrences. Three (9%) of 32 patients treated with surgery and postoperative radiotherapy recurred—two had negative- and one had positive-margin resections. Two were treated by surgery alone, and one was treated systemically. All three are alive without evidence of disease. The remaining 26 patients treated with combined therapy included three patients who received preoperative radiotherapy followed by surgery, none of whom recurred. Six (26%) of the remaining 23 patients did recur, necessitating treatment with multiple systemic therapies combined with preoperative radiotherapy and surgery—three were treated with various combinations of surgery plus other treatments, one was treated with surgery alone, and two were treated with systemic therapy alone. One patient died of extensive abdominal desmoid, three are alive with stable disease, and two are alive without evidence of disease after 24 and 44 months of follow-up.
Interseries Comparisons Several differences in the patient population emerged, suggesting a trend of referring desmoid patients to high-volume centers (Table 2). The number of desmoid patients referred to UTMDACC in the earlier series approximated six per year compared with 17 per year during the later time period. Consistent with this possibility, the percentage of patients with primary versus recurrent desmoid tumor in the older series was 45% and 55%, respectively, versus 74% primary and 26% recurrent in the newer series. Perhaps for similar reasons, seven (4%) of the old series, but 17 (9%) of the new series, were Gardner syndrome patients.
Treatment modalities also demonstrated differences, including an increase in systemic therapy alone from no patients in the old series to 29 (15%) of 189 more recently. Use of systemic therapy as part of a combined treatment program was done for 12 (21%) of 58 old series versus 23 (40%) of 58 in recent series patients. Any use of systemic therapy was observed in 12 (6%) of 189 old series versus 52 (28%) of 189 new series patients, perhaps reflecting increased awareness of desmoid systemic treatment efficacy. Reliance on surgery alone decreased from 59% to 49% (old v new series). Reliance on radiotherapy alone likewise decreased from 11% to 5%, perhaps reflecting increased recognition of combined therapy value, even in primary disease. Interseries treatment outcomes exhibited overall improvement over the two time periods (Fig 3A). Although the percentage of positive margins in all surgical patients were equivalent in both eras (46% v 47%), only four patients in the earlier time period had macroscopic residual disease after resection, whereas 15 had macroscopic disease after resection in the later time period, perhaps reflecting an increased incidence of difficult-to-resect tumors being referred. Although the median follow-up was 112 months compared with 68 months early versus later periods, respectively, 80% of the old series recurrences were within 3 years of treatment, and the majority of patients in the newer series have already been followed for at least 3 years. The local recurrence rate more recently (27 [14%] of 189) was improved compared with the earlier series (58 [31%] of 189). Moreover, local recurrence in surgery-alone patients in the earlier series (43 [35%] of 122) was unfavorable compared with the later surgery-alone patients (16[17%] of 93; Fig 3B). One additional comparison implies an improvement in surgery during these two periods—local recurrence in extremity tumors treated by surgery alone decreased from 15 (52%) of 29 to 11 (35%) of 31. Improvements in tumor imaging may account for some of these differences. Taking into account the difference in follow-up between the two series, interpretation of these results should be made with caution—the difference between the actuarial freedom from recurrence at 5 years of 80% (95% CI, 0.738 to 0.868) in the current series compared with 70% (95% CI, 63% to 77%). The older series suggests there has been a true improvement in outcome. Definitive conclusions about local recurrence improvements awaits bona fide 5-year follow-up available after 2010.
Finally, both series trended toward improved local control in patients treated with surgery followed by radiation (Fig 3B). Although earlier series' patients with negative resection margins had significantly improved disease-free survival (DFS) compared with those with positive margins, the recent series demonstrated that DFS was equivalent in margin-positive and margin-negative patients (Fig 3C), and both enjoyed DFS rates equivalent to that of the margin-negative group in the earlier series.
Desmoids are rare,13 and generating large patient cohorts treated by expert teams in a standard manner14-16 has been problematic. To our knowledge, the Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY),17,18 the Massachusetts General Hospital (MGH; Boston, MA),19 the Instituto Nazionale Tumori (Milan, Italy),20 and our own studies13 are the only reports of more than 100 patients. Most other series include less than 100 single-institution patients and are too small to establish optimal treatment conclusions.21 The experience reported here, as in the other studies, is limited because it is based on retrospective data analysis. Thus, all conclusions should be interpreted with caution and serve mainly to help identify issues requiring prospective trials rather than to provide definitive answers. Moreover, as a retrospective study, it was not always possible to establish the rationale underlying selection and sequence of certain treatments. These caveats notwithstanding, to our knowledge, ours is the largest aggregated single institution experience reported to date, making it possible to compare two large temporally distinct single-institution experiences. This demonstrates a remarkable increase in desmoid tumors (especially primaries) referred to a high-volume center, increased use of systemic therapies to avoid debilitating local approaches, and decreased rates of local recurrence in all patients as well as those treated by surgery alone. In comparing the four large institutional experiences, several critical unanswered questions emerge. The prognostic significance of microscopic margin positivity remains controversial. The MGH study19 demonstrated that microscopically positive margins significantly influenced local recurrence in a multivariate analysis (19% negative v 39% positive), whereas the MSKCC and Instituto Nazionale Tumori experiences demonstrated no such impact (22% negative v 24% positive17; 21% positive v 18% negative20). The earlier UTMDACC study suggested that margin positivity was a significant prognostic factor,13 a finding not substantiated in this current study. It is possible that margin positivity, per se, variably influenced subsequent adjuvant therapies chosen in different centers or even within the same center. Such biases would unlikely be detected in any of these retrospective reports, and they should be addressed prospectively. The role of radiotherapy in desmoid tumor management is also controversial. All four centers have used radiotherapy in lieu of surgery in very small numbers of patients whose tumors were unresectable, usually with adequate long-term palliative control. It is more challenging to demonstrate the role of radiotherapy in other patients, particularly those with microscopically positive margins after definitive surgery. There was a variation in radiation energy source and dose across and even within the four centers; moreover, the criteria for adjuvant radiotherapy use were not specifically, unequivocally articulated in any of these studies. While the earlier UTMDACC report13 and MGH 19 demonstrated improved recurrence-free survival in radiated microscopically margin-positive patients, MSKCC,17 Instituto Nazionale Tumori,20 and this report failed to show such benefit. A prospective evaluation of standardized adjuvant radiotherapy, stratified by margin status, may resolve which other patients should be offered radiotherapy in addition to those where anatomic constraints preclude gross total excision. The emerging applicability of systemic therapies is an additional area of controversy. Use ranged from 25% in this report to no reported use in the MGH19 and Instituto Nazionale Tumori20 series, and 4% at MSKCC.17 Initially described by Patel et al,22 chemotherapy has recently been prospectively validated by Gega et al23 in a cohort of familial adenomatous polyposis patients with deep-seated unresectable intra-abdominal desmoids.The recent effective use of imatinib mesylate10 adds an additional tool to a systemic armamentarium that already includes chemotherapy and hormonal therapy. Possible indications and sequencing of these various systemic approaches need to be prospectively evaluated, most likely in patients having anatomic barriers to effective surgery or radiotherapy, while accounting for respective efficacy-toxicity profiles. One final area of controversy lies in the reality that all four large desmoid series contains a small patient subset followed without therapy, usually due to patient preference.18 Six MSKCC patients confronting amputation chose observation only—none experienced disease progression, and three experienced some spontaneous tumor regression. Defining the role and extent of palliative interventions, including observation alone, mandates prospective outcome studies from which concensus can emerge. Given the rarity of this disease, trials such as those proposed, including correlative laboratory investigations, will require multicenter cooperation as well as vigorous patient-based advocacy. Such efforts may identify clinical or molecular criteria (such as beta-catenin overexpression24,25) by which patients can be selected for unimodal therapy or long-term observation alone versus those who need intensive multimodality approaches. Over time, such knowledge may be useful in designing personalized desmoid therapies that will complement our abilities to preserve life and limb for patients burdened by this disease.
The authors indicated no potential conflicts of interest.
Conception and design: Dina Lev, Alexander A. Lazar, Raphael E. Pollock Financial support: Dina Lev, Raphael E. Pollock Administrative support: Dina Lev Provision of study materials or patients: Dina Lev, Dhanasekaran Kotilingam, Matthew T. Ballo, Gunar K. Zagars, Peter W.T. Pisters, Alexander A. Lazar, Shreyaskumar R. Patel, Robert S. Benjamin, Raphael E. Pollock Collection and assembly of data: Dina Lev, Dhanasekaran Kotilingam, Raphael E. Pollock Data analysis and interpretation: Dina Lev, Dhanasekaran Kotilingam, Caimiao Wei, Peter W.T. Pisters, Raphael E. Pollock Manuscript writing: Dina Lev, Caimiao Wei, Matthew T. Ballo, Gunar K. Zagars, Peter W.T. Pisters, Robert S. Benjamin, Raphael E. Pollock Final approval of manuscript: Dina Lev, Dhanasekaran Kotilingam, Caimiao Wei, Matthew T. Ballo, Gunar K. Zagars, Peter W.T. Pisters, Alexander A. Lazar, Shreyaskumar R. Patel, Robert S. Benjamin, Raphael E. Pollock
This research was supported by the Desmoid Tumor Research Foundation. We appreciate the expert assistance provided by Paul Cuevas in the preparation and submission of this manuscript.
Supported in part by the Desmoid Tumor Research Foundation. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
)Familiar adenomatous polyposis patients. Use combination chemotherapy if life/limb threatened. Other cases use hormone therapy. (
)Further clinical trials need for this validation. XRT, radiation therapy.
