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Journal of Clinical Oncology, Vol 25, No 5 (February 10), 2007: pp. 501-506 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.2966 Vinblastine and Methotrexate for Desmoid Fibromatosis in Children: Results of a Pediatric Oncology Group Phase II Trial
From the Departments of Oncology and Radiological Sciences, St Jude Children's Research Hospital, Memphis, TN; Department of Hematology/Oncology, Cardinal Glennon Children's Hospital; Lauren V. Ackerman Laboratory of Surgical Pathology, St Louis Children’s Hospital, Washington University Medical Center, St Louis, MO; Department of Pediatric Oncology, Columbia Presbyterian College of Physicians and Surgeons, New York, NY; The Children's Oncology Group Data Center and Department of Epidemiology and Health Policy Research, University of Florida, Gainesville, FL; Departments of Pathology, Orthopedic Surgery, and Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and the Children's Hospital, Boston, MA; and Department of Pediatric Hematology/Oncology, Stanford University Medical Center, Palo Alto, CA Address reprint requests to Stephen X. Skapek, MD, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105; e-mail: steve.skapek{at}stjude.org
Purpose: To determine the efficacy and safety of using vinblastine (Vbl) and methotrexate (Mtx) in children with desmoid-type fibromatosis that is recurrent or not amenable to treatment with radiation or surgery. Patients and Methods: A phase II study was conducted within the Pediatric Oncology Group. Patients were treated using Vbl (5 mg/m2/dose) and Mtx (30 mg/m2/dose), both administered by intravenous injection weekly for 26 weeks and every other week for an additional 26 weeks. Response was assessed by bidimensional measurements of tumor on axial imaging (magnetic resonance imaging or computed tomography). Results: Over 35 months, 28 patients were enrolled; 27 were eligible, and 26 were assessable for response. A measurable response was documented in eight patients (31%), and 10 patients had stable disease documented as the best response to treatment. Eighteen patients had disease progression at a median time of 9.1 months. Eight patients remain free of disease progression at a median of 43.4 months from study entry. Nine patients reported no to moderate toxicity. Neutropenia was the most common toxicity (n = 22) and the most common grade 4 toxicity (n = 5). Anemia, nausea, vomiting, and elevations in hepatic transaminases were also common and were reversible with interruption of chemotherapy. Conclusion: Vbl and Mtx are well tolerated in children with desmoid-type fibromatosis. Furthermore, this combination can promote tumor regression or block tumor growth in most children.
Desmoid-type fibromatosis (also known as aggressive fibromatosis, desmoid tumor, and musculoaponeurotic fibromatosis) is classified by WHO as intermediate grade because of its propensity for locally invasive growth and the absence of metastatic potential.1 The incidence is estimated at two to four persons per million per year, with relative peaks in incidence between 6 and 15 years of age and between puberty and age 40 years in women.1,2 Risk factors for the development of desmoid-type fibromatosis include high estrogen states (like pregnancy), prior surgical trauma, and Gardner's syndrome, which is caused by inherited mutations in the adenomatous polyposis coli (APC) tumor suppressor gene.1,2 The most common tumor sites are the extremity (shoulder and thigh), trunk (chest wall and back), mesentery-omentum, and head and neck.1-3 The primary site can influence treatment strategies, particularly in prepubertal children for whom effects of surgery and radiation on growth and development must be considered. Surgical resection has been the standard treatment for desmoid-type fibromatosis. Most series indicate that local recurrence rates after surgical resection range from approximately 80% to approximately 10% when the margins are positive or negative, respectively.4-6 Radiation therapy, either alone or after subtotal surgical resection, has a well-established role in adults with desmoid-type fibromatosis. Radiation doses of 50 to 60 Gy achieve local control in 70% to 80% of adults treated for gross residual disease and may improve recurrence-free survival compared with surgery alone.6-8 However, results from a recent retrospective series suggest that radiation may be less effective in children.9 In children and adolescents, concern about the potential long-term cosmetic or functional morbidity associated with surgery or radiation has prompted the search for alternative strategies, including the use of cytotoxic and noncytotoxic chemotherapy. Retrospective studies in children report the efficacy of chemotherapy using vincristine, dactinomycin, and cyclophosphamide10; vinblastine (Vbl) and methotrexate (Mtx)11-13; and noncytotoxic chemotherapy with tamoxifen and the nonsteroidal anti-inflammatory drug diclofenac.13,14 These reports are somewhat limited by their retrospective nature and the small numbers of patients. To more formally address the potential role of chemotherapy in the treatment of desmoid-type fibromatosis in children, the Pediatric Oncology Group (POG) conducted a multi-institutional, prospective clinical trial of Vbl and Mtx in children with recurrent disease or newly diagnosed disease not amenable to standard approaches using surgery or radiation therapy.
Patients Patients with recurrent desmoid-type fibromatosis (stratum 1) or with newly diagnosed disease not deemed amenable to radiation or surgery (stratum 2) were enrolled onto the POG phase II clinical study (9650) from August 15, 1997, to February 16, 2001, exclusively at POG institutions (through October 18, 1999) and at both POG and Children's Cancer Group institutions (after April 28, 2000). A total of 28 patients were enrolled. The study was closed from October 18, 1999, to April 28, 2000, for interim analysis after meeting the accrual requirements for the first stage of the two-stage design. Pathology specimens were reviewed and confirmed to be diagnostic of desmoid-type fibromatosis. Disease status and response were assessed by magnetic resonance imaging (MRI; n = 25) or computed tomography (n = 1) in assessable patients. Data were frozen as of June 11, 2005. Patients' parents or guardians gave written informed consent in accord with cooperative group and local institutional guidelines before initiating study therapy.
Treatment Regimen
The treatment regimen was modified for certain toxicities as follows: Vbl and Mtx doses were halved for 1 week for an absolute neutrophil count (ANC) of less than 1,000/µL but
Response Assessment
Study Design Because of the rarity of this tumor, it was impossible to formally test whether the CR+PR rates differed between the two strata (see Patients section). If the initial analysis did not show a large difference in the response rates between the two strata, the data would be pooled to form an overall estimate of the combined CR+PR rate. A total of 25 patients would enable the CR+PR rate to be estimated with a maximum margin of error of 20% using a 95% CI. CI for the response rate was calculated using the method of Duffy and Santner.15 Progression-free survival was computed using the Kaplan-Meier method,16 and SEs of the estimates were determined according to Peto and Peto.17
Patient Characteristics The study was open to accrual for 35 months, with an overall annual accrual rate of 9.6 patients. The accrual rate was initially 7.4 patients per year but increased to 16 patients per year after April 29, 2000, when the study was opened to both POG and Children's Cancer Group institutions. Overall, 28 patients with either previously untreated or recurrent desmoid-type fibromatosis were enrolled; 27 patients were deemed eligible, and 26 were assessable for response. One patient was found to be ineligible as a result of diagnosis other than desmoid-type fibromatosis. Another patient with no measurable disease at study entry was determined to be nonassessable for response. Patient characteristics are listed in Table 1. Twenty (74%) of the 27 eligible patients were male, and 19 (70.4%) were white, non-Hispanic. Two patients were known to have Gardner's syndrome. The median age at diagnosis was 120.7 months (range, 1.8 to 219.6 months); the median age at enrollment onto study was 137.5 months (range, 7.2 to 245.9 months). Sixteen patients (59%) were enrolled for recurrent disease. The other patients had previously untreated disease that was not deemed amenable to surgical resection or radiation. The rationale behind the decision to not use surgery or radiation was not collected as part of the study. The median age at time of original diagnosis was similar in each stratum at 129.9 months (range, 1.8 to 219.6 months) and 113.7 months (range, 12.0 to 208.9 months) for patients with primary and recurrent disease, respectively (P = .90, two-sided Wilcoxon test). As might be expected, patients with newly diagnosed disease tended to be younger at study entry; median age at study entry was 129.9 months (range, 7.2 to 220.3 months) for patients with newly diagnosed disease compared with 148.2 months (range, 36.6 to 245.9 months) for patients with recurrent disease, but this difference was not statistically significant (P = .42, two-sided Wilcoxon test).
Most patients had tumors localized to a lower extremity or the head and neck region (Table 1). Head and neck sites included one patient with a tongue lesion. Radiographic imaging documented multifocal disease in four patients, three of whom entered the study for recurrent disease, whereas one had newly diagnosed disease. The average tumor size, documented by measurements on MRI reports for 22 patients, was 38.1 cm2 (standard deviation, 41.1 cm2; range, 1.5 to 162 cm2). Presenting symptoms were identified on prestudy forms for 18 patients and included tumor mass/swelling (n = 14), pain (n = 6), weakness (n = 1), decreased joint mobility (n = 2), and head tilt (n = 1). The duration of symptoms ranged from 1 day to 2 years before study entry.
Response to Therapy A measurable response (CR, PR, or MR) was documented in eight patients (31%), including one CR, four PRs, and three MRs (Table 2). Ten patients had stable disease as their best documented response (38%), and eight patients had progressive disease. The overall CR+PR rate was 19.2% (five of 26 patients; 95% CI, 6.6% to 43.7%). The two patients known to have Gardner's syndrome experienced disease progression (one patient after 12 weeks and the other at approximately 44 weeks after an initial PR).
Progression-Free Survival Figure 1 gives the progression-free survival curve for all patients on the study. No patient enrolled onto the study died. The progression-free interval was computed as time from enrollment onto study to disease progression or date of last contact if the patient was progression free.
Sixteen (62%) of 26 patients completed 17 to 52 weeks of chemotherapy without disease progression. Eight of these patients (50%) have experienced disease progression after cessation of chemotherapy, including the three patients whose chemotherapy was electively discontinued early. Disease progression was always at the site of previous disease. The median time to progression was 15.9 months (range, 7 to 35 months) after stopping therapy. The other eight patients have not had disease progression at a median time of 43.4 months (range, 12 to 71 months) from study entry. One of these patients was censored at 12 months when lost to follow-up. The remaining seven patients were free of disease progression at a median time of 50 months (range, 33 to 71 months). This represents 27% of the assessable patients and 44% of the patients whose disease did not progress during therapy. At last follow-up, four patients had stable disease evident on imaging, but three patients were free of disease; one of these three patients was rendered free of disease by surgical resection near the end of therapy, and two were rendered free of disease by chemotherapy alone. Of the latter, one patient did not achieve CR until 13 months after completing therapy. Ten patients experienced disease progression before the end of planned therapy. Only two of these patients had greater than 25% of the chemotherapy doses reduced or delayed for toxicity. Most patients with progressive disease had progression documented at or before the first MRI scheduled at approximately 12 weeks. However, one patient who later experienced progression had an initial PR at week 25, and two other patients had stable disease on initial assessment but experienced progression later. Over the entire study group, the median time to progression (n = 18) from study entry was 9.1 months (range, 2.1 to 47.3 months).
Toxicity
Our findings support the concept that chemotherapy can be used to control desmoid tumor in children for whom other approaches have failed or are thought not to be feasible. Nearly two thirds of the patients enrolled onto this study had disease stabilization or some degree of tumor shrinkage while receiving chemotherapy. The chemotherapy was clearly ineffective in the remaining patients, who had disease that progressed at or before the first evaluation period at 12 weeks. Clinical or pathologic factors that could prospectively identify patients who are likely to respond were not evident from our study. One of the more intriguing findings was that approximately 40% of the patients who had disease stabilization during the chemotherapy and who completed the planned therapy remain free of disease progression at a median of 50 months after treatment. Because all of our patients had progressing disease at the time they enrolled onto the study, we presume that the chemotherapy caused the disease stabilization or regression. However, it should be noted that desmoid tumor has occasionally been reported to undergo some degree of involution.18 A randomized trial, which may not be tenable in children with a rare neoplasm, would be required to establish a cause-and-effect relationship between the use of Vbl and Mtx and disease stabilization/regression. To our knowledge, the current study is the first prospective trial of chemotherapy for desmoid-type fibromatosis in children. Our findings compare favorably with previous retrospective reports of Vbl and Mtx in children and adults11,12,19 and one prospective study in adults.20 Additional retrospective studies of standard chemotherapy have reported that the combination of vincristine, dactinomycin, and cyclophosphamide has some efficacy in children10; similarly, regimens containing anthracyclines and/or alkylating agents have shown to be beneficial in some adult patients.21-23 How these other regimens compare with Vbl and Mtx cannot be confidently stated in the absence of prospective, randomized trials. Although the combination of Vbl and Mtx was chosen because it was anticipated to have mild adverse effects, five patients reported National Cancer Institute Common Toxicity Criteria grade 4 toxicity. Neutropenia was the only life-threatening adverse effect that seemed likely to be a result of the study therapy. Although it occurred in five of 27 patients, the toxicity was readily reversed, was not associated with medical complication, and was actually relatively uncommon given the total duration of therapy for all patients on the study. It is important to note that three patients (12%) electively discontinued therapy. Except for an acute, uncomplicated seizure in one patient, the toxicity reported for these three patients was similar to the group as a whole. Chronic, mild toxicity, such as nausea and vomiting, combined with the absence of radiographic evidence of response may have contributed to decisions to cease therapy. With this in mind, we believe it is important to set appropriate expectations with patients and their families because the biology of desmoid tumor may be such that objective, early responses are not typical. Because long-term disease control was achieved in at least some patients who completed 1 year of therapy, it seems reasonable to continue therapy as long as it is well-tolerated and there is no evidence of disease progression. The relative benefits of chemotherapy for desmoid-type fibromatosis must be weighed against the risks of either no therapy or treatment with surgery or radiation. Surgical resection (or re-resection) can often control the disease in children24; resection should remain the initial approach when it can be achieved with limited morbidity. The role of radiation in pediatric patients is less clear. A recent retrospective series from St Jude Children's Research Hospital reported disease recurrence in 11 of 13 children treated with a median radiation dose of 50 Gy.9 Nonetheless, depending on the site of disease and age of the child, consideration should be given to radiation therapy. Some have advocated expectant management of adults with asymptomatic desmoid-type fibromatosis.18,25,26 In selected pediatric patients, such an approach might be considered. Finally, insight into desmoid-type fibromatosis biology, such as expression of platelet-derived growth factor receptor,27-29 estrogen receptor,30,31 and cyclooxygenase-2,32 provides a rationale for targeted therapy using imatinib mesylate28,29 or estrogen antagonists with or without nonsteroidal anti-inflammatory drugs.13,14,33-37 An ongoing Children's Oncology Group study is formally evaluating high-dose tamoxifen and sulindac in a cohort of patients similar to those enrolled onto this study of Vbl and Mtx. Until targeted therapies are more fully evaluated, the current report indicates that treatment with Vbl and Mtx may be warranted in children with either newly diagnosed or recurrent, progressive desmoid-type fibromatosis when either surgery or radiation have proven to be ineffective or are felt to be associated with too much potential toxicity.
The authors indicated no potential conflicts of interest.
Conception and design: Stephen X. Skapek, William S. Ferguson, Linda Granowetter, Mark C. Gebhardt, Gary V. Dahl, Holcombe E. Grier Administrative support: Roseanne Speights Provision of study materials or patients: Stephen X. Skapek, William S. Ferguson, Linda Granowetter, Gary V. Dahl, Holcombe E. Grier Collection and assembly of data: Stephen X. Skapek, Meenakshi Devidas, Antonio R. Perez-Atayde, Louis P. Dehner, Fredric A. Hoffer, Roseanne Speights, Holcombe E. Grier Data analysis and interpretation: Stephen X. Skapek, Meenakshi Devidas, Antonio R. Perez-Atayde, Louis P. Dehner, Fredric A. Hoffer, Roseanne Speights, Holcombe E. Grier Manuscript writing: Stephen X. Skapek, William S. Ferguson, Linda Granowetter, Meenakshi Devidas, Mark C. Gebhardt, Gary V. Dahl, Holcombe E. Grier Final approval of manuscript: Stephen X. Skapek, William S. Ferguson, Linda Granowetter, Meenakshi Devidas, Antonio R. Perez-Atayde, Louis P. Dehner, Fredric A. Hoffer, Roseanne Speights, Mark C. Gebhardt, Gary V. Dahl, Holcombe E. Grier
We thank the following for their assistance: numerous Pediatric Oncology Group and Children's Cancer Group investigators; J.R. Anderson, W.S. Meyer, R.B. Womer, and other members of the Soft Tissue Sarcoma Committee of the Children's Oncology Group; clinical research associates M. Lewis and D. Poe; and B. McCarville, D.A. Hill, and J. Khoury for helpful discussions of desmoid tumor imaging and pathology.
Supported by National Institutes of Health Grants No. CA098543-02 (R.S.) and CA29139 (M.D.) and by the American Lebanese Syrian Associated Charities (S.X.S., F.A.H., R.S.). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Goldblum J, Fletcher JA: Desmoid-type fibromatosis, in Fletcher CDM, Unni KK, Mertens F (eds): World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France, International Agency for Research on Cancer Press, 2002, pp 83-84 2. Reitamo JJ, Scheinin TM, Hayry P: The desmoid syndrome: New aspects in the cause, pathogenesis and treatment of the desmoid tumor. Am J Surg 151:230-237, 1986[CrossRef][Medline] 3. Taylor LJ: Musculoaponeurotic fibromatosis: A report of 28 cases and review of the literature. Clin Orthop Relat Res 224:294-302, 1987[Medline] 4. Gronchi A, Casali PG, Mariani L, et al: Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: A series of patients surgically treated at a single institution. J Clin Oncol 21:1390-1397, 2003 5. Dormans JP, Spiegel D, Meyer J, et al: Fibromatoses in childhood: The desmoid/fibromatosis complex. Med Pediatr Oncol 37:126-131, 2001[CrossRef][Medline] 6. Ballo MT, Zagars GK, Pollack A, et al: Desmoid tumor: Prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy. J Clin Oncol 17:158-167, 1999 7. Ballo MT, Zagars GK, Pollack A: Radiation therapy in the management of desmoid tumors. Int J Radiat Oncol Biol Phys 42:1007-1014, 1998[CrossRef][Medline] 8. Kamath SS, Parsons JT, Marcus RB Jr, et al: Radiotherapy for local control of aggressive fibromatosis. Int J Radiat Oncol Biol Phys 36:325-328, 1996[Medline] 9. Merchant TE, Nguyen D, Walter AW, et al: Long-term results with radiation therapy for pediatric desmoid tumors. Int J Radiat Oncol Biol Phys 47:1267-1271, 2000[CrossRef][Medline] 10. Raney B, Evans A, Granowetter L, et al: Nonsurgical management of children with recurrent or unresectable fibromatosis. Pediatrics 79:394-398, 1987 11. Skapek SX, Hawk BJ, Hoffer FA, et al: Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children. J Clin Oncol 16:3021-3027, 1998 12. Reich S, Overberg-Schmidt US, Buhrer C, et al: Low-dose chemotherapy with vinblastine and methotrexate in childhood desmoid tumors. J Clin Oncol 17:1086, 1999 13. Lackner H, Urban C, Benesch M, et al: Multimodal treatment of children with unresectable or recurrent desmoid tumors: An 11-year longitudinal observational study. J Pediatr Hematol Oncol 26:518-522, 2004[CrossRef][Medline] 14. Lackner H, Urban C, Kerbi R, et al: Noncytotoxic drug therapy in children with unresectable desmoid tumors. Cancer 80:334-340, 1997[CrossRef][Medline] 15. Duffy D, Santner J: Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81-93, 1987[CrossRef] 16. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 17. Peto R, Peto J: Asymptotically efficient rank invariant test procedure. J R Stat Soc 135:185-198, 1972 18. Lewis JJ, Boland PJ, Leung DH, et al: The enigma of desmoid tumors. Ann Surg 229:866-872, 1999[CrossRef][Medline] 19. Weiss AJ, Lackman RD: Low-dose chemotherapy of desmoid tumors. Cancer 64:1192-1194, 1989[CrossRef][Medline] 20. Azzarelli A, Gronchi A, Bertulli R, et al: Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer 92:1259-1264, 2001[CrossRef][Medline] 21. Patel SR, Evans HL, Benjamin RS: Combination chemotherapy in adult desmoid tumors. Cancer 72:3244-3247, 1993[CrossRef][Medline] 22. Okuno SH, Edmonson JH: Combination chemotherapy for desmoid tumors. Cancer 97:1134-1135, 2003[CrossRef][Medline] 23. Gega M, Yanagi H, Yoshikawa R, et al: Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. 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Tsukada K, Church JM, Jagelman DG, et al: Noncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis. Dis Colon Rectum 35:29-33, 1992[CrossRef][Medline] 36. Kinzbrunner B, Ritter S, Domingo J, et al: Remission of rapidly growing desmoid tumors after tamoxifen therapy. Cancer 52:2201-2204, 1983[CrossRef][Medline] 37. Hansmann A, Adolph C, Vogel T, et al: High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer 100:612-620, 2004[CrossRef][Medline] Submitted July 17, 2006; accepted November 20, 2006. This article has been cited by other articles:
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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
500/µL or a platelet count of less than 100,000/µL but 
50%, respectively. Progressive disease represented an increase in tumor size by more than 25% or the appearance of new, biopsy-proven lesions. Changes not meeting any of these criteria represented stable disease. 
