Radiation therapy in the management of desmoid tumors

desmoid tumors have a high local relapse rate after surgery alone and radiation either given postOp or as radiation alone has a high rate of local control....see review article here, and the studies below and radiation summary here

Matthew T. Ballo M.D.   IJROBP. Volume 42, Issue 5, Pages 1007-1014 (1 December 1998)

Desmoid tumors (aggressive fibromatoses) are uncommon, locally aggressive soft tissue lesions. Their neoplastic nature has been confirmed by the demonstration that they are monoclonal processes, often carrying chromosomal aberrations, and by the finding that their excessive proliferation may be driven by reduced expression of the retinoblastoma gene. Microscopically, these tumors consist of spindle-shaped cells entirely lacking pleomorphic, atypical, or hyperchromatic nuclei. In keeping with this histopathology, desmoid tumors do not metastasize. However, despite a bland microscopic appearance that is uniform from one tumor to another, their clinical behavior varies and is frequently aggressive with wide local infiltration and with a marked propensity for recurrence after conservative resection. Because of this, aggressive wide local excision has become the preferred treatment. Nevertheless, local recurrence rates in recent surgical series remain high: 39%, 41%, 51%, 54%, 57%, 75%, and 79%. A major factor contributing to these high recurrence rates is the difficulty in achieving adequate surgical margins while maintaining acceptable function and cosmesis. Recognizing this, several investigators have reported on the potential benefits of radiation therapy, both as an adjuvant to surgical resection and as definitive treatment for inoperable desmoid tumors.

Whereas some reports suggest little or no benefit from radiation for this disease, the overall evidence is strong that external-beam radiation is helpful in the management of desmoid tumors. To evaluate the outcome of patients with extra-mesenteric desmoid tumors treated with radiation therapy, with or without surgery. The outcome for 75 patients receiving radiation for desmoid tumor with or without complete gross resection between 1965 and 1994 was retrospectively reviewed utilizing univariate and multivariate statistical methods. With a median follow-up of 7.5 years, the overall freedom from relapse was 78% and 75% at 5 and 10 years, respectively. Of the total, 23 patients received radiation for gross disease because it was not resectable. Of these 23 patients, 7 sustained local recurrence, yielding a 31% actuarial relapse rate at 5 years. Radiation dose was the only significant determinant of disease control in this group. A dose of 50 Gy was associated with a 60% relapse rate, whereas higher doses yielded a 23% relapse rate (p < 0.05). The other 52 patients received radiation in conjunction with gross total resection of tumor. The 5- and 10-year relapse rates were 18% and 23%, respectively. No factor correlated significantly with disease outcome. There was no evidence that radiation doses exceeding 50 Gy improved outcome. Positive resection margins were not significantly deleterious in this group of irradiated patients. For all 75 patients, there was no evidence that radiation margins exceeding 5 cm beyond the tumor or surgical field improved local-regional control. Ultimately, 72 of the 75 patients were rendered disease-free, but 3 required extensive surgery (amputation, hemipelvectomy) to achieve this status. Significant radiation complications were seen in 13 patients. Radiation dose correlated with the incidence of complications. Doses of 56 Gy or less produced a 5% 15-year complication rate, compared to a 30% incidence with higher doses (p < 0.05).

Conclusions: Radiation is an effective modality for desmoid tumors, either alone or as an adjuvant to resection. For patients with negative resection margins, postoperative radiation is not recommended. Patients with positive margins should almost always receive 50 Gy of postoperative radiation. Unresectable tumors should be irradiated to a dose of approximately 56 Gy, with a 75% expectation of local control.



Radiation therapy for aggressive fibromatosis (desmoid tumors): Results of a national Patterns of Care Study

Oliver Micke, IJROBP 2005;61: 882

A total of 101 institutions returned the questionnaire: 52.7% reported satisfactory clinical data and experience for inclusion in this analysis. A total accrual rate of 278 patients per year was reported with median number of 2 cases (1–7 cases) per institution. Satisfactory data for a long-term clinical evaluation was reported for 345 patients from 19 different institutions. The applied total doses ranged between 36 and 65 Gy (median, 60 Gy). The local control rate was 81.4% in primary RT for unresectable tumors and 79.6% in postoperative RT. No acute or late radiation toxicities > Grade 2 (RTOG) were observed. No clear dose–response relationship could be established, but there was a tendency toward a lower local control rate in patients with a higher number of operative procedures before RT and patients treated for recurrent aggressive fibromatosis.

Desmoids are rare benign neoplasms of connective tissue that arise from deep muscle fascia, aponeuroses, tendons, and scar tissue . The Anglo-American literature describes them as “aggressive fibromatosis”. The disease has been known since the 19th century: The terms “desmoid” and “desmoidfibrom” were coined by the German physiologist and comparative anatomist Johannes Müller (1801–1858) from Berlin in 1838. The name is derived from the ancient Greek and indicates a bandlike appearance. In 1832 the surgeon John McFarlane from Glasgow was the first to mention the entity in the English-speaking literature. Thus neoplasms in the abdominal walls of women who recently had given birth were described. Later similar tumors were found in other anatomic regions. The term “fibromatosis” was introduced for the first time by Arthur Purdy Stout from New York. He stated that desmoids are masses of proliferated, scarlike tissue, which despite the fact of tissue infiltration rarely recur (which is not true today!) and that do not become true malignant neoplasms.

Desmoids are very rare benign lesions representing less than 3% of all soft tissue tumors and 0.03% of all neoplasms. The incidence is 2–4 cases per million per year. Thus, the estimated frequency of desmoid tumors in the United States ranges from 500–1000 cases per year, and in Germany between 100 and 200 per year.

There is a female predominance (male:female ratio, 1:1.5–2.5). The highest incidence arises among patients in the third or fourth decade of life, but desmoids can occur in infants and the elderly as well.

Although the etiology of desmoids is poorly defined, numerous factors are acknowledged to be strongly associated with their development. Endocrine and physical factors seem to play an important role in the development of the disease . An antecedent history of trauma to the site of the tumor, often surgical in nature, may be elicited in approximately 25% of cases. In very rare cases desmoids can arise after surgery in scar tissue. Desmoid tumors developing around silicon or metal implants have also been described. However, so far no association between hip prostheses and desmoid tumors has been published in the world literature.

Intraabdominal and extraabdominal desmoids are significantly associated with familial adenomatous polyposis of the colon (FAP) and have an even more pronounced association with the subgroup of Gardner syndrome, an autosomal dominant hereditary disease

Clinically, desmoids show a slow, but locally aggressive growth pattern with a strong tendency to reappear after resection Some tumors display low-grade malignancy or spontaneous suspension of growth. Others progress to giant masses, leading to secondary clinical symptoms and complaints. Partial or temporary spontaneous remissions are possible. Some desmoids infiltrate organs or major vessels, leading to fatal outcome; the overall death rate is about 8% . Metastatic disease is always a rarity, but multifocal growth (e.g., on one extremity) instead has been described. In particular, in critical locations the differentiation into benign/malignant is inconsistent, e.g., in the mesenteric root.

Differentiation depending on location (extraabdominal, 70%; intraabdominal, 10%; confinement to the abdominal wall, 20%) can be of prognostic value. Extraabdominal manifestations also seem to have a higher recurrence rate, even after complete (in-sano) resection

The rarity of these tumors coupled with the variability in their clinical course does not allow the demonstration of the efficacy and, even more, the superiority of any specific intervention

The primary therapeutic approach is always radical surgical resection with wide safety margins (2–3 cm). Because of the indistinct tumor borders, however, “true” R0 resections are often very difficult to achieve

There has been a long tradition of using radiotherapy (RT) to achieve local control in primary or postoperative treatment. James Ewing  was the first to propose RT as a treatment modality for the management of desmoids not amenable to surgical resection. In 1928, he described that these lesions respond “slowly but satisfactorily” to RT.

In the next decades his observations were confirmed by several clinical studies . However, the role of RT in the management of desmoids is still not clearly defined today . Therefore, the analysis of larger collectives followed by the implementation of treatment guidelines and suitable tools for quality assurance is crucial for the further promotion of this treatment.

Outcome analysis in the context of PCS is an important tool to set up a national benchmark on treatment outcome that should be expected from RT in a specific disorder. So far this national PCS has collected the largest number of cases (345 patients from 34 institutions) ever reported on the use of RT for aggressive fibromatosis.

Our clinical data showed a long-term local control of 79.6% in postoperative RT and a slightly higher local control rate of more than 80% in unresectable tumors.

A review of recent literature on the management of aggressive fibromatosis revealed a wide range of treatment outcomes and heterogeneous treatment strategies. After surgery alone, local recurrence rates ranged between 20% and 80% .  Microscopic residual disease does not necessarily impair local control rates. One may well speculate that the recurrence rate depends highly on inherent characteristics of the disease, which might be more or less aggressive on its own, so that it might recur or not rather independently of the fine quality of surgery). It is recommended that high-risk surgical procedures to achieve negative margins be restricted to very special circumstances

Postoperative irradiation can reduce the recurrence rate significantly. Walther described a reduction from 80% to 10% with doses of at least 50 Gy. Other reports observed relapse rates of 5–40%, depending on patient selection

Obviously, aggressive fibromatosis is not a radioresistant disease. Even radiotherapy alone is able to achieve a high local control rate, comparable to the results of postoperative irradiation. Leibel reported a local control rate of 68% during a median follow-up of 8 years for 19 patients, who received doses between 50 Gy and 55 Gy. 

In the recent well-conducted meta-analysis of Nuyttens comprising 22 studies, a local control rate of 78% was shown, which is very similar to that achieved in our PCS. To achieve high local control rates with radiotherapy prompts the question whether this treatment approach can replace large and mutilating surgical interventions.

Other systemic therapeutic approaches such as hormonal therapies, chemotherapy, or immunotherapy are still lacking systematic evaluation. There have been several attempts of systemic therapy in primary and adjuvant settings at a high cost level and diverse response rates. A few reports deal with systemic hormonal therapy in aggressive fibromatosis, where the most commonly used antiestrogen is tamoxifen. Most reports, however, are single-case reports that have demonstrated either some response or disease stabilization during therapy. As large series are not available, no firm conclusion is possible regarding the effectiveness of tamoxifen. Nonsteroidal anti-inflammatory agents have an uncertain therapeutic impact and the precise mechanism remains to be investigated. The role of systemic chemotherapy is not yet clearly defined, including the use of alkylating agents with inconsistent results. No convincing results exist from conventional antineoplastic drugs, possibly owing to the low mitotic index exhibited by aggressive fibromatosis, although antisarcoma therapy primarily presented some promising results in small series Weiss and Lackman  found little effectiveness of vincristine and methotrexate. Generally, systemic treatment approaches should be reserved for selected cases

All participating institutions observed a low rate (27.8% < Grade II) of radiogenic side effects, which were mostly mild to moderate. Similarly, the complications reported in the literature were moderate (edema, pain paresthesias, stiffness, and weakness), caused no major disability, and were sometimes required to avoid an amputation. So far, in this PCS no radiation-associated malignancies were reported with a median follow-up of 43 months and a maximum of 306 months, while sporadic reports on secondary malignancies exist

Overall, the majority of German radiation oncologists in this national survey judged RT to be a worthwhile and useful treatment indication for aggressive fibromatosis. So far, this study comprises the largest database of cases reported for RT in aggressive fibromatosis. Radiotherapy achieves a high local control rate in the postoperative setting as well as in primary treatment of unresectable tumors. Despite some variations of the national RT praxis, the study presents the largest number of aggressive fibromatosis patients effectively treated by external beam RT.


The efficacy of radiotherapy as postoperative treatment for desmoid tumors
Jelinek JA, International Journal of Radiation Oncology*Biology*Physics - 1 May 2001 (Vol. 50, Issue 1, Pages 121-125)

Desmoid tumors are heterogeneous, benign tumors that originate from deep musculoaponeurotic structures. Also termed aggressive fibromatosis and well-differentiated fibromatosis, desmoid tumors display local infiltrative growth but do not metastasize. On gross examination, they appear as dense, rubbery gray-white masses. Desmoid tumors are nonencapsulated and tend to extend along fascial planes. They also have the potential to erode bone and surrounding blood vessels or nerves. Microscopically, desmoid tumors are associated with an abnormal proliferation of connective tissue but lack cytologic features of malignancy. They demonstrate extensive cellular peripheries, nearly acellular cores, and are characterized as a group of well-differentiated, spindle-shaped cells lacking pleomorphic, atypical, and hyperchromatic nuclei. Recently, the monoclonal composition of desmoid tumors has been substantiated. This indicates a true neoplastic nature of this heterogeneous tumor. Desmoid tumors can be distinguished from low-grade fibrosarcomas by a lack of mitotic activity, metastatic potential, and nuclear or cytoplasmic features of malignancy. Sarcolemmic giant cells are a common finding in desmoid tumors.

The estimated frequency of desmoid tumors in the United States ranges from 500–1000 cases per year. They account for approximately 0.03–0.1% of all solid tumors and 3.6% of the fibrous tissue neoplasms. The most common locations for desmoid tumors include the shoulder, chest wall, and thigh. Males and females of all ages can be affected by desmoid tumors, but a propensity for fertile women has been noted by many authors. Possible risk factors include estrogen status, pregnancy, physical and surgical trauma, radiation, skeletal abnormalities, and genetic determinants. Recurrence of desmoid tumors may be related to the age of the patient, the site of tumor, and the initial form of treatment. Desmoid tumors have been associated with Familial Adenomatous Polyposis (FAP) and Gardner’s Syndrome, suggesting a genetic predisposition to the disease. Recent studies have demonstrated two mutations, one germline and one somatic, in the adenomatous polypsis coli (APC) gene of patients with FAP. Inactivation of both alleles in the APC tumor-suppressor gene appears to be necessary for the formation of desmoid tumors in patients with FAP.

The primary mode of treatment for desmoid tumors is surgical excision. However, high recurrence rates (39–79%) have been reported when surgery is used alone. The goal of surgical excision is gross total resection with negative margins, but approximately one-third of desmoid tumors are not amenable to gross total resection. Local control rates have been reported to be a function of tumor location, ability to obtain negative margins, and adjuvant therapy. With respect to adjuvant radiation, there is controversy surrounding the dose, timing, and indications for treatment of desmoid tumors. Most of this controversy is related to the rarity of desmoid tumors and the limited information in the literature regarding adjuvant radiation.

A retrospective analysis was performed on 54 patients who underwent surgery without prior radiation at our institution between 1982 and 1998 to remove a desmoid tumor. Thirty-five patients had adjuvant radiation therapy after surgery, and 19 patients had surgery alone without immediate postoperative radiation. Sixteen of the 35 patients who underwent immediate postoperative radiation treatment had at least one prior resection before reoperation at our institution. Recurrence was defined as radiographic increase in tumor size after treatment. Follow-up interval (mean 39 months) and duration of local control were measured from the date of surgery at our institution. Potential prognostic factors for time to tumor progression were analyzed.

Results: Adjuvant treatment with radiation was the only significant prognostic factor for local control. The five-year actuarial local control rate was 81% for the 35 patients who underwent radiation in addition to surgery, compared to 53% for the 19 patients who underwent surgery alone (p = 0.018). For the patients who did not receive adjuvant radiation, only younger age at the time of surgery was associated with increased risk of failure (p = 0.035). Gross or microscopic margin status and number of prior operations were not detected as prognostic for local failure. For patients who did receive postoperative radiation, only abdominal location was associated with increased risk of failure (p = 0.0097).