The pharmacological treatment of aggressive fibromatosis: a systematic review

Annals of Oncology 14: 181–190, 2003 DOI: 10.1093/annonc/mdg064

Review

The pharmacological treatment of aggressive fibromatosis: a systematic review J. Janinis1*, M. Patriki1, L. Vini2, G. Aravantinos3 & J. S. Whelan4 1

Social Security Organization Oncology Center; 2Athens Medical Center, Athens; 3Saint Anargyri Cancer Center, Kifissia, Greece; 4The London Bone and Soft Tissue Tumour Service, Meyerstein Institute of Oncology, Middlesex Hospital, London, UK Received 25 March 2002 ; revised 16 August 2002; accepted 16 September 2002

Introduction The term aggressive fibromatosis (AF) describes a broad group of benign fibrous tissue proliferations of similar microscopic appearance that are intermediate in their biological behavior between benign fibrous tissues and fibrosarcomas [1]. AF (also known as desmoid tumors, from the Greek word desmos for ‘band of tendons’) is a relatively rare lesion representing <3% of all soft tissue tumors with a reported annual incidence of 0.2–0.5 per 100000 population [2–4]. The most frequent sites of involvement by these fibromatoses are the torso and the extremities. An important association of AF is reported in patients with familial adenomatous polyposis (FAP) (Gardner’s syndrome). Approximately 10% of patients with Gardner’s syndrome will develop mesenteric fibromatosis, which encases the mesenteric vasculature [5]. AF is characterized by low mitotic activity and a strong

*Correspondence to: Dr J. Janinis, 17 Kapodistriou Street, Pefki 15121, Athens, Greece. Tel: +30-10-6126582; Fax: +30-10-6126582; E-mail: [email protected] © 2003 European Society for Medical Oncology

infiltrative growth pattern along tissue planes, with an ability to invade adjacent tissues [6, 7]. Surgery and radiotherapy are the principal modalities of therapy and their aim is curative, especially for extra-abdominal, localized, small-volume disease. Local control rates after surgery can vary considerably depending on surgical margin status. Response rates of 72% and 41% have been reported for tumor-free and tumor-positive margins, respectively. The addition of postoperative radiotherapy in an adjunctive fashion yields superior results. Local control rates of 94% and 75% were reported for tumor-free and tumor-positive margins, respectively [8]. Radiotherapy without an attempt at resection may also achieve good results. Sherman et al. [9], using megavoltage radiotherapy with a median dose of 50 Gy, and McCollough et al. [10] achieved local control rates of 75% and 83%, respectively. It is noteworthy that spontaneous regressions have also been reported, a fact that supports a wait-and-see policy after resection without wide margins [11]. Local control is often achieved at a considerable cost, due to significant treatment-related morbidity from the high doses of

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

Background: Despite the use of surgery and radiotherapy, 20–35% of patients with aggressive fibromatosis (AF) will have local recurrence. The purpose of this review was to collect and analyze all available information regarding the role of non-cytotoxic and cytotoxic chemotherapy in AF that has been accumulated over the past few decades. Patients and methods: A systematic review of published clinical trials, studies and case series was carried out using the Medline Express Databases and the Cochrane Collaboration Database from 1970 to October 2000. Results: Most studies published in the literature are in the form of successful case reports and single-arm series with small patient numbers. Most commonly used agents include hormonal agents, non-steroidal antiinflammatory drugs (NSAIDs), interferons and cytotoxics. The literature data support the use of hormonal agents. Several questions, however, remain unresolved, such as which is the most suitable endocrine manipulation and what is the optimal dose and duration of treatment. NSAIDs and interferons have demonstrated activity against AF either alone or in combination with hormone therapy or chemotherapy but the precise mechanism of action is still unknown. Finally, there is growing evidence in the literature that chemotherapy is effective against AF with almost one in two patients being likely to respond. Conclusions: The evidence in the literature supports the opinion that both non-cytotoxic and cytotoxic chemotherapies are effective against AF. However, the lack of sufficient patient numbers and randomized trials compromises the validity of the reported results and mandates further investigation with properly designed prospective studies including larger patient numbers, with main end points to include not only tumor response rate and survival but also quality-of-life issues. Key words: aggressive fibromatosis, desmoid tumors, chemotherapy, hormonal therapy

182

Patients and methods Data available on the topic AF in the English language literature were obtained, reviewed and analyzed. Published trials, studies and series were identified using Medline Express databases (National Library of Medicine, Washington DC, USA) from 1970 to October 2000 and the Cochrane Collaboration database. The keywords ‘aggressive fibromatosis’, ‘desmoid tumors’, ‘hormonal therapy’ and ‘chemotherapy’ were used. Cross-referencing, using the references of all identified studies, helped complement the computeraided searches. Only cases that had adequate clinical information were included in the review. Basic clinical parameters that were required included patients’ age and sex, a history of FAP, tumor location (extra- versus intraabdominal), tumor status (primary versus recurrent), previous therapy, type of therapy, response and duration of response.

Results Non-cytotoxic agents Hormonal agents. A number of observations regarding the natural history of desmoid tumors suggest that they may be hormonally responsive. Desmoid tumors are more frequent in women. About 80% of these tumors occur in women [4]. Reitamo et al. [2] observed that the speed of growth of desmoid tumors is higher during pregnancy, in premenopausal compared with postmenopausal women, and in females relative to males. In fertile women the growth rate is double that observed in men, suggesting that estrogens stimulate the growth of AF. The theory of hormone dependency has been supported also by preclinical and in vitro studies. Lipschutz [18] described the formation of fibrous tumors histologically similar to desmoids in the abdominal organs, anterior abdominal wall, and thorax of guinea-pigs following prolonged estrogen administration. They also showed that it was possible to prevent these tumors by the administration of testosterone, progesterone and desoxycorticosterone [18, 19].

Estrogen receptors (ERs) have been demonstrated in desmoids of FAP patients, although the receptor levels were low [20, 21]. The presence of antiestrogen binding sites (AEBS) distinct from ERs probably plays an important role in modulating or mediating the action of antiestrogens. Furthermore, the presence of high levels of AEBS in desmoid tumors found to be ER-negative might explain responses to tamoxifen when the overall incidence and concentration of ERs is low in these tumors [22, 25]. Because of their rarity, there are no randomized studies conclusively proving that AF responds to endocrine manipulation. However, several single-arm trials and case reports document both stabilization and regression of desmoid tumors to hormones alone or in combination with other non-cytotoxic agents (Tables 1 and 2). A number of hormonal agents have been tested and found to be effective in AF. Such agents include tamoxifen and toremifene, progesterone, medroxyprogesterone acetate, prednizolone, testolactone and gosereline [26–44]. One of the most commonly used antiestrogens in AF is tamoxifen, with many citations in the literature [26–32, 35–37]. Most of these reports, however, include single-case reports that have demonstrated either some sort of response or disease stabilization during therapy. Since larger series of patients are not available it is not possible to reach any firm conclusions regarding the effectiveness of tamoxifen against AF. Triphenylethylenes other than tamoxifen also appear to be effective against desmoids as first- and second-line therapy. In a study by Brooks and co-workers [33], 20 patients with desmoid tumors of various sites were treated with toremifene at an average dose of 200 mg/day. With toremifene as first-line therapy (12 patients) the overall response rate was 50% (one complete and five partial responses) while an additional five patients (42%) had stabilization of their disease. Toremifene as second-line therapy (six patients) gave a response rate of 33% (two partial responses). One patient had disease stabilization. Based on Lipschutz’s observations that the development of estrogen-induced fibrous tumors in guinea-pigs was prevented by the simultaneous administration of progesterone [18, 19], Lanari reported a series of 11 patients with mediastinal and retroperitoneal AF treated with progesterone at a dose of 100 mg/day [38]. There was a complete response in six patients (55%). Significant data, however, were lacking from this study, such as duration of response, the age and sex of the patients and whether treatment was first- or second-line. Furthermore, these results have not been confirmed by other investigators. Another hormonal compound frequently tested was testolactone. Testolactone is not androgenic, estrogenic, progestational or antiprogestational in the usual sense but acts by irreversibly inhibiting aromatase, a rate-controlling enzyme responsible for the conversion of testosterone to estradiol and androstenedione to estrone [43]. The precise mechanism of action is unknown, although it is believed that testolactone acts through inhibition of cyclic AMP synthesis, which is known to influence growth and proliferation of fibroblasts [44]. The largest reported study on the activity of testolactone is that of Waddell and Kirsch in a series of 17 patients. Testolactone administered as a single agent gave an overall response rate of 40%, while combination with an anti-

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

external radiation therapy (>50 Gy) or the disfiguring surgical procedures that are often required. In addition, despite the use of surgery and radiation therapy 20–36% of patients will show local recurrence [8–18]. Recurrent tumors can progress locally and occasionally lead to death; however, it is an uncommon outcome. Thus although classified as benign, recurrent AF can result in death due to local destruction in a small but important fraction of patients. The potential morbidity of surgery and radiation therapy and the high local recurrence rates have lead investigators to assess the role of non-cytotoxic and cytotoxic chemotherapy in settings in which surgery and radiation therapy are either not possible or unsuccessful. A number of issues should be considered in clinical trials assessing the role of non-cytotoxic and cytotoxic chemotherapy in AF. These include: criteria and duration of response; the importance of disease stabilization; measuring and dating progressions; documentation of progressive disease before starting treatment; heterogeneity of patients; heterogeneity of previous treatment; and the timing and indications for the investigated treatment. All of these issues are important shortcomings hampering the validity of the results reported.

Table 1. Antiestrogen therapy in patients with aggressive fibromatosis: single-arm trials and case reports Author Kinzbrunner et al. 1983 [26]

No. of patients 1

Sex

Age, range (median)

History of FAP

Primary or recurrent

Location

Hormonal agent

NSAID

Response

Response duration

F

29

Yes

Recurrent

Multifocal

Tamoxifen 80 mg/day

No

PR

NR

Rock et al. 1984 [27]

5

NR

NR

NR

Recurrent

NR

Tamoxifen

No

2 SD, 3 PD

NR

Procter et al. 1987 [28]

1

F

26

No

Recurrent

Multifocal

Tamoxifen 40 mg/day

No

SD

14 months

Eagel et al. 1989 [29]

1

F

29

Yes

Recurrent

Mesentery

Tamoxifen 20 mg/day, megace 300 mg/day

No

SD

7 months

Sportiello and Hoogerland 1991 [30]

1

F

40

No

Recurrent

Pelvic

Tamoxifen 80 mg/day

No

CR

27 months

Thomas et al. 1990 [31]

1

F

30

No

Recurrent

Shoulder girdle

Tamoxifen 20 mg/day

No

CR

12 months

Wilcken and Tattersall 1991 [32]

2

F

40

No

Recurrent

Calf

Tamoxifen 20 mg/day

No

1 PR

8 years

F

40

No

Primary

Mesentery

Megace 500 mg/day

No

1 PR

10 months

15 F, 5 M

18–70 (29)

NR

12 Primary, 8 recurrent

14 Abdominal and pelvic

Toremifene 200 mg/day

No

1 CR, 10 PR, 6 SD

NR

1

F

17

NR

Primary

Retroperitoneum

Toremifene 200 mg/day

No

PR

9 months

Mukherjee et al. 1995 [35]

1

M

16

NR

Primary

Pelvis

Tamoxifen 20 mg/ day, prednisolone 60 mg/day

No

PR

2 years

Izes et al. 1996 [36]

1

M

54

NR

Primary

Pelvis

Tamoxifen 160 mg/day

Sulindac 300 mg/day

PR

54 months

Lackner et al. 1997 [37]

2

F

1

NR

Recurrent

Chest wall

Tamoxifen 2 mg/kg/day

Diclofenac 4 mg/kg/day

SD

4 years

F

1.5

NR

Primary

Mandible

as above

as above

SD

1 year

Brooks et al. 1992 [33]

20

Benson et al. 1994 [34]

CR, complete response; F, female; FAP, familial adenomatous polyposis; M, male; NR, not reported; NSAID, non-steroidal anti-inflammatory agent; PD, progressive disease; PR, partial response; SD, stable disease.

183

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

17 months PR Goserelin 3.6 mg/month, tamoxifen 30 mg/day Mesentery Recurrent Yes 26 F 1 Bauernhofer et al. 1996 [42]

CR, complete response; F, female; FAP, familial adenomatous polyposis; M, male; NR, not reported; NSAID, non-steroidal anti-inflammatory agent; PD, progressive disease; PR, partial response; SD, stable disease.

NR 5 PR, 1 SD, 1 PD Sulindac or indomethacin with warfarin NR 7 Waddell and Kirsch 1991 [41]

5 F, 2 M

21–38

NR

2 Mesentery, 2 abdominal wall

No

NR 2 CR, 2 PR, 6 PD

Testolactone 750 mg/day

12 years 1 PR

No

No Testolactone 150–200 mg/day

Testolactone 750 mg/day NR

5 Mesentery, 2 abdominal wall

Recurrent

4 Yes, 6 No 21–44 (27) 4 F, 6 M

1

10

Fujimoto and Hidai 1990 [40]

Waddell and Kirsch 1991 [41]

F

52

No

Head and neck

3 years SD Primary NR Khorsand and Karakousis 1985 [39]

1

NR

Yes

Mesentery

Testolactone

No

NR 6 CR NR 11 Lanari 1983 [38]

NR

NR

NR

Mediastinum, retroperitoneum

Progesterone 100 mg/day

No

Response duration Location Primary or recurrent History of FAP Age range (median) Sex No. of patients Author

Table 2. Other hormonal therapy in patients with aggressive fibromatosis: single-arm trials and case reports

inflammatory non-steroidal drug (NSAID) such as sulindac or indomethacin yielded a response rate of 70% [41]. Most of the data available in the literature are on testolactone, which is regarded as a first-generation steroidal and irreversible inactivator of aromatase. Whether the second- and third-generation steroidal aromatase inactivators, such as formestane and exemestane, will yield superior results against AF remains to be seen in future trials. Anti-inflammatory agents. The use of NSAIDs against AF was based on the surprising observation of total regression of a single recurrent desmoid tumor of the sternum in a patient taking indomethacin for radiation-induced pericarditis [45]. Furthermore, there is evidence that endogenous prostaglandin synthesis plays a role in neoplastic growth and that prostaglandin inhibitors can control the growth of experimental tumors [46, 47]. Subsequently, a variety of NSAIDs such as indomethacin and sulindac (a long-acting analog of indomethacin) were used to treat patients with desmoid tumors and were associated with partial and complete responses in several non-randomized retrospective studies (Table 3). NSAIDs have been tested either alone [23, 41, 48–50] or in combination with hormonal agents such as tamoxifen and testolactone [36, 37, 41]. Tsukada and co-workers assessed the efficacy of sulindac in 14 patients with a history of FAP and recurrent abdominal desmoid tumors [48]. The overall response rate was 57% and the majority of responders experienced a delayed response with a mean time of 24 months. Such delays in response have also been observed in patients treated with radiation therapy [10, 51] and with systemic chemotherapy [52–54]. Besides indomethacin and sulindac other NSAIDs such as colchicine have been tested against AF with success [50]. The response of AF to NSAIDs is an interesting phenomenon, the precise mechanism of which is still not clear and remains to be investigated. Biological agents. There is theoretical background to support the use of interferons (IFNs) in AF. In vitro observations and animal experimental data suggest an antiproliferative effect of both IFN-α and retinoic acid on fibroblasts [55, 56]. Furthermore, IFN-γ has been shown to inhibit fibroblast collagen synthesis [57]. The clinical experience with the use of interferons in AF, however, is limited in comparison with endocrine manipulation or cytotoxic chemotherapy. Most published studies utilized IFN-α [58–61], while anecdotal cases report on the efficacy of IFN-γ [42, 58]. From a total of nine patients with recurrent and measurable AF reported in the literature there were four responses (two with complete response) and the remaining five patients had stabilization of their disease lasting from 6 to 53 months (Table 4). Apart from mild toxicity related to IFN the treatment was well tolerated in all patients. There is also a suggestion that IFN-α can be used as adjuvant treatment for patients with completely resected AF in order to prevent further disease recurrence [61]. However, the number of patients analyzed so far is small and there is no comparison arm, therefore no conclusive statements can be made regarding the adjuvant role of interferons in AF. Whether IFN can be used as a non-cytotoxic alternative in

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

Hormonal agent

NSAID

Response

184

Table 3. Anti-inflammatory therapy in aggressive fibromatosis: case reports Author

No. of patients

Sex

Age (median)

History of FAP

Primary or recurrent

Location

Anti-inflammatory treatment

Other

Response

Response duration

Tsukada et al. 1992 [48]

14

NR

29

Yes

Recurrent

Abdominal

Sulindac 300 mg/day

No

1 CR, 7 PR, 4 SD

NR

Klein et al. 1987 [23]

3

2 M, 1 F

NR

Yes

Recurrent

Abdominal wall, mesentery

Indomethacin 100 mg/day

No

2 PD, 1 SD

NR

Waddell and Kirsch 1991 [41]

8

4 F, 4 M

22–76 (39)

4 Yes, 4 No

NR

4 Mesentery

Sulindac 300–400 mg/day or indomethacin 75–300 mg/day

Warfarin

3 PR, 3 SD, 2 PD

NR

Belliveau and Graham 1984 [49]

1

M

36

Yes

Primary

Mesentery

Sulindac 200 mg/day

No

1 PR

Dominguez-Malagon et al. 1992 [50]

3

F

30

No

Primary

Extra-abdominal

Colchicine 3 mg/day

No

PR

NR

F

21

No

Primary

as above

as above

No

PR

NR

M

47

No

Primary

as above

as above

No

PR

NR

CR, complete response; F, female; FAP, familial adenomatous polyposis; M, male; NR, not reported; PD, progressive disease; PR, partial response; SD, stable disease.

Table 4. Interferons in patients with aggressive fibromatosis Author

No. of patients

Sex

History of FAP

Primary or recurrent

Age

Location

Prior treatment

Treatment

Response

Follow-up

Acker et al. 1993 [58]

2

NR

NR

NR

NR

Mesentery

Tamoxifen, VAC

IFN-α

PR

53 months

NR

NR

NR

NR

Retroperitoneal

Tamoxifen, VAC

IFN-γ

PR

NR

Geurs and Kok 1993 [59]

1

F

Yes

Recurrent

40

Mesentery

Sulindac, tamoxifen

IFN-α 3 × 106 IU three times weekly

CR

2 years

Bauernhofer et al. 1996 [42]

1

F

Yes

Recurrent

26

Mesentery

Resection, tamoxifen, goserelin, megace

IFN-α 3 × 106 IU three times weekly

SD

6 months

Fernberg et al. 1999 [60]

1

M

No

Recurrent

21

Knee

Resection × 2

IFN-α-2c 3 × 106 IU/day ongoing

CR

8 years

Resection

IFN-α-2c 3.5 × 10 IU three times weekly + tretinoin 30 mg orally/day

4 SD

35 ± 3 months

Leithner et al. 2000 [61]

4

1 M, 3 F

No

1 Primary, 3 recurrent

14–32

Extremity

6

CR, complete response; F, female; FAP, familial adenomatous polyposis; IFN, interferon; M, male; NR, not reported; PR, partial response; SD, stable disease; VAC, vincristine, actinomycin-D, cyclophosphamide.

185

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

186 patients in whom endocrine therapy fails remains to be addressed in a properly designed study.

Cytotoxic chemotherapy

Regional chemotherapy. Regional chemotherapy in the form of isolated limb perfusion (ILP) is another alternative to systemic therapy in patients with limb desmoids. This is a particularly attractive method if one considers that AF rarely metastasizes. The first report on ILP in AF was published in 1989 by Klaase et al. [75]. In this study, ILP with melphalan and doxorubicin obtained three complete responses in seven patients for an overall response rate of 43% and duration of response ranging between 9 and 11 years. One patient with stable disease after ILP had been in a stable condition for 6 years at the time of the report. ILP with melphalan and tumor necrosis factor was recently attempted in six patients with recurrent limb desmoid tumors [74]. The overall response rate was 83% with 33% (two of six) complete responses and 50% (three of six) partial responses. The limb salvage rate was 100%. This method is primarily useful in patients with locally advanced or recurrent tumors not amenable to conservative resections. The high complete response rates achieved by this method mandates further confirmation in well-designed studies.

Discussion An endocrine approach to the management of AF is a rational one. However, the true role of endocrine therapy still remains unknown. There does not appear to be a correlation between response to tamoxifen and ER status. On the other hand a significant number of AF tumors exhibit AEBS. Whether levels of AEBS in AF can be predictive for a clinical response to tamoxifen or toremifene is an issue that has not been investigated yet. Further issues yet to be addressed include which is the most appropriate endocrine manipulation, at which dose and for how

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

Single-arm studies utilizing cytotoxic chemotherapy in AF (Table 5) were reported as early as 1982, although case reports on the successful use of chemotherapy in AF date back to 1977 [62–78]. The earliest reports involved pediatric patients suffering from AF of the head and neck in whom physicians were reluctant to use radiation therapy because of the risk of epiphyseal destruction and the subsequent deformation of the irradiated area [62, 63]. Subsequent reports showed the efficacy of chemotherapy on AF involving various sites such as mesentery in combination with FAP, abdominal wall, extra-abdominal and extremity desmoid tumors. Assessment of response during the early trials was more difficult to ascertain due to the retrospective nature of the studies and the lack of modern imaging techniques at the time. Subjective improvement of symptoms and direct visualization of the tumor by physical examination or at laparotomy were serving as the principal assessment modalities. However, with the advent of computed tomography scanning and magnetic resonance imaging, objective response assessment has become more feasible in recent years. There is limited information on single-agent activity of chemotherapy against AF. Seiter and Kemeny [76] reported on the use of single-agent doxorubicin in a case report. There have been no single-arm trials utilizing single-agent therapy in the literature. On the other hand, combination chemotherapy regimens were employed more frequently in these patients and most information regarding the effectiveness of cytotoxic chemotherapy is mainly derived from them [52–54, 63–75]. Overall response rates to combination chemotherapy in single-arm studies range between 17% and 100% with a median response rate of 50%. Most commonly used regimens included doxorubicin-based chemotherapy (doxorubicin with dacarbazine or doxorubicin with cyclophosphamide and vincristine) [52, 63, 67–69, 71, 76], actinomycinD-based chemotherapy [52, 64–66] or a combination of methotrexate with a vinca alkaloid (vinblastine or vinorelbine) [53, 70, 72, 73]. Doxorubicin-based chemotherapy is effective with responses similar to or even higher than those achieved in soft tissue sarcomas. The dose of doxorubicin ranged between 60 and 90 mg/m2/cycle. This combination, however, had considerable acute and late toxicity, mainly in the form of cardiotoxicity. To avoid this, some investigators discontinued doxorubicin or substituted it with carboplatin once a cumulative dose of 400–500 mg/m2 was reached [77]. A reasonable alternative to doxorubicin-based chemotherapy is the VAC (vincristine, actinomycin-D, cyclophosphamide) regimen with comparable responses. Main concerns with VAC chemotherapy are those of sterility and carcinogenesis, especially when treatment is administered to younger patient populations for protracted periods. The combination of methotrexate with vinblastine administered on a weekly basis was proposed as a less toxic alternative to doxorubicinbased and VAC chemotherapy. This is especially true for pediatric patients and young patients of child-bearing potential in whom treatment would have to be administered for prolonged

periods [53]. Weiss and Lackman [53] and Skapec [54] reported separately that the combination was effective in both adult and pediatric patients with minimal side-effects. Another report, however, by Azarrelli et al. demonstrated that weekly treatment was not feasible due to myelotoxicity and hepatotoxicity and the mean interval between cycles was found to be 15 days [70]. In a recent study the substitution of vinorelbine for vinblastine resulted in significantly less neurotoxicity without a compromise in response rates [72]. A number of reports suggest that the response of AF to chemotherapy may be slow [52–54]. This may be due to the unique pathological features of this tumor, which is characterized by the presence of abundant collagen tissue, scanty malignant cells, especially in the center of the tumor, and rare mitoses. A number of investigators observed no evidence of response in some patients for several months under cytotoxic chemotherapy. Pilz et al. recommends that chemotherapy should not be discontinued before the 20th week of treatment [52], while Skapec suggests that treatment should be continued for prolonged periods from 12 to 18 months even if there is no radiographic evidence of response [54]. Azzarelli et al. found that any response to treatment was not evident before 8–12 weekly cycles of treatment [70]. Similar delays in response have been shown in the case of radiation therapy, where response of desmoid tumors may be delayed by as much as 8–27 months [10, 57].

Table 5. Chemotherapy in patients with aggressive fibromatosis: single-arm studies Author

No. of patients

Sex

History of FAP

Primary or recurrent

Age range (median)

Extremity/axial

Chemotherapy

Duration of therapy

Responses

ORR (%)

Follow-up (months)

NR

2 months– 4 years

Head and neck

DOX + DTIC

NR

2 CR, 3 PR

100

NR

83

Goepfert et al. 1982 [63]

5

NR

NR

Raney et al. 1987 [64]

6

3 M, 3 F

NR

2/4

3 months– 7 years

1/5

VAC

3–56 weeks

4 CR, 1 PR

Delepine et al. 1987 [65]

6

NR

NR

NR

13–23 years

Extra-abdominal

VAC

NR

6 OR

Gansar and Krementz 1988 [66]

4

NR

NR

NR

14–39 years

Extra-abdominal

Mustard + DACT + thiotepa + MTX

NR

Weiss and Lackman 1989 [53]

8

1 M, 7 F

NR

3/5

21–56 years

5/3

MTX 50 mg/week, VBL 10 mg/week

Tsukada et al. 1991[67]

8

4 M, 4 F

NR

0/8

32 years

0/8

12

8 M, 4 F

4/12

0/12

16–66 years (29)

5

3 M, 2F

5

0/5

Skapec et al. 1998 [54]

10

6 M, 4 F

0

2/8

Azzarelli et al. 1998 [70]

27

17 M, 10 F

NR

27/0

7

5 M, 2 F

4/3

Weiss et al. 1999 [72]

13

7 M, 6 F

Reich et al. 1999 [73]

5

Lev-Chelouche et al. 1999 [74]

1–11 years

100

NR

1 CR, 1 PR

50

NR

NR

2 CR, 4 PR, 1 MR

75

2–30 months

DOX + CYC + VCR or 5-FU + VCR

NR

2 CR, 1 PR

37

12–72 months

3/9

DOX 60–90 mg/m2, DTIC 750–1000 mg/m2

5 cycles

2 CR, 4 PR, 1 MR, 2 SD

50

28–235 months

29–45 years (36)

0/5

DOX + DTIC × 7 cycles then CARBO + DTIC

6–19 cycles

1 CR, 3 PR, 1 SD

80

22 months

7–22 years (14)

6/4

MTX 20–30 mg/m2/week, VBL 3–6 mg/m2/week

∼52 weeks

3 CR, 2 PR, 3 SD, 2 PD

50

5–37 months

33 years

4/23

MTX 30 mg/m2/week, VBL 6 mg/m2/week

27 weeks

4 OR, 19 SD

17

6–96 months

2/5

17–66 years (40)

1/6

CYC + DOX or IFOS + VP-16 or MITO + DOX + CIS

3–12 months

3 OR

43

3 months– 15 years

NR

NR

NR

8/5

MTX 50 mg/week, VNR 20 mg/m2/week

NR

NR

60

<12 months

5M

NR

0/5

7–17 years

4/1

MTX 30 mg/m2/week, VBL 6 mg/m2/week

52 weeks

2 CR, 1 PR, 1 MR, 1 SD

60

7–76 months

6

3 M, 3 F

NR

1/5

14–52 years (25)

6/0

Melphalan (1–1.5 mg/kg) + TNF (3–4 mg) ILP

NR

2 CR, 3 PR, 1 MR

83

7–55 months

Klaase et al. 1989 [75]

7

NR

NR

0/7

NR

NR

Melphalan + doxorubicin ILP

NR

3 CR, 1 SD

43

NR

Pilz et al. 1999 [52]

19

NR

NR

NR

NR

NR

VAIA, VAC, CYC + IFO

8–52 weeks

4 CR, 5 PR

47

NR

Patel et al. 1993 [68] Schnitzler et al. 1997 [69]

Okuno and Edmonson 1999 [71]

CARBO, carboplatin; CIS, cisplatin; CR, complete response; CYC, cyclophosphamide; DACT, actinomycin-D; DOX, doxorubicin; DTIC, dacarbazine; FAP, familial adenomatous polyposis syndrome; 5FU, 5-fluorouracil; IFO ifosfamide; ILP, isolated limb perfusion; MITO, mitomycin; MR, minor response; MTX, methotrexate; NR, not reported; OR, objective response; PD, progressive disease; PR, partial response; SD, stable disease; TNF, tumor necrosis factor; VAC, vincristine, actinomycin-D, cyclophosphamide; VAIA, vincristine, doxorubicin, ifosfamide, actinomycin-D; VBL, vinblastine; VCR, vincristine; VNR, vinorelbine; VP-16, etoposide.

187

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

188 longed period (at least 1 year) unless there is evidence of disease progression or severe treatment-related toxicity, even if there is no radiographic evidence of response. These results should be interpreted with some caution, however, for two reasons. First, most trials have not been designed in a prospective fashion and secondly the numbers of participating patients are small. Nevertheless, the finding of considerable tumor regression or even complete disappearance with a long-lasting effect in several studies is encouraging. Still, most conclusions on the role of noncytotoxic and cytotoxic chemotherapy in AF are logical, based primarily on incomplete evidence in the form of low-powered phase II studies or case reports, the majority of which are supportive of the role of various agents against AF. High-level evidence in the form of randomized clinical trials or meta-analyses to support the role of non-cytotoxic and cytotoxic chemotherapy in AF is lacking. The identification of CD117 expression in AF has raised the question as to whether there is a role for imatinib in this disease. Currently there is insufficient evidence to support its use but hopefully its role will be explored in well-designed clinical trials. Systemic treatments should be considered in patients with AF for whom local treatment approaches have failed. Documentation of disease progression and/or assessable symptoms before the initiation of systemic chemotherapy is essential. All patients should be included in clinical trials whenever possible. In the absence of an appropriate clinical trial, initiation of treatment in a stepwise manner may be appropriate. The first logical step of systemic treatment should include an NSAID such as sulindac or indomethacin. If this fails and providing that the tumor’s growth rate is not rapid the second step should be with tamoxifen. If despite this AF continues to progress, cytotoxic chemotherapy should commence, the combination of methotrexate and vinblastine being the regimen with best results at lowest morbidity. The duration of any of these treatments should be based on tolerance and evidence of continued clinical benefit. It should be stressed, however, that AF is a variable disease with several different clinical entities existing within the same label (abdominal, extra-abdominal, extremity AF, etc.). In addition, several other factors, such as the high rate of spontaneous disease stabilization may confound analysis of chemotherapy effectiveness. The primary focus of this review was to present a comprehensive analysis of activity of different agents in AF. The final decision of how to incorporate the above information in everyday clinical practice should be a rational one based on patient characteristics and the tumor’s biological properties.

References 1. Chaudhuri B, Das Gupta TK. Pathology of soft tissue sarcomas. In Das Gupta TK, Chaudhuri PK (eds): Tumors of the Soft Tissues. Stamford, CT: Appleton and Lange 1998; 63–200. 2. Reitamo JJ, Scheinin TM, Havry P. The desmoid syndrome. New aspects in the cause, pathogenesis and treatment of the desmoid tumor. Am J Surg 1986; 151: 230–237. 3. Dahn J, Johnson N, Lundh G. Desmoid tumours. A series of 33 cases. Acta Chir Scand 1963; 126: 305–314.

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

long. Newer hormonal compounds such as the second and third generation steroidal aromatase inactivators may yield superior results against AF, but this remains to be seen in future trials. Other non-cytotoxic agents that appear to be active against AF either alone or in combination with cytotoxic chemotherapy include the NSAIDs and interferons. NSAIDs have been tested either alone or in combination with hormonal agents. The response of AF to NSAIDs is an interesting phenomenon, the precise mechanism of which is still not clear. The use of IFN as a noncytotoxic alternative for patients in whom endocrine therapy fails is an issue that remains to be addressed in a properly designed study. The role of chemotherapy in the treatment of desmoid tumors has not been adequately studied for several reasons: (i) They are relatively rare tumors that often respond to other treatment modalities such as surgery and local radiotherapy. These tumors, however, despite aggressive local therapy, tend to recur locally and frequently surgical removal or re-irradiation is no longer a reasonable option. Other medical treatment modalities such as hormonal manipulation or NSAIDs appear to be effective in controlling or even reversing the growth process of recurrent AF but they are effective only in a small percentage of patients and the effect is not long-lasting. (ii) There is a general misconception that chemotherapy will not be effective in this low-grade tumor, which is largely acellular, and (iii) many investigators are reluctant to propose cytotoxic chemotherapy because of concerns regarding the toxicity and its impact on the patients quality of life. With the recent advances in supportive care, however, especially after the introduction of the newer antibiotics, antiemetics, and growth factors, this concern should become less of an issue. Furthermore, the emotional and functional well-being in the long run should take precedence over short-term toxicities. There are certain situations where chemotherapy should be considered as a reasonable option in AF such as: (i) In those situations in which aggressive surgical resections in the form of limb-sacrificing surgical procedures, hemimandibulectomies, hemipelvectomies, or chest wall resections could result in severe disfigurement [13, 78]. The psychological impact of these procedures is even more compounded when applied to younger patients. (ii) In patients with large mesenteric or retroperitoneal tumors encasing vital structures such as vessels, nerves or ureters. In these situations surgery or radical radiation therapy is either not feasible or excessively morbid. (iii) In patients with tumors recurring after use of other non-cytotoxic treatment such as hormonal agents or NSAIDs. Most information on the use of cytotoxic chemotherapy is primarily based on combination chemotherapy regimens. There is substantial evidence in the literature that chemotherapy is effective against AF. Almost one in two patients with AF is likely to respond to cytotoxic chemotherapy. This is quite a satisfactory response since chemotherapy is often considered as a last resort in the management of AF, and the patients selected often have advanced inoperable or recurrent disease after combined therapeutic modalities such as surgery and radiation, presenting with severe complications. Although there is no general consensus, the data suggest that chemotherapy should be continued for a pro-

189 30. Sportiello DJ, Hoogerland DL. A recurrent pelvic desmoid tumor successfully treated with tamoxifen. Cancer 1991; 67: 1443–1446. 31. Thomas S, Datta-Gupta S, Kapur BM. Treatment of recurrent desmoid tumours with tamoxifen. Aust NZ J Surg 1990; 60: 919–921. 32. Wilcken N, Tattersall MHN. Endocrine therapy for desmoid tumors. Cancer 1991; 68: 1384–1388. 33. Brooks MD, Ebbs SR, Colletta AA et al. Desmoid tumors treated with triphenylethylenes. Eur J Cancer 1992; 28A: 1014–1018. 34. Benson JR, Mokbel K, Baum M. Management of desmoid tumors including a case report of toremifene. Ann Oncol 1994; 5: 173–177. 35. Mukherjee A, Malcolm A, De la Hunt M et al. Pelvic fibromatosis (desmoid)—treatment with steroids and tamoxifen. Br J Urol 1995; 75: 559–560. 36. Izes JK, Zinman LN, Larsen CR. Regression of large pelvic desmoid tumor by tamoxifen and sulindac. Urology 1996; 47: 756–759. 37. Lackner H, Urban C, Kerbl R et al. Noncytotoxic drug therapy in children with unresectable desmoid tumors. Cancer 1997; 80: 334–340. 38. Lanari A. Effect of progesterone on desmoid tumors (aggressive fibromatosis). N Engl J Med 1983; 309: 1523. 39. Khorsand J, Karakousis K. Desmoid tumors and their management. Am J Surg 1985; 149: 215–218. 40. Fujimoto Y, Hidai K. Aggressive fibromatosis in the neck. A case treated effectively by testolactone with a long follow-up study. Jpn J Surg 1990; 20: 453–457. 41. Waddell WR, Kirsch WM. Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors. Am J Surg 1991; 161: 416–421. 42. Bauernhofer T, Stoger H, Schmid M et al. Sequential treatment of recurrent mesenteric desmoid tumor. Cancer 1996; 77: 1061–1065. 43. Barone RM, Shamonki IM, Siiteri PKD et al. Inhibition of peripheral aromatization of androstenedione to estrone in post-menopausal women with breast cancer using ∆1- testolactone. J Clin Endocrinol Metab 1979; 49: 672–676. 44. Rozengurt E. Synergistic stimulation of DNA synthesis by cyclic AMP derivatives and growth factors in mouse 3T3 cells. J Cell Physiol 1982; 112: 243–250. 45. Waddell WR, Gerner RE. Indomethacin and ascorbate inhibit desmoid tumours. J Surg Oncol 1980; 15: 85–90. 46. Hial V, Horakova A, Shaff RE. Alteration of tumour growth by aspirin and indomethacin: studies with two transplantable tumors in mouse. Eur J Pharmacol 1976; 37: 367–376. 47. Fischer SM, Mills GD, Slaga TJ. Inhibition of mouse skin tumor promotion by several inhibitors of arachidonic acid metabolism. Carcinogenesis 1982; 3: 1243–1245. 48. Tsukada K, Church JM, Jagelman DJ et al. Noncytotoxic therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis. Dis Colon Rectum 1992; 35: 29–33. 49. Belliveau P, Graham AM. Mesenteric desmoid tumor in Gardner’s syndrome treated by sulindac. Dis Colon Rectum 1984; 27: 53–54. 50. Dominguez-Malagon HR, Alfeiran-Ruiz A, Chavaria-Xicotencatl P et al. Clinical and cellular effects of colchicine in fibromatosis. Cancer 1992; 69: 2478–2483. 51. Kiel KD, Suit HD. Radiation therapy in the treatment of aggressive fibromatosis (desmoid tumors). Cancer 1984; 54: 2051–2055. 52. Pilz T, Pilgrim TB, Bisogno G et al. Chemotherapy in fibromatoses of childhood and adolescence: results from the Cooperative soft tissue sarcoma study (CWS) and the Italian Cooperative study group (ICG-AIEOP). Klin Padiatr 1999; 211: 291–295. 53. Weiss AJ, Lackman RD. Low-dose chemotherapy of desmoid tumors. Cancer 1989; 64: 1192–1194. 54. Skapec 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 1998; 16: 3021–3027.

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

4. McAdam WAF, Goligher JC. The occurrence of desmoids in patients with familial polyposis coli. Br J Surg 1970; 57: 618–631. 5. Naylor EW, Gardner EJ, Richards RC. Desmoid tumors and mesenteric fibromatosis in Gardner’s syndrome. Arch Surg 1979; 114: 1181–1185. 6. Enzinger FM, Weiss SW. Fibromatosis. In Harshberger SE (ed): Soft Tissue Tumors. St Louis, MO: CV Mosby 1983; 40–70. 7. MacKenzie DH. The fibromatoses: a clinicopathological concept. Br Med J 1972; 4: 277–281. 8. Nuyttens JJ, Rust PF, Thomas CR, Turrisi AT III. Surgery versus radiation therapy for patients with aggressive fibromatosis or desmoid tumors. A comparative review of 22 articles. Cancer 2000; 88: 1517– 1523. 9. Sherman NE, Romsdahl M, Evans H et al. Desmoid tumors: a 20-year radiotherapy experience. Int J Radiat Oncol Biol Phys 1990; 19: 37–40. 10. McCollough WM, Parsons JT, van der Griend et al. Radiation therapy for aggressive fibromatosis: the experience at the University of Florida. J Bone Joint Surg 1991; 73(A): 717–725. 11. Spear MA, Jennings LC, Mankin HJ et al. Individualizing management of aggressive fibromatoses. Int J Radiat Oncol Biol Phys 1998; 40: 637–645. 12. Faulkner LB, Hadju SI, Kher U et al. Pediatric desmoid tumor: retrospective review of 63 cases. J Clin Oncol 1996; 13: 2813–2818. 13. Pritchard DJ, Nascimento AG, Petersen IA et al. Local control of extraabdominal desmoid tumor. J Bone Joint Surg 1996; 78A: 848–854. 14. Leibel SA, Wara WM, Hill DR et al. Desmoid tumors: local control and patterns of relapse following radiation therapy. Int J Radiat Oncol Biol Phys 1983; 9: 1167–1171. 15. Taylor LJ. Musculoaponeurotic fibromatosis: a report of 28 cases and review of the literature. Clin Orthop 1987; 224: 294–302. 16. Stockdale AD, Cassoni AM, Coe MA et al. Radiotherapy and conservative surgery in the management of musculo-aponeurotic fibromatosis. Int J Radiat Oncol Biol Phys 1988; 15: 851–857. 17. Sherman NE, Romsdahl M, Evans H et al. Desmoid tumors: a 20-year radiotherapy experience. Int J Radiat Oncol Biol Phys 1990; 19: 37–40. 18. Lipschutz A. Steroid Hormones and Tumors. Baltimore, MD: Williams and Wilkins 1950. 19. Lipschutz A, Jadrijevitc D, Girardi S et al. Antifibromatogenic potency of 9-fluoro derivatives of progesterone. Nature 1956; 178: 139. 20. Jadrijevic D, Mardones E, Lipschutz A. Antifibromatogenic activity of 19-nor-A-ethinyltestosterone in the guinea pig. Proc Soc Exp Biol Med 1956; 91: 38–39. 21. Bruzzone S, Elqueta H, Lipschutz A. Oestrogen-induced fibroids of the thoracic serosa. Br J Cancer 1948; 2: 267. 22. Havry P, Reitamo JJ, Vihko R et al. The desmoid tumor. III. A biochemical and genetic analysis. Am J Clin Pathol 1982; 77: 681–685. 23. Klein WA, Miller HH, Anderson M et al. The use of indomethacin, sulindac, and tamoxifen for the treatment of desmoid tumors associated with familial polyposis. Cancer 1987; 60: 2863–2868. 24. Sutherland RL, Murphy LC, Foo MS et al. High affinity antiestrogen binding site distinct from the estrogen receptor. Nature 1980; 288: 273–275. 25. Lim CL, Walker MJ, Mehta RR et al. Estrogen and antiestrogen binding sites in desmoid tumors. Eur J Cancer Clin Oncol 1986; 22: 583–587. 26. Kinzbrunner B, Ritter S, Domingo J et al. Remission of rapidly growing desmoid tumors after tamoxifen therapy. Cancer 1983; 52: 2201–2204. 27. Rock MG, Pritchard DJ, Reiman HM et al. Extra-abdominal desmoid tumors. J Bone Joint Surg Am 1984; 66A: 1369–1374. 28. Procter H, Singh L, Baun M et al. Response of multicentric desmoid tumors to tamoxifen. Br J Surg 1987; 74: 401. 29. Eagel BA, Zentler-Munro P, Smith IE. Mesenteric desmoid tumours in Gardner’s syndrome—review of medical treatments. Postgrad Med J 1989; 65: 497–501.

190 55. Gabbert HE, Gerharz CD, Biesalski HK et al. Terminal differentiation and growth inhibition of a rat rhabdomyosarcoma cell line (BAHAN-1C) in vitro after exposure to retinoic acid. Cancer Res 1988; 48: 5264–5269. 56. Balkwill FR, Bokhonko AI. Differential effects of pure human alpha and gamma interferons on fibroblast cell growth and the cell cycle. Exp Cell Res 1984; 55: 190–197. 57. Duncan MR, Berman B. Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of lymphoblast collagen production and late not early fibroblast proliferation. J Exp Med 1985; 162: 516–527. 58. Acker JC, Bossen EH, Halperin EC. The management of desmoid tumours. Int J Radiat Oncol Phys 1993; 26: 851–858. 59. Geurs F, Kok TC. Regression of a great abdominal desmoid tumor by interferon-α. J Clin Gastrenterol 1993; 16: 264–265.

61. Leithner A, Schnack B, Katterschafka T et al. Treatment of extraabdominal desmoid tumors with interferon-alpha with or without tretinoin. J Surg Oncol 2000; 73: 21–25. 62. Stein R. Chemotherapeutic response in fibromatosis of the neck. J Pediatr 1977; 90: 482–483. 63. Goepfert H, Cangir A, Ayala AG et al. Chemotherapy of locally aggressive head and neck tumors in the pediatric age group. Am J Surg 1982; 144: 437–444. 64. Raney B, Evans A, Granowetter L et al. Nonsurgical management of children with recurrent or unresectable fibromatosis. Pediatrics 1987; 79: 394–398. 65. Delepine N, Delepine G, Desbois JC et al. Objective response of desmoid fibroma to chemotherapy. Biomed Pharmacother 1987; 41: 146–148. 66. Gansar GF, Krementz ET. Desmoid tumors: experience with new modes of therapy. South Med J 1988; 81: 794–796.

Downloaded from http://annonc.oxfordjournals.org/ at Oxford Journals on May 30, 2014

60. Fernberg JO, Brosjo O, Larsson O et al. Interferon-induced remission in aggressive fibromatosis of the lower extremity. Acta Oncol 1999; 38: 971–972.

67. Tsukada K, Church JM, Jagelman DG et al. Systemic cytotoxic chemotherapy and radiation therapy for desmoid in familial adenomatous polyposis. Dis Colon Rectum 1991; 34: 1090–1092. 68. Patel SR, Evans HL, Benjamin RS. Combination chemotherapy in adult desmoid tumors. Cancer 1993; 72: 3244–3247. 69. Schnitzler M, Cohen Z, Blackstein M et al. Chemotherapy for desmoid tumours in association with familial adenomatous polyposis. Dis Colon Rectum 1997; 40: 798–801. 70. Azzarelli A, Casali P, Fissi S et al. Effective control of advanced aggressive fibromatosis with chemotherapy. Eight years experience with methotrexate and vinblastine in 27 patients. Proceedings Fourth Annual Meeting Connective Tissue Oncology Society, Milan 1998. 71. Okuno SH, Edmonson JH. Combination chemotherapy for desmoid tumors. Proceedings Fifth Annual Meeting Connective Tissue Oncology Society, Arlington, VA 1999; 32. 72. Weiss AJ, Horowitz S, Lackman RD. Therapy of desmoid tumors and fibromatosis using vinorelbine. Am J Clin Oncol 1999; 22: 193–195. 73. Reich S, Overberg-Schmidt US, Buhrer C et al. Low-dose chemotherapy with vinblastine and methotrexate in childhood desmoid tumors. J Clin Oncol 1999; 17: 1086. 74. Lev-Chelouche D, Abu-Abeid, Nakache R et al. Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan. Surgery 1999; 126: 963–967. 75. Klaase JM, Kroon BB, Benckhuijsen C et al. Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities. Cancer 1989; 64: 616–621. 76. Seiter K, Kemeny N. Successful treatment of a desmoid tumor with doxorubicin. Cancer 1993; 71: 2242–2244. 77. Lynch HT, Fitzgibbons R, Chong S et al. Use of doxorubicin and dacarbazine for the management of unresectable intra-abdominal desmoid tumors in Gardner’s syndrome. Dis Colon Rectum 1994; 37: 260–267. 78. Rao BN, Horowitz ME, Parham DM et al. Challenges in the treatment of childhood fibromatosis. Arch Surg 1987; 122: 1296–1298.