Familial Cancer DOI 10.1007/s10689-014-9760-1
ORIGINAL ARTICLE
Desmoid tumour in familial adenomatous polyposis patients: responses to treatments Thibault Desurmont • Je´re´mie H. Lefe`vre • Conor Shields • Chrystelle Colas • Emmanuel Tiret Yann Parc
•
Ó Springer Science+Business Media Dordrecht 2014
Abstract No guidelines for desmoid tumors (DT) management are available and DT have now become the first cause of death in FAP patients who had restorative proctocolectomy. We aimed to assess the results of the different treatments used for DT in Familial Adenomatous Polyposis (FAP) patients. All patients followed for FAP who developed a DT between 1970 and 2010 were collated. We analysed separately the history of DT according to location: mesenteric, parietal or mixed. 79 FAP patients [45 females (56 %); mean age 33.3 ± 12.5] presented 149 DT and were included; 16(20 %) had a DT diagnosed during or before first abdominal surgery and 47 (59 %) had isolated mesenteric DT. 11 patients had only surgical treatment, 17 only medical treatments, 31 had combined treatment and 20 had no treatment with spontaneous DT regression or stabilization. Overall, 80 treatment lines were administered to patients with a progression free or regression rate of 43 % (34/80). Response rates were: chemotherapy 77 % (10/13); Sulindac ? tamoxifen 50 % (6/12); Tamoxifen 40 % (6/15); Imatinib 36 % (4/11); Sulindac 28 % (8/29). Among the 42 surgical procedures, an R0 resection was
T. Desurmont J. H. Lefe`vre (&) C. Shields E. Tiret Y. Parc Department of Digestive Surgery, Hoˆpital Saint-Antoine, Assistance Publique Hoˆpitaux de Paris, Universite´ Pierre et Marie Curie, Paris VI, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France e-mail: [email protected] C. Colas Laboratory of Angiogenetics and Oncogenetics, Hoˆpital Pitie´Salpe´trie`re (AP-HP), Universite´ Pierre et Marie Curie, Paris VI, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
performed in 26 (62 %) allowing the absence of recurrence for 54 %. After a median follow-up of 81 months, 8 patients died of their DT and 6 died of other cause. Overall and DT-specific survival at 20 years were 52 and 79 %, respectively. Chemotherapy was the most efficient treatment. For intra-abdominal DT, we consider it as a first choice treatment and reserve surgery when it is impossible or when DT are life threatening. Keywords Desmoid tumor Familial adenomatous polyposis Sulindac Tamoxifen
Introduction Desmoid tumours (DT) are rare fibroblastic benign tumours. They grow by infiltrating the soft tissues, sometimes very significantly and decaying. The overall incidence is reported to be 2–4/1000000 inhabitants [1]. One of the identified risk factors is mutation of the adenomatous polyposis coli (APC) gene [2–4] or mutation in the betacatenine gene CTNNB1 for sporadic DT [5]. Incidence of DT in FAP patients is estimated between 10 and 25 % [6] with influencing factors such as: prior abdominal surgery, localization of the germline mutation and familial history of DT [2, 7]. Abdominal desmoids represent the majority of FAP DT [8], while extra-abdominal DT represent the majority of non-FAP DT [9]. With the increasing number of patient who underwent prophylactic colectomy in FAP to prevent colorectal carcinoma, DT have now become the first cause of death in FAP patients who had restorative proctocolectomy [6]. The evolution of these tumours is unpredictable [10]. If parietal tumour infiltration may be responsible for major and debilitating deformations, mesenteric tumour can cause digestive problems, intestinal
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obstruction, intestinal perforation, fistulas and other life threatening complications. There are not actual guidelines for DT management. If surgical resection of extra mesenteric DT is often safe, surgery for mesenteric DT is more discussed. Moreover, extensive resections are frequently required and associated to a high mortality [8, 11]. Therefore, non-surgical treatment such has anti-inflammatory drug or chemotherapy has been proposed [12–18]. There are very few limited cohort studies reporting the results of these treatments [11]. The limited number of patients with FAP developing DT represents the major limitation of these retrospective studies. The heterogeneity of presentation and evolution are also a factor limiting the possibility to elaborate prospective controlled study to validate specific treatment. The aim of this study was then to assess the results of the different treatments used for DT developed in FAP patients in our institution.
Success of a medical treatment was defined by the regression or the stabilisation of the DT lesion on CT scan or MRI (but with no objective measurement) without development of new lesions and. Surgical success was defined by the absence of recurrence or the correction of the life threatening symptoms with or without maintenance medical treatment. Statistics Results are presented as median values (interquartile range) or mean ± standard deviation for continuous variables and numbers (percentages) for categorical variables. Chi square or Fisher exact tests were used for categorical variables and t test or Wilcoxon test for continuous variables. All tests were two-sided at 0.05 significance level. Analyses were performed using the Statview computer program (Version 5, 1992–1998, SAS Institute Inc., Cary, NC) and R statistical package (R Foundation for Statistical Computing, Vienna, Austria).
Patients and methods Patients
Results
All patients followed for FAP in our institution who developed a DT between June 1970 and July 2010 were collated. Demographic data, surgical details, pathologic, clinical data, treatments and status at the end of follow-up were noted. We analysed separately the history of DT according to their location: intra-abdominal isolated (or mesenteric), parietal isolated or mixed. Size of tumours was collected at diagnostic and during treatment to evaluate their evolution. DT were classified with the Church score [10]. In case of multiple DT, the larger and most progressive lesion (worst DT) was used to classify the disease. Patients with only desmoid reaction with no mass were not included in the present study as it has no clear relation with intra-abdominal desmoid [19].
Patients
Treatments Surgical treatment consisted of explorative laparotomy, digestive or parietal resection, intestinal bypass, surgical treatment of intestinal perforation and stoma formation. Medical treatment included non-steroid anti-inflammatory drug (sulindac, from 400 to 800 mg/day), antiestrogen therapy (tamoxifen, 120 mg/day), tyrosine kinase inhibitor (Imatinib, from 200 to 600 mg/day according to the body surface) or chemotherapy. Different chemotherapy regimens have been used combining doxorubicin (60–90 mg/ m2) daily 3 times repeated every 3–4 weeks, methotrexate (30 mg/m2) and vinblastine (6 mg/m2), and more recently cisplatin (60 mg/m2 every 4 weeks) [12, 20, 21].
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Seventy-nine FAP patients [45 females (56 %)] presented 149 DT and were included in the present study. The majority have had a colo-rectal resection. DT characteristics at the time of diagnosis are given in Table 1. Sixteen (20.2 %) patients had a DT diagnosed during or before first abdominal surgery. There was no significant difference between the mean age of these 16 patients at the DT diagnostic and the remaining 63 patients (33.6 ± 13.9 vs. 33.2 ± 12.2 years) (p = 0.924) nor the size of DT at the diagnosis (8.4 ± 5 cm vs. 7.8 ± 4.6 cm; p = 0.6219). DT staging at time of diagnosis All patients with associated parietal and mesenteric DT had a stage 3 or 4. No difference of stage was observed between patients with isolated parietal (8/17; 47 %) or isolated mesenteric DT (24/47; 51 %), (p = 0.777) (Table 1). The number of DT by patients was correlated with staging: mean number of DT for stage 1 patients was 1.6 ± 0.84 versus 2.5 ± 1.56 for stage 4 (p = 0.036). Development of DT before or after any abdominal surgery was not correlated with staging. Mean DT stage was 2.45 ± 0.94 when DT was diagnosed before first abdominal surgery and 2.52 ± 0.9 after (p = 0.97). Age at DT diagnosis and DT score were correlated. The mean age at DT diagnosis for patients with stage 1 tumour was 40.1 ± 12.7 years versus 29.2 ± 9.1 years (p = 0.0104)
Treatment of desmoid tumors Table 1 Patients’ characteristics at DT diagnosis Overall cohort (n = 79)
Isolated parietal DT (n = 17)
Isolated mesenteric DT (n = 47)
Associated DT (n = 15)
35 (44 %)
5 (29.4 %)
25 (53.2 %)
5 (33.3 %)
RPC ? IPAA Subtotal colectomy
51 (64.5 %) 23 (29 %)
9 (52.9 %) 6 (35.3 %)
31 (65.6 %) 14 (29.8 %)
11 (73.3 %) 3 (33.3 %)
Other
5 (6.5 %)
2 (11.8 %)
2 (4.2 %)
1 (6.7 %)
Mean ± SD
28.6 ± 10.9
26.1 ± 7.3
29.3 ± 12.16
29 ± 10,2
Median (range)
26.9 (14.3–66.8)
26.2 (15.1–41.6)
25.8 (14.3–66.7)
29 (15–49)
9 (11 %)
1 (5.9 %)
4 (8.5 %)
4 (26.7 %) 30.5 ± 9.6
Male Gender First abdominal surgery:
Age at first abdominal surgery (years)
Adenocarcinoma diagnosed at the time of colectomy Age at DT diagnosis (years) Mean ± SD
33.3 ± 12.5
33.4 ± 10.8
34.2 ± 14
Median (range)
30.5 (16.1–77.7)
35.3 (16.1–52.7)
28.7 (16.7–77.7)
29 (17.1–47.5)
149
23
78
48
Number of DT Number of DT per patient Mean ± SD
1.8 ± 1.3
1.35 ± 1
1.66 ± 1
3.2 ± 1.5
Median (range)
1 (1–7)
1 (1–5)
1 (1–5)
3 (1–7)
7.9 ± 4.7 7 (1–20)
7.1 ± 5.1 5 (3–20)
6.8 ± 3.7 7 (1–15)
12.4 ± 4.6 12 (4.4–20)
Largest DT (cm) Mean ± SD Median (range) Mean ± SD size of DT at diagnosis (cm) Diagnosis before or during first abdominal surgery
7.7 ± 4.7
7.5 ± 5.4
7.4 ± 4
11.6 ± 8.5
Diagnosis after the first abdominal surgery
7.9 ± 4.7
7 ± 5.3
6.7 ± 3.7
9.9 ± 6.15
I
19 (24 %)
3 (17.6 %)
16 (34.0 %)
0
II
13 (16.4 %)
6 (35.3 %)
7 (14.9 %)
0
Church’s Classification at the diagnosis
III
33 (41.7 %)
6 (35.3 %)
16 (34.0 %)
11 (73.3 %)
IV
14 (17.7 %)
2 (11.8 %)
8 (17.0 %)
4 (26.7 %)
Follow–up (months) Mean ± SD
97.7 ± 83.8
127.9 ± 109.4
89.4 ± 76.2
89.3 ± 70.2
Median (range)
81 (1.7–437.1)
135.2 (17.4–437.1)
72.6 (1.7–280)
84 (15.4–266)
Death
14 (17 %)
3 (17.6 %)
8 (17.0 %)
3 (20 %)
Deaths related to TD
6 (7.5 %)
1 (5.9 %)
5 (10.6 %)
0 (0 %)
RPC ? IPAA: total coloproctectomy ? ileal pouch anal anastomosis; DT desmoid tumour, SD standard deviation
for stage 4 patients. There was no significant difference between age at first abdominal surgery and DT staging at diagnostic time. Treatment Among the 79 patients, 31 (39.2 %) had never received medical treatment: 11 had only surgical treatment, 20 had no treatment with spontaneous DT regression or stabilization. Two patients had radiotherapy associated to medical treatment. In the first case, radiotherapy has led to significant
radiation enteritis complicated by several occlusive episodes. Gastrointestinal bypass was then practiced. In the second case, radiotherapy was responsible of tumour necrosis complicated by intestinal perforation and peritonitis. Resection with stoma formation was required. The 20 patients who hadn’t treatment, had a significant smaller DT size than other patients (4.4 cm ± 2.2, vs. 9.1 cm ± 4.7) (p = 0.0001). Stage at DT diagnosis was also significantly lower for these patients [stage 1–2 for 19/20 patients (95 %)] than for the remaining (stage 1–2 13/59 patients (22 %) (p \ 0.001)].
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T. Desurmont et al. Table 2 Details about efficiency of adjuvant therapy to first DT surgical resection and global efficiency of medical treatment Medical treatment
n
Adjuvant treatment after surgical resection
10 patients
Success n (%) 4 (40 %)
Sulindac
5
3
Tamoxifen
2
1
Sulindac ? tamoxifen
2
0
Imatinib
1
Global efficiency of medical products
80 lines
0 34 (42.5 %)
Sulindac (n = 29)
29
Tamoxifen (n = 15)
15
6 (40 %)
Sulindac ? Tamoxifen (n = 12)
12
6 (50 %)
Imatinib (n = 11) Chemotherapy (n = 13)
8 (27.6 %)
11
4 (36.3 %)
13
10 (76.9 %)
Medical treatment Seventeen patients (21.5 %) had only medical treatments and 31 (39.2 %) had combined medical and surgical treatments. After first DT surgical resection, 10 patients had an adjuvant treatment, mainly with sulindac (n = 5). In four patients, no recurrence occured while tumoral relapse and/or evolution were observed in 6 patients (Table 2). Nineteen patients have received medical treatment after any kind of DT surgery (resection, intestinal bypass or surgical treatment of peritonitis). For 10 patients (52.6 %) the association of surgical treatment and adjuvant therapy was effective. Overall, 80 treatment lines were administered to patients with a progression free or regression rate of 43 % (34/80). Chemotherapy was the most efficient treatment with a response rate of 77 % (10/13) (Table 2).
prophylactic total colectomy and ileorectal anastomosis as the rectum was not resectable. Forty-two patients (53.1 %) underwent surgical treatment for a total of 63 operations with an overall postoperative mortality of 4.8 % (n = 2). Among these 42 patients, first surgical procedure was an R0 resection in 26 (62 %) (Table 3). Eighteen patients had been reoperated for recurrence or persistence of DT after a median delay of 24 months (range 3–150). Four patients required reoperation after long delay (from 64 to 150 months). Stage 3 or 4 DT at diagnosis were significantly correlated with a need of surgical treatment [stage 3: 20/33 (60.6 %); stage 4: 13/14 (92.6 %) versus stage 1 and 2 (9/ 32; 28.2 %)] (p = 0.0001). Thus 70.2 % of stage 3 or 4 mesenteric, parietal or mixed DT at diagnosis were operated. Survival Median follow-up from DT diagnostic was 81 months (range 2–437). Eight patients died of their DT and 6 died of other cause: 2 of metastatic duodenal adenocarcinoma, 1 of indeterminate peritoneal carcinomatosis, 1 of splenic necrosis unrelated to his DT, despite performing splenectomy, and 2 of metastatic colic or rectal adenocarcinoma (Table 4). Overall survival at 10 and 20 years were 83 and 52 %, respectively (Fig. 1). DT specific survival at 10 and 20 years were 90 and 79 %, respectively. Initial DT score and initial DT location at diagnosis were not found to influence survival (p [ 0.05) (Fig. 1). The 20 years survival of patients with DT diagnosed before or during a first abdominal surgery (n = 16) was significantly lower than for patients with DT diagnosed after surgery (n = 63) (42 vs. 53 %; p = 0.033) (Fig. 1).
Surgical treatment Discussion For 5 patients, the first abdominal surgery was not a colorectal resection. First patient underwent a small bowel resection and anastomosis by laparotomy for a voluminous mesenteric and occlusive DT. Second patient underwent a splenopancreatectomy for DT. For these two patients a restorative coloproctectomy was performed later (2.5 and 7 months). Other patient underwent a gastro-jejunostomy and lateral ileostomy for occlusive non-resectable mesenteric DT. For the fourth, an explorative laparotomy for a voluminous and occlusive mesenteric DT can only be performed. No resection or bypass was feasible and this patient died of its DT. In the fifth case, first abdominal surgery was a hepatectomy for adenoma, with TD development 1 year later, leading to the achievement of a
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Although the development of DT is usually slow and insidious, their potential morbidity can be significant [22]. DT is a major cause of death for FAP patients [23–25]. Publications on treatment of DT in FAP are rare [11, 18]. This paucity of publication is related to the small number of patients. With these limitations, we tried by the analysis of our series, to find some clue to develop a treatment strategy for these patients. We have considered that a stop in tumour progression, was a success as well as a tumour regression [17, 18, 26]. We didn’t report the APC mutation as it is not used in the management of DT. Moreover, for some de novo patients, no germline mutation is found.
Treatment of desmoid tumors Table 3 Details about surgical management of desmoid tumors Patients
Surgery
Patients with DT (n = 79)
42 (53.2 %)
Details
Success
Complete R0 resection
No recurrence (n = 14, 53.8 %)
(n = 26, 61.9 %) Other procedures (n = 16, 38.1 %) Intestinal bypass (n = 8)
Stabilization (n = 5, 31.2 %)
Explorative laparotomy (n = 4) Management of gastrointestinal perforation (n = 3) Incomplete resection associated with bypass (n = 1) Patients, with isolated parietal DT at diagnosis (n = 17)
12 (70.6 %)
Patients, with isolated mesenteric DT at diagnosis (n = 47)
17 (36.2 %)
Complete R0 resection
9 (75 %)
(n = 11, 91.7 %) Impossible resection (n = 1, 8.3 %) Complete R0 resection (n = 6, 35.3 %)
3 (17.6 %)
Other procedures (n = 11, 64.7 %) Intestinal bypass (n = 6) Explorative laparotomy (n = 3) Management of intestinal perforation (n = 2)
Table 4 Details about patients who died due to their DT Patients
Initial location
Stage at diagnosis
Age at diagnosis (years)
Delay from diagnosis to death (months)
Cause of death
Age at death (years)
Patients directly dead due to their DT 1
Mesenteric
3
43.2
22.4
Intestinal occlusion and digestive hemorragia
45
2 3
Mesenteric Parietal
2 4
17.7 43.3
44.8 43.8
Peritonitis by digestive perforation DT evolution
21.3 46.7
4
Mesenteric
3
25
5
Mesenteric
4
18.6
27.6
6
Mesenteric
3
20.3
204.8
4.9
Tumoral necrosis
28.9
Tumoral necrosis and chronical intestinal occlusion
20.9
Jejuno-ileal multiple fistulas
35.8
Suicide because of multiple DT and multiples surgical procedure
55
Rectal adenocarcinoma in a rectal stump let in place because of inextirpable mesenteric DT
43
Patients indirectly dead due to their DT 1
Parietal
3
52.7
2
Mesenteric
2
34.5
21.25 101.6
NSAIDs (sulindac) has been described as first line treatment in FAP for DT [6, 27, 28]. In this series, we didn’t find this treatment very effective, as stabilization or regression of the DT was observed in only a quarter of the patients receiving this drug. As adjuvant to surgery, 3 of 7 patients achieved remission under sulindac, but it is impossible to determine if surgery alone would not have achieved such result. Few publications analyzed the effectiveness of NSAIDs [27]. Nieuwenhuis et al. [18] reported a series of 12 patients treated with NSAIDs and showed a 50 % rate of progression-free survival at 5 years. De Camargo et al. [16] reported their experience with NSAIDs as an adjuvant treatment after surgery. They
didn’t specify the number of treatment begun among the 68 patients treated for sporadic and FAP-related DT, but they didn’t found any tumour reduction under NSAIDs [16]. Clarck et al. [8] have shown a rate of regression or stabilization of DT lesions of 29 % under NSAIDs. All these findings, seems to demonstrate that if sulindac is proposed as a first line treatment, it is proposed without obvious proof demonstrating an efficiency of this treatment. Moreover, the rate of stabilization and regression observed after such treatment might be identical to the one observed without any treatment. However, when a DT is found, as it is impossible to predict its evolution, sulindac is proposed after or during a ‘‘wait and evaluate’’ attitude most of the
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T. Desurmont et al. 100
B
80
Percent survival
Percent survival
A
60
40
Parietal DT Mixed DT Mesenteric tumor
100
80
60
40
20
20
0
0 0
50
100
150
200
250
0
300
Follow-up from diagnosis of Desmoid Tumors (months) 100
D
100
150
200
250
300
100
80
80
Percent survival
Percent survival
C
50
Follow-up from diagnosis of Desmoid Tumors (months)
60 Stage 1 Stage 2 Stage 3 Stage 4
40
60
40 DT diagnosed after DT diagnosed before
20
20
0
0 0
50
100
150
200
250
300
Follow-up from diagnosis of Desmoid Tumors (months)
0
50
100
150
200
250
300
Follow-up from diagnosis of Desmoid Tumors (months)
Fig. 1 Survival curves of patients monitored for DT in a PAF context, for the overall group (a), according to DT initial location at diagnosis (b), DT grade at diagnosis (c) and depending on whether DT diagnosis has been made before (or during) or after the prophylactic colectomy (d)
time in our experience. It seems possible, then, to consider this attitude without treatment and to go for a much more efficient but also aggressive treatment if required, only. As DT were considered hormonally responsive and in particular to oestrogen [26, 29, 30], anti-oestrogens are used alone or adjuvant to surgery [8, 26]. Anti-oestrogen or combination of anti-oestrogen and sulindac are effective in 40 and 50 % of our patients, respectively. These results are in line with previous reports. Clarck et al. [8] observed a stabilization or regression of 19 % of DT treated by antioestrogens in the context of FAP. Hansmann et al. have presented a series of 13 patients who received anti-oestrogens (tamoxifen) and NSAIDs (sulindac). Six patients had then a stable disease and 4 a partial regression [26]. Such results are not so different to the one observed after sulindac. The attitude, just proposed with this last treatment, should even more be considered, when anti-oestrogens treatment are discussed with their risks of side effects like flushing, headache and bleeding. Furthermore, the necessity to associate with anti-oestrogens, contraception and anti-thrombotic at curative dose, represent also evident disadvantages.
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Imatinib has also been proposed in this situation. Nieuwenhuis et al. [18] have reported their experience of three patients and have shown that imatinib had no evident positive effect. Chugh et al. [31] have presented a survival study of 51 patients treated with imatinib for aggressive fibromatosis not controlled by surgery or for whom surgical indication was not retained. Rates of progression-free survival at 2 months, 4 months and 1 year was respectively 94, 88 and 66 %. But only 3 patients (6 %) had an objective tumour response in this study. In the present series, with 11 patients treated with imatinib, we observed that slightly less than half of patients achieved a regression or stabilization. More studies are required to consider imatinib has a treatment for DT in FAP, as the response rate might not be so different that the ones observed with sulindac and anti-oestrogens, and so, might be consider also as doubtful. More recently the French Sarcoma Group (FSG) published a phase II trial of 40 patients with DT (but only 6 were belonging to a FAP family) (ref). The non-progression rate was 67 % at 12 months [32]. This group of clinical research is willing to propose a consensus algorithm for the treatment of DT.
Treatment of desmoid tumors
In our experience, chemotherapy is administered to patients with DT in progression while under conventional therapy. Our results show efficacy in three-quarters of our patients and therefore is the most effective treatment (77 % in our experience), regardless of treatment previously administered. These results are consistent with those published in the literature [6, 12, 13, 15, 16, 21]. In 1993, Patel et al. [21] showed with a series of 9 patients treated with a median of 5 cycles of doxorubicin combined with dacarbazine, a major response in six patients, a minor response in one patient and a stabilization in 2 patients. Hamilton et al. published, few years later, a series of three patients treated for nonresectable PAF-related DT resistant to hormonal treatment. This protocol associated high doses of doxorubicine (60–90 mg/m2) and dacarbazine (1000 mg/ m2) for seven cycles. They obtained, for each of the three patients, clinical and radiological regression [20]. With the threat of side effects, a reduced-dose protocol has been proposed. Azzarelli et al. have treated 30 patients with a methotrexate (30 mg/m2) and vinblastine (6 mg/m2) based chemotherapy every 10 days, (median of 38 cycles) to diminish toxicity. They obtained a partial tumour response in 12 patients and a tumour stabilization in 18 [12]. More recently, Nieuwenhuis et al. presented the results of 10 patients treated for FAP-related DT with doxorubicin combined with others agent like carboplatine, dacarbazin or ifosfamide. Effects of chemotherapy were variable. Four patients obtained regression or stabilization of their lesions but five had progression [18]. However, with the results of this series and those of the literature, it seems that chemotherapy for the treatment of FAP-related DT is frequently effective. For this reason, we consider to propose chemotherapy as a first line treatment when required. Actually, there are several ongoing studies for the medical treatment of DT: DESMOPAZ (NCT01876082) evaluating the Pazopanib which is an inhibitor of multi-target tyrosine kinase or the NCT01981551 trial evaluating a Gammasecretase inhibitor. We hope that these trials will increase the therapeutic armamentorium. The problem is then to consider when a treatment is required. Church et al. [10] proposed a score to classify the intra-abdominal DT in FAP. This score use various criteria: symptoms of the tumour, maximum diameter, obstructive nature, and evolution. In case of multiple tumours, the patient is graded according to tumour highest score. In our series of 79 patients, with expanded criteria of classification chosen by Church et al. to parietal DT and mixed tumours, we were unable to find that this classification could predict mortality. Only tumours of stage 1 had a predictable evolution with no mortality, but these tumours are easily identified and as evolution is part of the score are those that are not progressing. The absence of a score or any valid classification that would help to predict the
possible evolution should not be an obstacle. In fact, a DT in rapid progression or with life threatening complication should be consider immediately for chemotherapy, and we should skip the less aggressive treatment phase that we usually proposed as a first step. Considering chemotherapy for patients with DT in progression, it remains the question of possible surgery as an alternative option. In the cases of abdominal wall lesions, surgical excisions seem safe [33, 34]. We did not observed any death in our series, like others [11, 18], and morbidity was low. So the principal problem is to obtain clear margins to reduce the risk of recurrence [33]. Our 18 % recurrence rate after abdominal wall DT resection is comparable to the 40 % reported by Clark et al. [8]. This finding, in the optic of our strategy makes us consider surgery more than chemotherapy for abdominal wall DT. For intra-abdominal DT, among our 47 patients without parietal lesion, only 17 have undergone a surgical procedure and only 6 patients could have a tumour resection. The other 11 procedures were performed with palliative intent or in emergency. Two of our patients operated on for abdominal DT died after surgery. The St Mark’s hospital team reported 36 % mortality after surgical excision of intra-abdominal DT and nearly half of their surviving patients require chronic parenteral nutrition postoperatively [8]. Nieuwenhuis et al. [18] reported, in a series of 62 patients, in whom complete resection of DT was intended in about 60 % of their patients, that none of intra-abdominal DT could be fully resected and a 10 years disease-free survival of 32.9 %. Moreover, Burke et al. [34, 35] reported on 10 FAP patients operated on for intra-abdominal DT, a post-operative mortality of 50 % and a recurrence rate of 90 %. Berk et al. [36] also had shown a very high rate of recurrence of abdominal DT resection, with in their series of 13 patients a recurrence rate of 85 %. All these observations highlight the great risk and the poor results of surgery after intra-abdominal DT resection. For these reasons, we are more likely to consider chemotherapy as a first choice treatment in this situation and to reserve surgery when chemotherapy is not possible or when DT are, or about to be, life threatening lesions.
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ORIGINAL ARTICLE
Desmoid tumour in familial adenomatous polyposis patients: responses to treatments Thibault Desurmont • Je´re´mie H. Lefe`vre • Conor Shields • Chrystelle Colas • Emmanuel Tiret Yann Parc
•
Ó Springer Science+Business Media Dordrecht 2014
Abstract No guidelines for desmoid tumors (DT) management are available and DT have now become the first cause of death in FAP patients who had restorative proctocolectomy. We aimed to assess the results of the different treatments used for DT in Familial Adenomatous Polyposis (FAP) patients. All patients followed for FAP who developed a DT between 1970 and 2010 were collated. We analysed separately the history of DT according to location: mesenteric, parietal or mixed. 79 FAP patients [45 females (56 %); mean age 33.3 ± 12.5] presented 149 DT and were included; 16(20 %) had a DT diagnosed during or before first abdominal surgery and 47 (59 %) had isolated mesenteric DT. 11 patients had only surgical treatment, 17 only medical treatments, 31 had combined treatment and 20 had no treatment with spontaneous DT regression or stabilization. Overall, 80 treatment lines were administered to patients with a progression free or regression rate of 43 % (34/80). Response rates were: chemotherapy 77 % (10/13); Sulindac ? tamoxifen 50 % (6/12); Tamoxifen 40 % (6/15); Imatinib 36 % (4/11); Sulindac 28 % (8/29). Among the 42 surgical procedures, an R0 resection was
T. Desurmont J. H. Lefe`vre (&) C. Shields E. Tiret Y. Parc Department of Digestive Surgery, Hoˆpital Saint-Antoine, Assistance Publique Hoˆpitaux de Paris, Universite´ Pierre et Marie Curie, Paris VI, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France e-mail: [email protected] C. Colas Laboratory of Angiogenetics and Oncogenetics, Hoˆpital Pitie´Salpe´trie`re (AP-HP), Universite´ Pierre et Marie Curie, Paris VI, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
performed in 26 (62 %) allowing the absence of recurrence for 54 %. After a median follow-up of 81 months, 8 patients died of their DT and 6 died of other cause. Overall and DT-specific survival at 20 years were 52 and 79 %, respectively. Chemotherapy was the most efficient treatment. For intra-abdominal DT, we consider it as a first choice treatment and reserve surgery when it is impossible or when DT are life threatening. Keywords Desmoid tumor Familial adenomatous polyposis Sulindac Tamoxifen
Introduction Desmoid tumours (DT) are rare fibroblastic benign tumours. They grow by infiltrating the soft tissues, sometimes very significantly and decaying. The overall incidence is reported to be 2–4/1000000 inhabitants [1]. One of the identified risk factors is mutation of the adenomatous polyposis coli (APC) gene [2–4] or mutation in the betacatenine gene CTNNB1 for sporadic DT [5]. Incidence of DT in FAP patients is estimated between 10 and 25 % [6] with influencing factors such as: prior abdominal surgery, localization of the germline mutation and familial history of DT [2, 7]. Abdominal desmoids represent the majority of FAP DT [8], while extra-abdominal DT represent the majority of non-FAP DT [9]. With the increasing number of patient who underwent prophylactic colectomy in FAP to prevent colorectal carcinoma, DT have now become the first cause of death in FAP patients who had restorative proctocolectomy [6]. The evolution of these tumours is unpredictable [10]. If parietal tumour infiltration may be responsible for major and debilitating deformations, mesenteric tumour can cause digestive problems, intestinal
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obstruction, intestinal perforation, fistulas and other life threatening complications. There are not actual guidelines for DT management. If surgical resection of extra mesenteric DT is often safe, surgery for mesenteric DT is more discussed. Moreover, extensive resections are frequently required and associated to a high mortality [8, 11]. Therefore, non-surgical treatment such has anti-inflammatory drug or chemotherapy has been proposed [12–18]. There are very few limited cohort studies reporting the results of these treatments [11]. The limited number of patients with FAP developing DT represents the major limitation of these retrospective studies. The heterogeneity of presentation and evolution are also a factor limiting the possibility to elaborate prospective controlled study to validate specific treatment. The aim of this study was then to assess the results of the different treatments used for DT developed in FAP patients in our institution.
Success of a medical treatment was defined by the regression or the stabilisation of the DT lesion on CT scan or MRI (but with no objective measurement) without development of new lesions and. Surgical success was defined by the absence of recurrence or the correction of the life threatening symptoms with or without maintenance medical treatment. Statistics Results are presented as median values (interquartile range) or mean ± standard deviation for continuous variables and numbers (percentages) for categorical variables. Chi square or Fisher exact tests were used for categorical variables and t test or Wilcoxon test for continuous variables. All tests were two-sided at 0.05 significance level. Analyses were performed using the Statview computer program (Version 5, 1992–1998, SAS Institute Inc., Cary, NC) and R statistical package (R Foundation for Statistical Computing, Vienna, Austria).
Patients and methods Patients
Results
All patients followed for FAP in our institution who developed a DT between June 1970 and July 2010 were collated. Demographic data, surgical details, pathologic, clinical data, treatments and status at the end of follow-up were noted. We analysed separately the history of DT according to their location: intra-abdominal isolated (or mesenteric), parietal isolated or mixed. Size of tumours was collected at diagnostic and during treatment to evaluate their evolution. DT were classified with the Church score [10]. In case of multiple DT, the larger and most progressive lesion (worst DT) was used to classify the disease. Patients with only desmoid reaction with no mass were not included in the present study as it has no clear relation with intra-abdominal desmoid [19].
Patients
Treatments Surgical treatment consisted of explorative laparotomy, digestive or parietal resection, intestinal bypass, surgical treatment of intestinal perforation and stoma formation. Medical treatment included non-steroid anti-inflammatory drug (sulindac, from 400 to 800 mg/day), antiestrogen therapy (tamoxifen, 120 mg/day), tyrosine kinase inhibitor (Imatinib, from 200 to 600 mg/day according to the body surface) or chemotherapy. Different chemotherapy regimens have been used combining doxorubicin (60–90 mg/ m2) daily 3 times repeated every 3–4 weeks, methotrexate (30 mg/m2) and vinblastine (6 mg/m2), and more recently cisplatin (60 mg/m2 every 4 weeks) [12, 20, 21].
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Seventy-nine FAP patients [45 females (56 %)] presented 149 DT and were included in the present study. The majority have had a colo-rectal resection. DT characteristics at the time of diagnosis are given in Table 1. Sixteen (20.2 %) patients had a DT diagnosed during or before first abdominal surgery. There was no significant difference between the mean age of these 16 patients at the DT diagnostic and the remaining 63 patients (33.6 ± 13.9 vs. 33.2 ± 12.2 years) (p = 0.924) nor the size of DT at the diagnosis (8.4 ± 5 cm vs. 7.8 ± 4.6 cm; p = 0.6219). DT staging at time of diagnosis All patients with associated parietal and mesenteric DT had a stage 3 or 4. No difference of stage was observed between patients with isolated parietal (8/17; 47 %) or isolated mesenteric DT (24/47; 51 %), (p = 0.777) (Table 1). The number of DT by patients was correlated with staging: mean number of DT for stage 1 patients was 1.6 ± 0.84 versus 2.5 ± 1.56 for stage 4 (p = 0.036). Development of DT before or after any abdominal surgery was not correlated with staging. Mean DT stage was 2.45 ± 0.94 when DT was diagnosed before first abdominal surgery and 2.52 ± 0.9 after (p = 0.97). Age at DT diagnosis and DT score were correlated. The mean age at DT diagnosis for patients with stage 1 tumour was 40.1 ± 12.7 years versus 29.2 ± 9.1 years (p = 0.0104)
Treatment of desmoid tumors Table 1 Patients’ characteristics at DT diagnosis Overall cohort (n = 79)
Isolated parietal DT (n = 17)
Isolated mesenteric DT (n = 47)
Associated DT (n = 15)
35 (44 %)
5 (29.4 %)
25 (53.2 %)
5 (33.3 %)
RPC ? IPAA Subtotal colectomy
51 (64.5 %) 23 (29 %)
9 (52.9 %) 6 (35.3 %)
31 (65.6 %) 14 (29.8 %)
11 (73.3 %) 3 (33.3 %)
Other
5 (6.5 %)
2 (11.8 %)
2 (4.2 %)
1 (6.7 %)
Mean ± SD
28.6 ± 10.9
26.1 ± 7.3
29.3 ± 12.16
29 ± 10,2
Median (range)
26.9 (14.3–66.8)
26.2 (15.1–41.6)
25.8 (14.3–66.7)
29 (15–49)
9 (11 %)
1 (5.9 %)
4 (8.5 %)
4 (26.7 %) 30.5 ± 9.6
Male Gender First abdominal surgery:
Age at first abdominal surgery (years)
Adenocarcinoma diagnosed at the time of colectomy Age at DT diagnosis (years) Mean ± SD
33.3 ± 12.5
33.4 ± 10.8
34.2 ± 14
Median (range)
30.5 (16.1–77.7)
35.3 (16.1–52.7)
28.7 (16.7–77.7)
29 (17.1–47.5)
149
23
78
48
Number of DT Number of DT per patient Mean ± SD
1.8 ± 1.3
1.35 ± 1
1.66 ± 1
3.2 ± 1.5
Median (range)
1 (1–7)
1 (1–5)
1 (1–5)
3 (1–7)
7.9 ± 4.7 7 (1–20)
7.1 ± 5.1 5 (3–20)
6.8 ± 3.7 7 (1–15)
12.4 ± 4.6 12 (4.4–20)
Largest DT (cm) Mean ± SD Median (range) Mean ± SD size of DT at diagnosis (cm) Diagnosis before or during first abdominal surgery
7.7 ± 4.7
7.5 ± 5.4
7.4 ± 4
11.6 ± 8.5
Diagnosis after the first abdominal surgery
7.9 ± 4.7
7 ± 5.3
6.7 ± 3.7
9.9 ± 6.15
I
19 (24 %)
3 (17.6 %)
16 (34.0 %)
0
II
13 (16.4 %)
6 (35.3 %)
7 (14.9 %)
0
Church’s Classification at the diagnosis
III
33 (41.7 %)
6 (35.3 %)
16 (34.0 %)
11 (73.3 %)
IV
14 (17.7 %)
2 (11.8 %)
8 (17.0 %)
4 (26.7 %)
Follow–up (months) Mean ± SD
97.7 ± 83.8
127.9 ± 109.4
89.4 ± 76.2
89.3 ± 70.2
Median (range)
81 (1.7–437.1)
135.2 (17.4–437.1)
72.6 (1.7–280)
84 (15.4–266)
Death
14 (17 %)
3 (17.6 %)
8 (17.0 %)
3 (20 %)
Deaths related to TD
6 (7.5 %)
1 (5.9 %)
5 (10.6 %)
0 (0 %)
RPC ? IPAA: total coloproctectomy ? ileal pouch anal anastomosis; DT desmoid tumour, SD standard deviation
for stage 4 patients. There was no significant difference between age at first abdominal surgery and DT staging at diagnostic time. Treatment Among the 79 patients, 31 (39.2 %) had never received medical treatment: 11 had only surgical treatment, 20 had no treatment with spontaneous DT regression or stabilization. Two patients had radiotherapy associated to medical treatment. In the first case, radiotherapy has led to significant
radiation enteritis complicated by several occlusive episodes. Gastrointestinal bypass was then practiced. In the second case, radiotherapy was responsible of tumour necrosis complicated by intestinal perforation and peritonitis. Resection with stoma formation was required. The 20 patients who hadn’t treatment, had a significant smaller DT size than other patients (4.4 cm ± 2.2, vs. 9.1 cm ± 4.7) (p = 0.0001). Stage at DT diagnosis was also significantly lower for these patients [stage 1–2 for 19/20 patients (95 %)] than for the remaining (stage 1–2 13/59 patients (22 %) (p \ 0.001)].
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T. Desurmont et al. Table 2 Details about efficiency of adjuvant therapy to first DT surgical resection and global efficiency of medical treatment Medical treatment
n
Adjuvant treatment after surgical resection
10 patients
Success n (%) 4 (40 %)
Sulindac
5
3
Tamoxifen
2
1
Sulindac ? tamoxifen
2
0
Imatinib
1
Global efficiency of medical products
80 lines
0 34 (42.5 %)
Sulindac (n = 29)
29
Tamoxifen (n = 15)
15
6 (40 %)
Sulindac ? Tamoxifen (n = 12)
12
6 (50 %)
Imatinib (n = 11) Chemotherapy (n = 13)
8 (27.6 %)
11
4 (36.3 %)
13
10 (76.9 %)
Medical treatment Seventeen patients (21.5 %) had only medical treatments and 31 (39.2 %) had combined medical and surgical treatments. After first DT surgical resection, 10 patients had an adjuvant treatment, mainly with sulindac (n = 5). In four patients, no recurrence occured while tumoral relapse and/or evolution were observed in 6 patients (Table 2). Nineteen patients have received medical treatment after any kind of DT surgery (resection, intestinal bypass or surgical treatment of peritonitis). For 10 patients (52.6 %) the association of surgical treatment and adjuvant therapy was effective. Overall, 80 treatment lines were administered to patients with a progression free or regression rate of 43 % (34/80). Chemotherapy was the most efficient treatment with a response rate of 77 % (10/13) (Table 2).
prophylactic total colectomy and ileorectal anastomosis as the rectum was not resectable. Forty-two patients (53.1 %) underwent surgical treatment for a total of 63 operations with an overall postoperative mortality of 4.8 % (n = 2). Among these 42 patients, first surgical procedure was an R0 resection in 26 (62 %) (Table 3). Eighteen patients had been reoperated for recurrence or persistence of DT after a median delay of 24 months (range 3–150). Four patients required reoperation after long delay (from 64 to 150 months). Stage 3 or 4 DT at diagnosis were significantly correlated with a need of surgical treatment [stage 3: 20/33 (60.6 %); stage 4: 13/14 (92.6 %) versus stage 1 and 2 (9/ 32; 28.2 %)] (p = 0.0001). Thus 70.2 % of stage 3 or 4 mesenteric, parietal or mixed DT at diagnosis were operated. Survival Median follow-up from DT diagnostic was 81 months (range 2–437). Eight patients died of their DT and 6 died of other cause: 2 of metastatic duodenal adenocarcinoma, 1 of indeterminate peritoneal carcinomatosis, 1 of splenic necrosis unrelated to his DT, despite performing splenectomy, and 2 of metastatic colic or rectal adenocarcinoma (Table 4). Overall survival at 10 and 20 years were 83 and 52 %, respectively (Fig. 1). DT specific survival at 10 and 20 years were 90 and 79 %, respectively. Initial DT score and initial DT location at diagnosis were not found to influence survival (p [ 0.05) (Fig. 1). The 20 years survival of patients with DT diagnosed before or during a first abdominal surgery (n = 16) was significantly lower than for patients with DT diagnosed after surgery (n = 63) (42 vs. 53 %; p = 0.033) (Fig. 1).
Surgical treatment Discussion For 5 patients, the first abdominal surgery was not a colorectal resection. First patient underwent a small bowel resection and anastomosis by laparotomy for a voluminous mesenteric and occlusive DT. Second patient underwent a splenopancreatectomy for DT. For these two patients a restorative coloproctectomy was performed later (2.5 and 7 months). Other patient underwent a gastro-jejunostomy and lateral ileostomy for occlusive non-resectable mesenteric DT. For the fourth, an explorative laparotomy for a voluminous and occlusive mesenteric DT can only be performed. No resection or bypass was feasible and this patient died of its DT. In the fifth case, first abdominal surgery was a hepatectomy for adenoma, with TD development 1 year later, leading to the achievement of a
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Although the development of DT is usually slow and insidious, their potential morbidity can be significant [22]. DT is a major cause of death for FAP patients [23–25]. Publications on treatment of DT in FAP are rare [11, 18]. This paucity of publication is related to the small number of patients. With these limitations, we tried by the analysis of our series, to find some clue to develop a treatment strategy for these patients. We have considered that a stop in tumour progression, was a success as well as a tumour regression [17, 18, 26]. We didn’t report the APC mutation as it is not used in the management of DT. Moreover, for some de novo patients, no germline mutation is found.
Treatment of desmoid tumors Table 3 Details about surgical management of desmoid tumors Patients
Surgery
Patients with DT (n = 79)
42 (53.2 %)
Details
Success
Complete R0 resection
No recurrence (n = 14, 53.8 %)
(n = 26, 61.9 %) Other procedures (n = 16, 38.1 %) Intestinal bypass (n = 8)
Stabilization (n = 5, 31.2 %)
Explorative laparotomy (n = 4) Management of gastrointestinal perforation (n = 3) Incomplete resection associated with bypass (n = 1) Patients, with isolated parietal DT at diagnosis (n = 17)
12 (70.6 %)
Patients, with isolated mesenteric DT at diagnosis (n = 47)
17 (36.2 %)
Complete R0 resection
9 (75 %)
(n = 11, 91.7 %) Impossible resection (n = 1, 8.3 %) Complete R0 resection (n = 6, 35.3 %)
3 (17.6 %)
Other procedures (n = 11, 64.7 %) Intestinal bypass (n = 6) Explorative laparotomy (n = 3) Management of intestinal perforation (n = 2)
Table 4 Details about patients who died due to their DT Patients
Initial location
Stage at diagnosis
Age at diagnosis (years)
Delay from diagnosis to death (months)
Cause of death
Age at death (years)
Patients directly dead due to their DT 1
Mesenteric
3
43.2
22.4
Intestinal occlusion and digestive hemorragia
45
2 3
Mesenteric Parietal
2 4
17.7 43.3
44.8 43.8
Peritonitis by digestive perforation DT evolution
21.3 46.7
4
Mesenteric
3
25
5
Mesenteric
4
18.6
27.6
6
Mesenteric
3
20.3
204.8
4.9
Tumoral necrosis
28.9
Tumoral necrosis and chronical intestinal occlusion
20.9
Jejuno-ileal multiple fistulas
35.8
Suicide because of multiple DT and multiples surgical procedure
55
Rectal adenocarcinoma in a rectal stump let in place because of inextirpable mesenteric DT
43
Patients indirectly dead due to their DT 1
Parietal
3
52.7
2
Mesenteric
2
34.5
21.25 101.6
NSAIDs (sulindac) has been described as first line treatment in FAP for DT [6, 27, 28]. In this series, we didn’t find this treatment very effective, as stabilization or regression of the DT was observed in only a quarter of the patients receiving this drug. As adjuvant to surgery, 3 of 7 patients achieved remission under sulindac, but it is impossible to determine if surgery alone would not have achieved such result. Few publications analyzed the effectiveness of NSAIDs [27]. Nieuwenhuis et al. [18] reported a series of 12 patients treated with NSAIDs and showed a 50 % rate of progression-free survival at 5 years. De Camargo et al. [16] reported their experience with NSAIDs as an adjuvant treatment after surgery. They
didn’t specify the number of treatment begun among the 68 patients treated for sporadic and FAP-related DT, but they didn’t found any tumour reduction under NSAIDs [16]. Clarck et al. [8] have shown a rate of regression or stabilization of DT lesions of 29 % under NSAIDs. All these findings, seems to demonstrate that if sulindac is proposed as a first line treatment, it is proposed without obvious proof demonstrating an efficiency of this treatment. Moreover, the rate of stabilization and regression observed after such treatment might be identical to the one observed without any treatment. However, when a DT is found, as it is impossible to predict its evolution, sulindac is proposed after or during a ‘‘wait and evaluate’’ attitude most of the
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T. Desurmont et al. 100
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Fig. 1 Survival curves of patients monitored for DT in a PAF context, for the overall group (a), according to DT initial location at diagnosis (b), DT grade at diagnosis (c) and depending on whether DT diagnosis has been made before (or during) or after the prophylactic colectomy (d)
time in our experience. It seems possible, then, to consider this attitude without treatment and to go for a much more efficient but also aggressive treatment if required, only. As DT were considered hormonally responsive and in particular to oestrogen [26, 29, 30], anti-oestrogens are used alone or adjuvant to surgery [8, 26]. Anti-oestrogen or combination of anti-oestrogen and sulindac are effective in 40 and 50 % of our patients, respectively. These results are in line with previous reports. Clarck et al. [8] observed a stabilization or regression of 19 % of DT treated by antioestrogens in the context of FAP. Hansmann et al. have presented a series of 13 patients who received anti-oestrogens (tamoxifen) and NSAIDs (sulindac). Six patients had then a stable disease and 4 a partial regression [26]. Such results are not so different to the one observed after sulindac. The attitude, just proposed with this last treatment, should even more be considered, when anti-oestrogens treatment are discussed with their risks of side effects like flushing, headache and bleeding. Furthermore, the necessity to associate with anti-oestrogens, contraception and anti-thrombotic at curative dose, represent also evident disadvantages.
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Imatinib has also been proposed in this situation. Nieuwenhuis et al. [18] have reported their experience of three patients and have shown that imatinib had no evident positive effect. Chugh et al. [31] have presented a survival study of 51 patients treated with imatinib for aggressive fibromatosis not controlled by surgery or for whom surgical indication was not retained. Rates of progression-free survival at 2 months, 4 months and 1 year was respectively 94, 88 and 66 %. But only 3 patients (6 %) had an objective tumour response in this study. In the present series, with 11 patients treated with imatinib, we observed that slightly less than half of patients achieved a regression or stabilization. More studies are required to consider imatinib has a treatment for DT in FAP, as the response rate might not be so different that the ones observed with sulindac and anti-oestrogens, and so, might be consider also as doubtful. More recently the French Sarcoma Group (FSG) published a phase II trial of 40 patients with DT (but only 6 were belonging to a FAP family) (ref). The non-progression rate was 67 % at 12 months [32]. This group of clinical research is willing to propose a consensus algorithm for the treatment of DT.
Treatment of desmoid tumors
In our experience, chemotherapy is administered to patients with DT in progression while under conventional therapy. Our results show efficacy in three-quarters of our patients and therefore is the most effective treatment (77 % in our experience), regardless of treatment previously administered. These results are consistent with those published in the literature [6, 12, 13, 15, 16, 21]. In 1993, Patel et al. [21] showed with a series of 9 patients treated with a median of 5 cycles of doxorubicin combined with dacarbazine, a major response in six patients, a minor response in one patient and a stabilization in 2 patients. Hamilton et al. published, few years later, a series of three patients treated for nonresectable PAF-related DT resistant to hormonal treatment. This protocol associated high doses of doxorubicine (60–90 mg/m2) and dacarbazine (1000 mg/ m2) for seven cycles. They obtained, for each of the three patients, clinical and radiological regression [20]. With the threat of side effects, a reduced-dose protocol has been proposed. Azzarelli et al. have treated 30 patients with a methotrexate (30 mg/m2) and vinblastine (6 mg/m2) based chemotherapy every 10 days, (median of 38 cycles) to diminish toxicity. They obtained a partial tumour response in 12 patients and a tumour stabilization in 18 [12]. More recently, Nieuwenhuis et al. presented the results of 10 patients treated for FAP-related DT with doxorubicin combined with others agent like carboplatine, dacarbazin or ifosfamide. Effects of chemotherapy were variable. Four patients obtained regression or stabilization of their lesions but five had progression [18]. However, with the results of this series and those of the literature, it seems that chemotherapy for the treatment of FAP-related DT is frequently effective. For this reason, we consider to propose chemotherapy as a first line treatment when required. Actually, there are several ongoing studies for the medical treatment of DT: DESMOPAZ (NCT01876082) evaluating the Pazopanib which is an inhibitor of multi-target tyrosine kinase or the NCT01981551 trial evaluating a Gammasecretase inhibitor. We hope that these trials will increase the therapeutic armamentorium. The problem is then to consider when a treatment is required. Church et al. [10] proposed a score to classify the intra-abdominal DT in FAP. This score use various criteria: symptoms of the tumour, maximum diameter, obstructive nature, and evolution. In case of multiple tumours, the patient is graded according to tumour highest score. In our series of 79 patients, with expanded criteria of classification chosen by Church et al. to parietal DT and mixed tumours, we were unable to find that this classification could predict mortality. Only tumours of stage 1 had a predictable evolution with no mortality, but these tumours are easily identified and as evolution is part of the score are those that are not progressing. The absence of a score or any valid classification that would help to predict the
possible evolution should not be an obstacle. In fact, a DT in rapid progression or with life threatening complication should be consider immediately for chemotherapy, and we should skip the less aggressive treatment phase that we usually proposed as a first step. Considering chemotherapy for patients with DT in progression, it remains the question of possible surgery as an alternative option. In the cases of abdominal wall lesions, surgical excisions seem safe [33, 34]. We did not observed any death in our series, like others [11, 18], and morbidity was low. So the principal problem is to obtain clear margins to reduce the risk of recurrence [33]. Our 18 % recurrence rate after abdominal wall DT resection is comparable to the 40 % reported by Clark et al. [8]. This finding, in the optic of our strategy makes us consider surgery more than chemotherapy for abdominal wall DT. For intra-abdominal DT, among our 47 patients without parietal lesion, only 17 have undergone a surgical procedure and only 6 patients could have a tumour resection. The other 11 procedures were performed with palliative intent or in emergency. Two of our patients operated on for abdominal DT died after surgery. The St Mark’s hospital team reported 36 % mortality after surgical excision of intra-abdominal DT and nearly half of their surviving patients require chronic parenteral nutrition postoperatively [8]. Nieuwenhuis et al. [18] reported, in a series of 62 patients, in whom complete resection of DT was intended in about 60 % of their patients, that none of intra-abdominal DT could be fully resected and a 10 years disease-free survival of 32.9 %. Moreover, Burke et al. [34, 35] reported on 10 FAP patients operated on for intra-abdominal DT, a post-operative mortality of 50 % and a recurrence rate of 90 %. Berk et al. [36] also had shown a very high rate of recurrence of abdominal DT resection, with in their series of 13 patients a recurrence rate of 85 %. All these observations highlight the great risk and the poor results of surgery after intra-abdominal DT resection. For these reasons, we are more likely to consider chemotherapy as a first choice treatment in this situation and to reserve surgery when chemotherapy is not possible or when DT are, or about to be, life threatening lesions.
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