Ann Surg Oncol DOI 10.1245/s10434-014-4123-6
ORIGINAL ARTICLE – BONE AND SOFT TISSUE SARCOMAS
Abdominal Desmoplastic Small Round Cell Tumor: Multimodal Treatment Combining Chemotherapy, Surgery, and Radiotherapy is the Best Option Charles Honore´, MD1, Koceila Amroun, MD1, Laurence Vilcot, MD2, Olivier Mir, MD3, Julien Domont, MD3, Philippe Terrier, MD4, Axel Le Cesne, MD3, Cecile Le Pe´choux, MD5, and Sylvie Bonvalot, MD, PhD1 Department of Surgical Oncology, Gustave Roussy Cancer Center, Villejuif, France; 2Department of Radiology, Gustave Roussy Cancer Center, Villejuif, France; 3Department of Medical Oncology, Gustave Roussy Cancer Center, Villejuif, France; 4Department of Pathology, Gustave Roussy Cancer Center, Villejuif, France; 5Department of Radiation Oncology, Gustave Roussy Cancer Center, Villejuif, France 1
ABSTRACT Background. With nearly 450 cases reported since 1991, desmoplastic small round cell tumor (DSRCT) is a rare abdominal tumor typically arising in adolescent and young adult white men. With no large series described, the best therapeutic strategy remains unclear. Methods. All consecutive patients treated in our tertiary care center between January 1991 and December 2013 for a DSRCT were retrospectively studied. Results. Thirty-eight patients with a median age of 27 years (range 13–57 years) were identified; 71 % were men. At the time of diagnosis, 47.4 % patients had extraperitoneal metastases (EPM): 78 % were located in the liver and 11 % were located in the lungs. Fourteen patients (37 %) were treated exclusively with systemic chemotherapy, with a median survival of 21.1 months. Twentythree patients underwent surgery, 12 (52 %) experienced complete removal of all macroscopic disease, 5 (21.7 %) received additional intraperitoneal chemotherapy, and 7 (30 %) received postoperative whole abdominopelvic radiotherapy (WAP RT). With a median follow-up of 59.9 months, the median survival was 37.7 months, and the median disease-free survival was 15.5 months. The factors predictive of 3-year overall survival were the absence of EPM, complete surgical resection, postoperative WAP RT,
Ó Society of Surgical Oncology 2014 First Received: 30 May 2014 S. Bonvalot, MD, PhD e-mail: [email protected]
and postoperative chemotherapy. The intraperitoneal chemotherapy had no impact on overall survival. Conclusions. DSRCT is a rare and aggressive disease. In patients without EPM, a multimodal treatment combining systemic chemotherapy, complete macroscopic resection, and postoperative WAP RT could enable prolonged survival. No benefit of surgery was demonstrated for patients with EPM. The value of associated hyperthermic intraperitoneal chemotherapy remains unproven.
Desmoplastic small round cell tumor (DSRCT) is a rare abdominal tumor with only approximately 450 cases described in the literature (among which more than 60 are case reports) since its first description in 1991 by Gerald et al..1 DSRCT typically occurs in adolescent and young adult white men. The male/female ratio in the literature is 6/1.2–11 The median age ranges between 14 and 26 years (with extremes from 1.5 to 58 years).2–11 This tumor type has a strong tendency to spread within the peritoneum but can also give rise to extraperitoneal metastases, mainly in the liver and lungs.4,5,8,9 Symptoms are nonspecific and are mostly related to the abdominal bulk.12 A translocation, t(11:32)(p13;q12), of gene ESWR1-WT is highly specific and allows a formal diagnosis of DSRCT.13–15 The origin of this tumor is yet unknown, but it is speculated that it arises from the serosal lining cells of the peritoneum.16 The primary site is frequently unknown, as it is most often discovered at the stage of a disseminated tumor within the abdomen.5 DSRCT has an extremely aggressive clinical course and is associated with a very poor prognosis, with a reported median survival ranging from 17 to 25 months.12 With no large series in the
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literature, there is no consensus as to the optimal treatment, and the best therapeutic strategy remains unclear and challenging.12 The aim of our study was to analyze our experience in the treatment of DSRCT to define the most appropriate therapeutic strategy. METHODS Patient Selection All consecutive patients treated in our single tertiarycare center between January 1991 and December 2013 for a DSRCT by a single team were included in this study. The histology was systematically confirmed by an experienced pathologist. The patients’ files were retrospectively reviewed for demographic data, diagnostic circumstances, and tumor and treatment variables, including the type of surgery, perioperative radiotherapy and/or chemotherapy, and outcome. All patients were retrospectively staged according to the MD Anderson DSRCT staging criteria.11 For patients who underwent surgery, the peritoneal extent of the disease was evaluated preoperatively and scored with the peritoneal cancer index.17 Multimodal treatment was defined as a combination of one or more subsequent therapeutic treatments (chemotherapy, intraperitoneal chemotherapy, radiotherapy, surgery). The treatments and sequence were systematically discussed in a multidisciplinary team meeting.
resection in a patient without extraperitoneal metastases. Surgical biopsy was not considered to be CRS. Intraperitoneal Treatment When provided, intraperitoneal chemotherapy was administered either using hyperthermic intraperitoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC). HIPEC was performed using an open coliseum technique with an intraperitoneal bath of 300 mg/m2 of oxaliplatin and 200 mg/m2 of irinotecan heated to a temperature of 43 °C for 30 min in association with intravenous fluorouracil at 400 mg/m2. For EPIC, four intraperitoneal drains were placed at time of operation, and the abdomen was filled directly after closure with 2 L of Ringer lactate to avoid intraperitoneal adhesions. The day after surgery, the Ringer lactate was drained, and intraperitoneal chemotherapy was provided continuously over five postoperative days with a combination of doxorubicin 0.1 mg/kg and cisplatin 15 mg/m2 diluted in 2 L of Ringer lactate per day. Postoperative Morbidity Surgical complications were retrospectively graded according to the Clavien–Dindo classification.19 Complications were considered severe when above 2.
Chemotherapy and Radiotherapy
Long-Term Follow-Up
Induction chemotherapy was provided to patients with extraperitoneal metastases (EPM) or patients without EPM but with bulky peritoneal disease at imaging. The chemotherapy regimen was retrospectively recorded. Radiologic response was evaluated by response evaluation criteria in solid tumors (RECIST).18 The dose and technique of delivery of whole abdominal pelvic radiotherapy (WAP RT) were recorded.
Recurrences were diagnosed either on a clinical or radiologic basis and were confirmed in a multidisciplinary team meeting. Progressive disease was defined as tumor growth documented on imaging (either by magnetic resonance imaging or computed tomographic scan) using RECIST.18
Surgery Cytoreductive surgery (CRS) was defined as the resection of all peritoneal implants, preserving the macroscopically noninvaded peritoneum. The completeness of the peritoneal cytoreduction was classified according to the Sugarbaker completeness of cytoreduction (CC) score, as follows: CC 0, no residual macroscopic disease; CC 1, residual nodules measuring less than 2.5 mm; CC 2, residual nodules measuring between 2.mm and 2.5 cm; and CC 3, residual nodules greater than 2.5 cm.17 No surgery for EPM was performed. Surgery was considered complete in case of CC 0
Statistical Analysis The cutoff date for survival analyses was August 1, 2013, for the censored data analysis. Categorical variables were compared within groups by the Chi square and Fisher’s exact test, when appropriate. The survival analysis was performed using the Kaplan–Meier method and compared by the log-rank test. Overall survival (OS) was computed from the date of diagnosis to the date of death or the last follow-up. Time to local and time to distant recurrence were computed from the date of primary tumor resection to the date of local or distant recurrence. All statistical analyses were performed by IBM SPSS statistics software, version 20.0. Data were expressed as mean ± the
Multimodal Treatment of DSRCT TABLE 1 Patient and tumor characteristics
TABLE 2 Treatments
Characteristic
Value
Treatment
Value
No. of patients
38 (100 %)
Systemic chemotherapy
38 (100 %)
Age, year, median (range)
27 (13–57)
Preoperative
16 (42.1 %)
Sex ratio, M/F
2.4
Postoperative
17 (44.7 %)
Gender
Surgery
23 (60.5 %)
Male
27 (71 %)
CC 0
12 (31.6 %)
Female
11 (29 %)
CC 1
3 (7.9 %)
General status (WHO scale) 0
24 (63.2 %)
1
6 (15.8 %)
2 NA BMI, kg/m2, median (range)
CC 2–3
5 (13.2 %)
Associated LM
3 (7.9 %)
Associated IPC
5 (13.2 %)
1(2.6 %)
HIPEC
2 (40 %)
5 (18.4 %) 22.4 (16.7–34.2)
EPIC NA
2 (40 %) 1 (20 %)
Postoperative morbidity
7 (30.4 %)
Yes
6 (15.8 %)
Postoperative mortality
0 (0 %)
No
32 (84.2 %)
WAP RT
8 (21.1 %)
Postoperative WAP RT
7 (18.4 %)
Malnutrition
Symptoms Yes
32 (84.2 %)
2D or 3D RT
4 (57.1 %)
No
6 (15.8 %)
IMRT
3 (42.9 %)
Type of symptoms Abdominal mass
17 (44.7 %)
Abdominal pain
14 (36.8 %)
Urinary disorders
3 (7.9 %)
Intestinal disorders
2 (5.3 %)
Tumor size, cm, median (range)
12 (4.5–30)
Preoperative PCI, median (range)
13 (3–19)
Extraperitoneal metastases Yes No
18 (47.4 %) 20 (52.6 %)
Liver metastases
14 (36.8 %)
Lung metastases
5 (13.2 %)
MD Anderson stage I
10 (26.3 %)
II
6 (15.8 %)
III
11 (28.9 %)
IV
6 (15.8 %)
NA
5 (13.2 %)
WHO World Health Organization, BMI body mass index, PCI peritoneal cancer index, NA not applicable
standard error of the mean, unless otherwise stated. A p value of less than 0.05 was considered significant. RESULTS Patient Demographics Between January 1991 and December 2013, 38 patients were treated at our center for abdominal DSRCT. Thirty-
CC completeness of cytoreduction, LM liver metastases, IPC intraperitoneal chemotherapy, HIPEC hyperthermic intraperitoneal chemotherapy, EPIC early postoperative intraperitoneal chemotherapy, WAP whole abdominopelvic, RT radiotherapy, IMRT intensitymodulated radiotherapy, NA not applicable
one patients had a retrospectively confirmed EWSR1-WT translocation. For the remaining 7 patients, no formal proof was retrospectively recoverable, but the diagnosis had systematically been confirmed by our expert pathologist. The patients and tumor characteristics are reported in Table 1. Seventy-one percent of the patients were men. EPM were present at the time of initial diagnosis in 18 patients (47.4 %) and were mainly located in the liver (78 %) and lungs (11 %). Other metastatic locations included lymph nodes and the spleen. Thirty-two patients (84 %) were symptomatic at the time of diagnosis (clinically palpable abdominal mass and/or abdominal pain in 31 cases, 81 %). Chemotherapy The details of treatments are reported in Table 2. All but 7 patients received induction chemotherapy. Fourteen patients (37 %) had disease that was not amenable to surgery and were treated exclusively with systemic chemotherapy. One patient (3 %), whose tumor was deemed inoperable, received an exclusive combination of chemotherapy and WAP RT. Induction chemotherapy was based on the combination of doxorubicin and ifosfamide in 28 patients. The following regimens were used: NEO-AI (doxorubicin
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Surgery Among the 23 patients who underwent surgery, 16 (70 %) received induction chemotherapy and 17 (74 %) received postoperative adjuvant chemotherapy. Seven (48 %) received pre- and postoperative chemotherapy. The median peritoneal cancer index at laparotomy was 9 (range 8–18). Fifteen patients (65 %) underwent complete surgical removal of all macroscopic peritoneal disease, but three of them had associated bilobar synchronous liver metastases that were not removed. Therefore, 12 patients (52 % of the surgical patients) experienced macroscopically complete surgical resection of all tumoral disease (CC 0). Five patients (22 %) received intraperitoneal chemotherapy. Five patients (22 %) developed severe postoperative complications, which all required reoperation. There were no postoperative deaths. Radiotherapy One patient (3 %), whose tumor was deemed inoperable, received an exclusive combination of chemotherapy and radiotherapy at the dose of 22.5 Gy. Among the 23 surgical patients, 7 (30 %) received postoperative WAP RT at a median dose of 30 Gy. Four patients received conventional radiotherapy with two opposed fields to the entire abdominal cavity. The kidneys were shielded after 12– 15 Gy, and the liver after 25 Gy. Treatment was delivered with fractions of 1.5–1.55 Gy. Patients with residual tumor in the pelvis had a boost up to a median dose of 45–50 Gy. Three patients had intensity modulated WAP RT, with 9field modulated beam arrangement, with 6 MV photons. The clinical target volume included the whole peritoneal
Whole population (n=38) 100 80
Percent survival
60 mg/m2 day 1 ? ifosfamide 3 g/m2/day days 1–3 ? mesna, day 1 = day 21), n = 14; AI (doxorubicin 60 mg/m2 day 1 ? ifosfamide 3 g/m2/day days 1–2 ? mesna, day 1 = day 21 ? G-CSF support), n = 2; API-AI regimen n = 2; other doxorubicin-based regimen (AI alternated with etoposide 100 mg/m2/day days 1–3 ? ifosfamide 3 g/m2/ day days 1–3 ? mesna, day 1 = day 21), n = 10.20 Cisplatin-5-fluorouracil and VACA were provided to 2 and 1 patient, respectively.21 Patients received a median number of 4 cycles (range 4–7 cycles). In the postoperative setting, 17 patients received chemotherapy: VAC, n = 4; PAVEP, n = 2; etoposide ? ifosfamide based regimens, n = 5, API, n = 1; or other (cyclophosphamide based or etoposide– cisplatin, n = 5), for a median of 4 cycles (range 3–10 cycles).22,23 Partial radiologic response and stable disease were observed in 68 and 23 % of the patients, respectively. There was no complete radiologic response. Twenty-three cases (64 %) had disease that was ultimately deemed operable.
60 40 20 0 0
20
40
60
80
Months
FIG. 1 OS of entire population
cavity and the retroperitoneum, treated up to a dose of 30.60 Gy in 1.55 Gy daily fractions. The mean dose to both kidneys was less than 10 Gy, and the mean dose to the liver did not exceed 25 Gy. After a median of 26.3 months after the end of radiotherapy, no patient had developed significant late toxicity. Overall Survival After a median follow-up of 59.9 months (range 7.9– 266.8 months), the median OS was 25.7 months (range 7.9–69.0 months). The survival curve for the entire population is reported in Fig. 1. Prognostic Factors In a univariate analysis, the absence of EPM, complete CRS, postoperative WAP RT, and postoperative chemotherapy were predictive factors for the 3-year OS (Table 3). Because of the small number of patients, no multivariate analysis was performed. Among the 12 patients with complete macroscopic resection of all tumoral disease (CC 0), the median survival was 37.7 months (range 15.1– 58.2 months). The 1-, 3- and 5-year OS rates were 94.7 % (95 % confidence interval [CI] 87.6–100), 31.6 % (95 % CI 29.6–39.2), and 8.3 % (95 % CI 0–25.8), respectively. The patients with EPM treated with exclusive chemotherapy had a median survival of 21.1 months (range 7.9– 42.9 months). The 3 patients who had synchronous nonresectable liver metastases but had complete peritoneal CRS had a median survival of 14.8 months (range 7.9– 20.1 months). Disease-Free Survival Among the 12 patients without EPM who had a macroscopically complete CRS, the 1- and 3-year disease-free
Multimodal Treatment of DSRCT TABLE 3 Predictive factors of 3-year overall survival Population
Deceased (n = 26)
Alive (n = 12)
p 0.19
Age
25 (13–57)
27 (16–57)
Male gender
16 (61.5 %)
11 (91.7 %)
0.28
PCI
12.4 ± 5.2
11.1 ± 5.6
0.59
Tumor size
10.9 ± 5.7
13.3 ± 4.6
0.34
Extraperitoneal metastases
16 (61.5 %)
2 (16.7 %)
0.015
Preoperative chemotherapy
20 (76.9 %)
10 (83.3 %)
0.99
HR
95 % CI
8
1.444–44.32
CC 0 surgery
5 (19.2 %)
7 (58.3 %)
0.026
0.17
0.038–0.767
CC 0–1 surgery
7 (26.9 %)
8 (66.7 %)
0.0326
0.184
0.042–0.81
IPC
2 (7.7 %)
3 (25 %)
0.067
Postoperative chemotherapy
8 (30.8 %)
9 (75 %)
0.016
0.148
0.031–0.698
Postoperative WAP RT
2 (7.7 %)
5 (41.7 %)
0.022
0.117
0.018–0.737
PCI peritoneal cancer index, CC completeness of cytoreduction, IPC intraperitoneal chemotherapy, WAP whole abdominopelvic, RT radiotherapy, HR hazard ratio, CI confidence interval
survival rates were 41.6 % (95 % CI 10.3–72.9) and 16.7 % (95 % CI 0–40), respectively. The median diseasefree survival was 15.5 months (range 4.2–21.8 months). Among the 4 patients who received complete multimodal treatment, including complete CRS, perioperative chemotherapy, and postoperative WAP RT, 1 died of recurrence (peritoneal and extraperitoneal) after 16 months, 1 is still alive after 15 months with lymph node recurrence, and 2 are alive and free of disease after 32 and 37 months, respectively.
Patterns of Recurrence after Complete Surgery Seven patients experienced disease recurrence after macroscopically complete CRS. The mean time before recurrence was 12.6 months. The sites of first recurrence were the liver, lymph nodes, lung, and peritoneum in 4 patients (57 %), 3 patients (43 %), 2 patients (29 %), and 1 patient (14 %), respectively. One patient had liver surgery for hepatic recurrence. He developed further metastases 6.6 months later in the lung and liver. All other recurrences were treated with systemic chemotherapy alone until progression. DISCUSSION This study is the largest reporting the multimodal management of abdominal DSRCT. After a median followup of 59.9 months, the median OS of the entire population was 25.7 months, confirming the severity of the disease. We were able to identify 4 prognostic factors: the absence of EPM, CRS, WAP RT, and postoperative chemotherapy. These findings underline the paramount role of multidisciplinary management in this disease.
Our study confirms that EPM are very common in DSRCT, affecting nearly half of the patients at the time of diagnosis. These findings are consistent with the literature, reporting rates ranging from 33 to 50 %.4,5,7–9 We also found that EPM are highly predictive of a poor prognosis.5,24 The median OS after peritoneal CRS in patients with synchronous liver metastases was only 14.8 months, which is comparable to the results obtained with systemic chemotherapy alone.2 Therefore, we believe that surgery is inappropriate for this group of patients, who should instead be treated with systemic chemotherapy alone. Most chemotherapy combinations used for DSRCT are based on alkylating agents, similar to those used in other childhood small round cell tumors or Ewing sarcomas, which share the same EWS fusion protein.7 Because these tumors have a highly specific identified mutation (translocation t(11:32)(p13;q12)), targeted therapies could become part of the therapeutic strategy in the future. Phase I studies using anti-ILG R1, trabectedin, tyrosine kinase inhibitors, ganitumab, temsirolimus alone, and temsirolimus combined with cixutumumab (a fully human IgG1 monoclonal antibody directed against insulin growth factor 1 receptor, IGF1R) have reported interesting results in this disease.25–30 On the basis of our results, patients should receive induction chemotherapy because it may select the best candidates for surgery and improve rates of complete resection. A radiologic response was observed in 68 % of our patients. Similar significant response rates to neoadjuvant chemotherapy ranging between 39 and 50 % have been reported.2,9,31 The median survival was 37.7 months in a selected group of patients who could undergo macroscopically complete resection of all peritoneal disease (CC 0); therefore, we confirm that surgery should be discussed after neoadjuvant chemotherapy because it is a major component in the treatment of potential long-term DSRCT
C. Honore´ et al.
survivors. Hassan et al. showed that the median OS of patients who underwent complete surgical resection combined with systemic chemotherapy was 34 months, whereas with chemotherapy alone, it was only 14 months.9 Similarly, Lal et al. reported a significantly better OS after macroscopically complete surgery, reporting a 3-year OS after CC 0 of 58 % compared with 0 % when gross deposits remained.5,7 A study from Hayes-Jordan et al. reported that residual deposits above 2.5 mm (i.e., CC 2–3) led to a poor outcome, with a median OS of 12.8 months, even after intensive adjuvant treatment including systemic chemotherapy, HIPEC, and WAP RT.11 In contrast, a median survival of 31.1 months was observed after CC 0 resection combined with a similar perioperative treatment.11 However, complete CRS is challenging and has only been achieved in 25–44 % of all patients with DSRCT.7,10 We confirmed this technical difficulty, as complete macroscopic CRS could only be performed in 15 (65 %) of our 23 patients undergoing surgery. The benefit of intraperitoneal chemotherapy (either HIPEC or EPIC) after resection in DSRCT is highly controversial. Data are scarce, monocentric, and without randomization, and they often come from series including fewer than four cases.11,32–34 The only randomized trial available comparing the administration or not of intraperitoneal chemotherapy after complete macroscopic resection sarcomatosis failed to demonstrate an impact of additional intraperitoneal chemotherapy on OS.35 Currently, most expert centers have stopped using this technique for this indication.36–38 In the present series, intraperitoneal chemotherapy was not associated with a better outcome. As in other studies, we confirmed that postoperative WAP RT should be part of the combined modality treatment of DSRCT, as it could contribute to improve outcomes. In the series reported by Kretschmar et al., the only 2 long-term survivors received adjuvant radiotherapy.2,39 More recently, in a series of 31 patients treated with surgery, chemotherapy, and postoperative WAP RT at a dose of 30 Gy, the 3-year OS and progression-free survival rates were 50 and 24 %, respectively.20 WAP intensity-modulated radiotherapy compared with 2D or even 3D WAP RT resulted in fewer hematologic, renal, and gastrointestinal toxicities, with the possibility of focal dose escalation in specific areas, which could affect local control.20,40,41 Even if the role of chemotherapy is essential in this aggressive tumor, a combination of treatments including pre- and postoperative chemotherapy, macroscopically complete peritoneal CRS, and postoperative WAP intensity-modulated radiotherapy appears to achieve the best results in DSRCT. As reported earlier by Lal et al., the 3year OS after this complete multimodal treatment was
55 % compared with 27 % if one of the therapeutic modalities was missing.7 Because complete multimodal treatment is essential, an up-front multidisciplinary team decision from an expert sarcoma team is mandatory before starting any therapy. The surgeon must balance the extent of the required resection to achieve CC 0 and the subsequently expected postoperative morbidity that could prevent further adjuvant treatment. The limitation of this study is the small number of patients having this extremely rare disease, preventing the realization of a multivariate analysis for prognostic factors. Although not randomized, the patients were treated homogenously by the same team, with a long follow-up and using all types of major treatments, thus enabling an accurate comparison between the therapeutic strategies. In conclusion, for patients with DSRCT without EPM, multimodal treatment combining systemic pre- and postoperative chemotherapy, complete macroscopic resection of the peritoneal disease, and postoperative WAP intensitymodulated radiotherapy could achieve prolonged survival. No benefit of surgery was demonstrated in patients with EPM. The value of associated HIPEC remains unproven. DISCLOSURE
The authors declare no conflict of interest.
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Multimodal Treatment of DSRCT 11. Hayes-Jordan A, Green HL, Lin H, et al. Complete cytoreduction and HIPEC improves survival in desmoplastic small round cell tumor. Ann Surg Oncol. 2014;21:220–4. 12. Dufresne A, Cassier P, Couraud L, et al. Desmoplastic small round cell tumor: current management and recent findings. Sarcoma. 2012;2012:714986. 13. Chan AS, MacNeill S, Thorner P, Squire J, Zielenska M. Variant EWS-WT1 chimeric product in the desmoplastic small round cell tumor. Pediatr Dev Pathol. 1999;2:188–92. 14. Ladanyi M, Gerald W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor. Cancer Res. 1994;54:2837– 40. 15. Rodriguez E, Sreekantaiah C, Gerald W, Reuter VE, Motzer RJ, Chaganti RS. A recurring translocation, t(11;22)(p13;q11.2), characterizes intra-abdominal desmoplastic small round-cell tumors. Cancer Genet Cytogenet. 1993;69:17–21. 16. Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, Bard JB. The expression of the Wilms’ tumour gene, WT1, in the developing mammalian embryo. Mech Dev. 1993;40:85–97. 17. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. In: Sugarbaker PH, editor. Peritoneal carcinomatosis: principles of management. Boston: Kluwer Academic; 1996. pp. 359–74. 18. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16. 19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205– 13. 20. Assi H, Missenard G, Terrier P, et al. Intensive induction chemotherapy without methotrexate in adult patients with localized osteosarcoma: results of the Institut Gustave-Roussy phase II trial. Curr Oncol. 2010;17:23–31. 21. Paulussen M, Ahrens S, Dunst J, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing’s sarcoma. Study CESS 86. J Clin Oncol. 2001;19:1818–29. 22. Le Deley MC, Paulussen M, Lewis I, et al. Cyclophosphamide compared with ifosfamide in consolidation treatment of standardrisk ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014;32:2440–8. 23. Watanabe T, Miyamoto S, Kitagori K, et al. A case of long-term survival of metastatic desmoplastic small round cell tumor treated with multimodal therapy. Oncol Lett. 2012;3:30–4. 24. Desai NB, Stein NF, LaQuaglia MP, et al. Reduced toxicity with intensity modulated radiation therapy (IMRT) for desmoplastic small round cell tumor (DSRCT): an update on the whole abdominopelvic radiation therapy (WAP-RT) experience. Int J Radiat Oncol Biol Phys. 2013;85:e67–72. 25. Chao J, Budd GT, Chu P, et al. Phase II clinical trial of imatinib mesylate in therapy of KIT and/or PDGFRalpha-expressing Ewing sarcoma family of tumors and desmoplastic small round cell tumors. Anticancer Res. 2010;30:547–52. 26. Thijs AM, van der Graaf WT, van Herpen CM. Temsirolimus for metastatic desmoplastic small round cell tumor. Pediatr Blood Cancer. 2010;55:1431–2.
27. Lo´pez-Gonza´lez A, Cantos B, Tejerina E, Provencio M. Activity of trabectidin in desmoplastic small round cell tumor. Med Oncol. 2011;28:S644–6. 28. Naing A, LoRusso P, Fu S, et al. Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing’s sarcoma family tumors. Clin Cancer Res. 2012;18:2625–31. 29. Tap WD, Demetri G, Barnette P, et al. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol. 2012;30:1849–56. 30. Wong HH, Hatcher HM, Benson C, et al. Desmoplastic small round cell tumour: characteristics and prognostic factors of 41 patients and review of the literature. Clin Sarcoma Res. 2013; 3:14. 31. Bertuzzi A, Castagna L, Nozza A, et al. High-dose chemotherapy in poor-prognosis adult small round-cell tumors: clinical and molecular results from a prospective study. J Clin Oncol. 2002;20:2181–8. 32. Lauridant-Philippin G, Ledem N, Lemoine F, et al. Optimal treatment with systemic chemotherapy, complete surgical excision and hyperthermic intraperitoneal chemotherapy for a desmoplastic small round cell tumor in an adult male patient. Gastroenterol Clin Biol. 2010;34:321–4. 33. Msika S, Gruden E, Sarnacki S, et al. Cytoreductive surgery associated to hyperthermic intraperitoneal chemoperfusion for desmoplastic round small cell tumor with peritoneal carcinomatosis in young patients. J Pediatr Surg. 2010;45:1617–21. 34. Philippe-Chomette P, Kabbara N, Andre N, et al. Desmoplastic small round cell tumors with EWS-WT1 fusion transcript in children and young adults. Pediatr Blood Cancer. 2012;58:891–7. 35. Bonvalot S, Cavalcanti A, Le Pe´choux C, et al. Randomized trial of cytoreduction followed by intraperitoneal chemotherapy versus cytoreduction alone in patients with peritoneal sarcomatosis. Eur J Surg Oncol. 2005;31:917–23. 36. Lim SJ, Cormier JN, Feig BW, et al. Toxicity and outcomes associated with surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with sarcomatosis. Ann Surg Oncol. 2007;14:2309–18. 37. Rossi CR, Deraco M, De Simone M, et al. Hyperthermic intraperitoneal intraoperative chemotherapy after cytoreductive surgery for the treatment of abdominal sarcomatosis: clinical outcome and prognostic factors in 60 consecutive patients. Cancer. 2004;100:1943–50. 38. Elias D, Goe´re´ D, Dumont F, et al. Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases. Eur J Cancer. 2014;50:332–40. 39. Kushner BH, LaQuaglia MP, Wollner N, et al. Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol. 1996;14:1526–31. 40. Goodman KA, Wolden SL, La Quaglia MP, Kushner BH. Whole abdominopelvic radiotherapy for desmoplastic small round-cell tumor. Int J Radiat Oncol Biol Phys. 2002;54:170–6. 41. Casey DL, Wexler LH, Laquaglia MP, Meyers PA, Wolden SL. Favorable outcomes after whole abdominopelvic radiation therapy for pediatric and young adult sarcoma. Pediatr Blood Cancer. 2014;61:1565–9.
ORIGINAL ARTICLE – BONE AND SOFT TISSUE SARCOMAS
Abdominal Desmoplastic Small Round Cell Tumor: Multimodal Treatment Combining Chemotherapy, Surgery, and Radiotherapy is the Best Option Charles Honore´, MD1, Koceila Amroun, MD1, Laurence Vilcot, MD2, Olivier Mir, MD3, Julien Domont, MD3, Philippe Terrier, MD4, Axel Le Cesne, MD3, Cecile Le Pe´choux, MD5, and Sylvie Bonvalot, MD, PhD1 Department of Surgical Oncology, Gustave Roussy Cancer Center, Villejuif, France; 2Department of Radiology, Gustave Roussy Cancer Center, Villejuif, France; 3Department of Medical Oncology, Gustave Roussy Cancer Center, Villejuif, France; 4Department of Pathology, Gustave Roussy Cancer Center, Villejuif, France; 5Department of Radiation Oncology, Gustave Roussy Cancer Center, Villejuif, France 1
ABSTRACT Background. With nearly 450 cases reported since 1991, desmoplastic small round cell tumor (DSRCT) is a rare abdominal tumor typically arising in adolescent and young adult white men. With no large series described, the best therapeutic strategy remains unclear. Methods. All consecutive patients treated in our tertiary care center between January 1991 and December 2013 for a DSRCT were retrospectively studied. Results. Thirty-eight patients with a median age of 27 years (range 13–57 years) were identified; 71 % were men. At the time of diagnosis, 47.4 % patients had extraperitoneal metastases (EPM): 78 % were located in the liver and 11 % were located in the lungs. Fourteen patients (37 %) were treated exclusively with systemic chemotherapy, with a median survival of 21.1 months. Twentythree patients underwent surgery, 12 (52 %) experienced complete removal of all macroscopic disease, 5 (21.7 %) received additional intraperitoneal chemotherapy, and 7 (30 %) received postoperative whole abdominopelvic radiotherapy (WAP RT). With a median follow-up of 59.9 months, the median survival was 37.7 months, and the median disease-free survival was 15.5 months. The factors predictive of 3-year overall survival were the absence of EPM, complete surgical resection, postoperative WAP RT,
Ó Society of Surgical Oncology 2014 First Received: 30 May 2014 S. Bonvalot, MD, PhD e-mail: [email protected]
and postoperative chemotherapy. The intraperitoneal chemotherapy had no impact on overall survival. Conclusions. DSRCT is a rare and aggressive disease. In patients without EPM, a multimodal treatment combining systemic chemotherapy, complete macroscopic resection, and postoperative WAP RT could enable prolonged survival. No benefit of surgery was demonstrated for patients with EPM. The value of associated hyperthermic intraperitoneal chemotherapy remains unproven.
Desmoplastic small round cell tumor (DSRCT) is a rare abdominal tumor with only approximately 450 cases described in the literature (among which more than 60 are case reports) since its first description in 1991 by Gerald et al..1 DSRCT typically occurs in adolescent and young adult white men. The male/female ratio in the literature is 6/1.2–11 The median age ranges between 14 and 26 years (with extremes from 1.5 to 58 years).2–11 This tumor type has a strong tendency to spread within the peritoneum but can also give rise to extraperitoneal metastases, mainly in the liver and lungs.4,5,8,9 Symptoms are nonspecific and are mostly related to the abdominal bulk.12 A translocation, t(11:32)(p13;q12), of gene ESWR1-WT is highly specific and allows a formal diagnosis of DSRCT.13–15 The origin of this tumor is yet unknown, but it is speculated that it arises from the serosal lining cells of the peritoneum.16 The primary site is frequently unknown, as it is most often discovered at the stage of a disseminated tumor within the abdomen.5 DSRCT has an extremely aggressive clinical course and is associated with a very poor prognosis, with a reported median survival ranging from 17 to 25 months.12 With no large series in the
C. Honore´ et al.
literature, there is no consensus as to the optimal treatment, and the best therapeutic strategy remains unclear and challenging.12 The aim of our study was to analyze our experience in the treatment of DSRCT to define the most appropriate therapeutic strategy. METHODS Patient Selection All consecutive patients treated in our single tertiarycare center between January 1991 and December 2013 for a DSRCT by a single team were included in this study. The histology was systematically confirmed by an experienced pathologist. The patients’ files were retrospectively reviewed for demographic data, diagnostic circumstances, and tumor and treatment variables, including the type of surgery, perioperative radiotherapy and/or chemotherapy, and outcome. All patients were retrospectively staged according to the MD Anderson DSRCT staging criteria.11 For patients who underwent surgery, the peritoneal extent of the disease was evaluated preoperatively and scored with the peritoneal cancer index.17 Multimodal treatment was defined as a combination of one or more subsequent therapeutic treatments (chemotherapy, intraperitoneal chemotherapy, radiotherapy, surgery). The treatments and sequence were systematically discussed in a multidisciplinary team meeting.
resection in a patient without extraperitoneal metastases. Surgical biopsy was not considered to be CRS. Intraperitoneal Treatment When provided, intraperitoneal chemotherapy was administered either using hyperthermic intraperitoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC). HIPEC was performed using an open coliseum technique with an intraperitoneal bath of 300 mg/m2 of oxaliplatin and 200 mg/m2 of irinotecan heated to a temperature of 43 °C for 30 min in association with intravenous fluorouracil at 400 mg/m2. For EPIC, four intraperitoneal drains were placed at time of operation, and the abdomen was filled directly after closure with 2 L of Ringer lactate to avoid intraperitoneal adhesions. The day after surgery, the Ringer lactate was drained, and intraperitoneal chemotherapy was provided continuously over five postoperative days with a combination of doxorubicin 0.1 mg/kg and cisplatin 15 mg/m2 diluted in 2 L of Ringer lactate per day. Postoperative Morbidity Surgical complications were retrospectively graded according to the Clavien–Dindo classification.19 Complications were considered severe when above 2.
Chemotherapy and Radiotherapy
Long-Term Follow-Up
Induction chemotherapy was provided to patients with extraperitoneal metastases (EPM) or patients without EPM but with bulky peritoneal disease at imaging. The chemotherapy regimen was retrospectively recorded. Radiologic response was evaluated by response evaluation criteria in solid tumors (RECIST).18 The dose and technique of delivery of whole abdominal pelvic radiotherapy (WAP RT) were recorded.
Recurrences were diagnosed either on a clinical or radiologic basis and were confirmed in a multidisciplinary team meeting. Progressive disease was defined as tumor growth documented on imaging (either by magnetic resonance imaging or computed tomographic scan) using RECIST.18
Surgery Cytoreductive surgery (CRS) was defined as the resection of all peritoneal implants, preserving the macroscopically noninvaded peritoneum. The completeness of the peritoneal cytoreduction was classified according to the Sugarbaker completeness of cytoreduction (CC) score, as follows: CC 0, no residual macroscopic disease; CC 1, residual nodules measuring less than 2.5 mm; CC 2, residual nodules measuring between 2.mm and 2.5 cm; and CC 3, residual nodules greater than 2.5 cm.17 No surgery for EPM was performed. Surgery was considered complete in case of CC 0
Statistical Analysis The cutoff date for survival analyses was August 1, 2013, for the censored data analysis. Categorical variables were compared within groups by the Chi square and Fisher’s exact test, when appropriate. The survival analysis was performed using the Kaplan–Meier method and compared by the log-rank test. Overall survival (OS) was computed from the date of diagnosis to the date of death or the last follow-up. Time to local and time to distant recurrence were computed from the date of primary tumor resection to the date of local or distant recurrence. All statistical analyses were performed by IBM SPSS statistics software, version 20.0. Data were expressed as mean ± the
Multimodal Treatment of DSRCT TABLE 1 Patient and tumor characteristics
TABLE 2 Treatments
Characteristic
Value
Treatment
Value
No. of patients
38 (100 %)
Systemic chemotherapy
38 (100 %)
Age, year, median (range)
27 (13–57)
Preoperative
16 (42.1 %)
Sex ratio, M/F
2.4
Postoperative
17 (44.7 %)
Gender
Surgery
23 (60.5 %)
Male
27 (71 %)
CC 0
12 (31.6 %)
Female
11 (29 %)
CC 1
3 (7.9 %)
General status (WHO scale) 0
24 (63.2 %)
1
6 (15.8 %)
2 NA BMI, kg/m2, median (range)
CC 2–3
5 (13.2 %)
Associated LM
3 (7.9 %)
Associated IPC
5 (13.2 %)
1(2.6 %)
HIPEC
2 (40 %)
5 (18.4 %) 22.4 (16.7–34.2)
EPIC NA
2 (40 %) 1 (20 %)
Postoperative morbidity
7 (30.4 %)
Yes
6 (15.8 %)
Postoperative mortality
0 (0 %)
No
32 (84.2 %)
WAP RT
8 (21.1 %)
Postoperative WAP RT
7 (18.4 %)
Malnutrition
Symptoms Yes
32 (84.2 %)
2D or 3D RT
4 (57.1 %)
No
6 (15.8 %)
IMRT
3 (42.9 %)
Type of symptoms Abdominal mass
17 (44.7 %)
Abdominal pain
14 (36.8 %)
Urinary disorders
3 (7.9 %)
Intestinal disorders
2 (5.3 %)
Tumor size, cm, median (range)
12 (4.5–30)
Preoperative PCI, median (range)
13 (3–19)
Extraperitoneal metastases Yes No
18 (47.4 %) 20 (52.6 %)
Liver metastases
14 (36.8 %)
Lung metastases
5 (13.2 %)
MD Anderson stage I
10 (26.3 %)
II
6 (15.8 %)
III
11 (28.9 %)
IV
6 (15.8 %)
NA
5 (13.2 %)
WHO World Health Organization, BMI body mass index, PCI peritoneal cancer index, NA not applicable
standard error of the mean, unless otherwise stated. A p value of less than 0.05 was considered significant. RESULTS Patient Demographics Between January 1991 and December 2013, 38 patients were treated at our center for abdominal DSRCT. Thirty-
CC completeness of cytoreduction, LM liver metastases, IPC intraperitoneal chemotherapy, HIPEC hyperthermic intraperitoneal chemotherapy, EPIC early postoperative intraperitoneal chemotherapy, WAP whole abdominopelvic, RT radiotherapy, IMRT intensitymodulated radiotherapy, NA not applicable
one patients had a retrospectively confirmed EWSR1-WT translocation. For the remaining 7 patients, no formal proof was retrospectively recoverable, but the diagnosis had systematically been confirmed by our expert pathologist. The patients and tumor characteristics are reported in Table 1. Seventy-one percent of the patients were men. EPM were present at the time of initial diagnosis in 18 patients (47.4 %) and were mainly located in the liver (78 %) and lungs (11 %). Other metastatic locations included lymph nodes and the spleen. Thirty-two patients (84 %) were symptomatic at the time of diagnosis (clinically palpable abdominal mass and/or abdominal pain in 31 cases, 81 %). Chemotherapy The details of treatments are reported in Table 2. All but 7 patients received induction chemotherapy. Fourteen patients (37 %) had disease that was not amenable to surgery and were treated exclusively with systemic chemotherapy. One patient (3 %), whose tumor was deemed inoperable, received an exclusive combination of chemotherapy and WAP RT. Induction chemotherapy was based on the combination of doxorubicin and ifosfamide in 28 patients. The following regimens were used: NEO-AI (doxorubicin
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Surgery Among the 23 patients who underwent surgery, 16 (70 %) received induction chemotherapy and 17 (74 %) received postoperative adjuvant chemotherapy. Seven (48 %) received pre- and postoperative chemotherapy. The median peritoneal cancer index at laparotomy was 9 (range 8–18). Fifteen patients (65 %) underwent complete surgical removal of all macroscopic peritoneal disease, but three of them had associated bilobar synchronous liver metastases that were not removed. Therefore, 12 patients (52 % of the surgical patients) experienced macroscopically complete surgical resection of all tumoral disease (CC 0). Five patients (22 %) received intraperitoneal chemotherapy. Five patients (22 %) developed severe postoperative complications, which all required reoperation. There were no postoperative deaths. Radiotherapy One patient (3 %), whose tumor was deemed inoperable, received an exclusive combination of chemotherapy and radiotherapy at the dose of 22.5 Gy. Among the 23 surgical patients, 7 (30 %) received postoperative WAP RT at a median dose of 30 Gy. Four patients received conventional radiotherapy with two opposed fields to the entire abdominal cavity. The kidneys were shielded after 12– 15 Gy, and the liver after 25 Gy. Treatment was delivered with fractions of 1.5–1.55 Gy. Patients with residual tumor in the pelvis had a boost up to a median dose of 45–50 Gy. Three patients had intensity modulated WAP RT, with 9field modulated beam arrangement, with 6 MV photons. The clinical target volume included the whole peritoneal
Whole population (n=38) 100 80
Percent survival
60 mg/m2 day 1 ? ifosfamide 3 g/m2/day days 1–3 ? mesna, day 1 = day 21), n = 14; AI (doxorubicin 60 mg/m2 day 1 ? ifosfamide 3 g/m2/day days 1–2 ? mesna, day 1 = day 21 ? G-CSF support), n = 2; API-AI regimen n = 2; other doxorubicin-based regimen (AI alternated with etoposide 100 mg/m2/day days 1–3 ? ifosfamide 3 g/m2/ day days 1–3 ? mesna, day 1 = day 21), n = 10.20 Cisplatin-5-fluorouracil and VACA were provided to 2 and 1 patient, respectively.21 Patients received a median number of 4 cycles (range 4–7 cycles). In the postoperative setting, 17 patients received chemotherapy: VAC, n = 4; PAVEP, n = 2; etoposide ? ifosfamide based regimens, n = 5, API, n = 1; or other (cyclophosphamide based or etoposide– cisplatin, n = 5), for a median of 4 cycles (range 3–10 cycles).22,23 Partial radiologic response and stable disease were observed in 68 and 23 % of the patients, respectively. There was no complete radiologic response. Twenty-three cases (64 %) had disease that was ultimately deemed operable.
60 40 20 0 0
20
40
60
80
Months
FIG. 1 OS of entire population
cavity and the retroperitoneum, treated up to a dose of 30.60 Gy in 1.55 Gy daily fractions. The mean dose to both kidneys was less than 10 Gy, and the mean dose to the liver did not exceed 25 Gy. After a median of 26.3 months after the end of radiotherapy, no patient had developed significant late toxicity. Overall Survival After a median follow-up of 59.9 months (range 7.9– 266.8 months), the median OS was 25.7 months (range 7.9–69.0 months). The survival curve for the entire population is reported in Fig. 1. Prognostic Factors In a univariate analysis, the absence of EPM, complete CRS, postoperative WAP RT, and postoperative chemotherapy were predictive factors for the 3-year OS (Table 3). Because of the small number of patients, no multivariate analysis was performed. Among the 12 patients with complete macroscopic resection of all tumoral disease (CC 0), the median survival was 37.7 months (range 15.1– 58.2 months). The 1-, 3- and 5-year OS rates were 94.7 % (95 % confidence interval [CI] 87.6–100), 31.6 % (95 % CI 29.6–39.2), and 8.3 % (95 % CI 0–25.8), respectively. The patients with EPM treated with exclusive chemotherapy had a median survival of 21.1 months (range 7.9– 42.9 months). The 3 patients who had synchronous nonresectable liver metastases but had complete peritoneal CRS had a median survival of 14.8 months (range 7.9– 20.1 months). Disease-Free Survival Among the 12 patients without EPM who had a macroscopically complete CRS, the 1- and 3-year disease-free
Multimodal Treatment of DSRCT TABLE 3 Predictive factors of 3-year overall survival Population
Deceased (n = 26)
Alive (n = 12)
p 0.19
Age
25 (13–57)
27 (16–57)
Male gender
16 (61.5 %)
11 (91.7 %)
0.28
PCI
12.4 ± 5.2
11.1 ± 5.6
0.59
Tumor size
10.9 ± 5.7
13.3 ± 4.6
0.34
Extraperitoneal metastases
16 (61.5 %)
2 (16.7 %)
0.015
Preoperative chemotherapy
20 (76.9 %)
10 (83.3 %)
0.99
HR
95 % CI
8
1.444–44.32
CC 0 surgery
5 (19.2 %)
7 (58.3 %)
0.026
0.17
0.038–0.767
CC 0–1 surgery
7 (26.9 %)
8 (66.7 %)
0.0326
0.184
0.042–0.81
IPC
2 (7.7 %)
3 (25 %)
0.067
Postoperative chemotherapy
8 (30.8 %)
9 (75 %)
0.016
0.148
0.031–0.698
Postoperative WAP RT
2 (7.7 %)
5 (41.7 %)
0.022
0.117
0.018–0.737
PCI peritoneal cancer index, CC completeness of cytoreduction, IPC intraperitoneal chemotherapy, WAP whole abdominopelvic, RT radiotherapy, HR hazard ratio, CI confidence interval
survival rates were 41.6 % (95 % CI 10.3–72.9) and 16.7 % (95 % CI 0–40), respectively. The median diseasefree survival was 15.5 months (range 4.2–21.8 months). Among the 4 patients who received complete multimodal treatment, including complete CRS, perioperative chemotherapy, and postoperative WAP RT, 1 died of recurrence (peritoneal and extraperitoneal) after 16 months, 1 is still alive after 15 months with lymph node recurrence, and 2 are alive and free of disease after 32 and 37 months, respectively.
Patterns of Recurrence after Complete Surgery Seven patients experienced disease recurrence after macroscopically complete CRS. The mean time before recurrence was 12.6 months. The sites of first recurrence were the liver, lymph nodes, lung, and peritoneum in 4 patients (57 %), 3 patients (43 %), 2 patients (29 %), and 1 patient (14 %), respectively. One patient had liver surgery for hepatic recurrence. He developed further metastases 6.6 months later in the lung and liver. All other recurrences were treated with systemic chemotherapy alone until progression. DISCUSSION This study is the largest reporting the multimodal management of abdominal DSRCT. After a median followup of 59.9 months, the median OS of the entire population was 25.7 months, confirming the severity of the disease. We were able to identify 4 prognostic factors: the absence of EPM, CRS, WAP RT, and postoperative chemotherapy. These findings underline the paramount role of multidisciplinary management in this disease.
Our study confirms that EPM are very common in DSRCT, affecting nearly half of the patients at the time of diagnosis. These findings are consistent with the literature, reporting rates ranging from 33 to 50 %.4,5,7–9 We also found that EPM are highly predictive of a poor prognosis.5,24 The median OS after peritoneal CRS in patients with synchronous liver metastases was only 14.8 months, which is comparable to the results obtained with systemic chemotherapy alone.2 Therefore, we believe that surgery is inappropriate for this group of patients, who should instead be treated with systemic chemotherapy alone. Most chemotherapy combinations used for DSRCT are based on alkylating agents, similar to those used in other childhood small round cell tumors or Ewing sarcomas, which share the same EWS fusion protein.7 Because these tumors have a highly specific identified mutation (translocation t(11:32)(p13;q12)), targeted therapies could become part of the therapeutic strategy in the future. Phase I studies using anti-ILG R1, trabectedin, tyrosine kinase inhibitors, ganitumab, temsirolimus alone, and temsirolimus combined with cixutumumab (a fully human IgG1 monoclonal antibody directed against insulin growth factor 1 receptor, IGF1R) have reported interesting results in this disease.25–30 On the basis of our results, patients should receive induction chemotherapy because it may select the best candidates for surgery and improve rates of complete resection. A radiologic response was observed in 68 % of our patients. Similar significant response rates to neoadjuvant chemotherapy ranging between 39 and 50 % have been reported.2,9,31 The median survival was 37.7 months in a selected group of patients who could undergo macroscopically complete resection of all peritoneal disease (CC 0); therefore, we confirm that surgery should be discussed after neoadjuvant chemotherapy because it is a major component in the treatment of potential long-term DSRCT
C. Honore´ et al.
survivors. Hassan et al. showed that the median OS of patients who underwent complete surgical resection combined with systemic chemotherapy was 34 months, whereas with chemotherapy alone, it was only 14 months.9 Similarly, Lal et al. reported a significantly better OS after macroscopically complete surgery, reporting a 3-year OS after CC 0 of 58 % compared with 0 % when gross deposits remained.5,7 A study from Hayes-Jordan et al. reported that residual deposits above 2.5 mm (i.e., CC 2–3) led to a poor outcome, with a median OS of 12.8 months, even after intensive adjuvant treatment including systemic chemotherapy, HIPEC, and WAP RT.11 In contrast, a median survival of 31.1 months was observed after CC 0 resection combined with a similar perioperative treatment.11 However, complete CRS is challenging and has only been achieved in 25–44 % of all patients with DSRCT.7,10 We confirmed this technical difficulty, as complete macroscopic CRS could only be performed in 15 (65 %) of our 23 patients undergoing surgery. The benefit of intraperitoneal chemotherapy (either HIPEC or EPIC) after resection in DSRCT is highly controversial. Data are scarce, monocentric, and without randomization, and they often come from series including fewer than four cases.11,32–34 The only randomized trial available comparing the administration or not of intraperitoneal chemotherapy after complete macroscopic resection sarcomatosis failed to demonstrate an impact of additional intraperitoneal chemotherapy on OS.35 Currently, most expert centers have stopped using this technique for this indication.36–38 In the present series, intraperitoneal chemotherapy was not associated with a better outcome. As in other studies, we confirmed that postoperative WAP RT should be part of the combined modality treatment of DSRCT, as it could contribute to improve outcomes. In the series reported by Kretschmar et al., the only 2 long-term survivors received adjuvant radiotherapy.2,39 More recently, in a series of 31 patients treated with surgery, chemotherapy, and postoperative WAP RT at a dose of 30 Gy, the 3-year OS and progression-free survival rates were 50 and 24 %, respectively.20 WAP intensity-modulated radiotherapy compared with 2D or even 3D WAP RT resulted in fewer hematologic, renal, and gastrointestinal toxicities, with the possibility of focal dose escalation in specific areas, which could affect local control.20,40,41 Even if the role of chemotherapy is essential in this aggressive tumor, a combination of treatments including pre- and postoperative chemotherapy, macroscopically complete peritoneal CRS, and postoperative WAP intensity-modulated radiotherapy appears to achieve the best results in DSRCT. As reported earlier by Lal et al., the 3year OS after this complete multimodal treatment was
55 % compared with 27 % if one of the therapeutic modalities was missing.7 Because complete multimodal treatment is essential, an up-front multidisciplinary team decision from an expert sarcoma team is mandatory before starting any therapy. The surgeon must balance the extent of the required resection to achieve CC 0 and the subsequently expected postoperative morbidity that could prevent further adjuvant treatment. The limitation of this study is the small number of patients having this extremely rare disease, preventing the realization of a multivariate analysis for prognostic factors. Although not randomized, the patients were treated homogenously by the same team, with a long follow-up and using all types of major treatments, thus enabling an accurate comparison between the therapeutic strategies. In conclusion, for patients with DSRCT without EPM, multimodal treatment combining systemic pre- and postoperative chemotherapy, complete macroscopic resection of the peritoneal disease, and postoperative WAP intensitymodulated radiotherapy could achieve prolonged survival. No benefit of surgery was demonstrated in patients with EPM. The value of associated HIPEC remains unproven. DISCLOSURE
The authors declare no conflict of interest.
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