Management of retroperitoneal sarcomas: does dose escalation impact on locoregional control?

Fein DA, Corn BW, Lanciano RM, Herbert SH, Hoffman JP, Coia LR.  Int J Radiat Oncol Biol Phys 1995 Jan 1;31(1):129-34

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111.

PURPOSE: Only 50% of patients with retroperitoneal sarcomas undergo complete resection and of these, 47% develop local tumor recurrence. To determine whether irradiation with dose escalation improves locoregional control, we reviewed the experience with adjuvant radiotherapy in the treatment of retroperitoneal sarcomas at the Fox Chase Cancer Center and the Hospital of the University of Pennsylvania. METHODS AND MATERIALS: Twenty-one patients with retroperitoneal sarcomas were treated with curative intent with surgical resection and radiation therapy at Fox Chase Cancer Center or the Hospital of the University of Pennsylvania between May 1965 and July 1992. Follow-up ranged from 14-340 months. Nineteen patients were treated postoperatively and 2 preoperatively. Radiation doses were between 36.0 Gy and 90.0 Gy (median 54.0 Gy). RESULTS: The 2-year rates of local control and survival were 72% and 69%, respectively. Tumor size, stage, grade, and histology did not influence local control. Two of eight patients (25%) who received a total dose of > 55.2 Gy experienced local failure compared to 5 of 13 (38%) who received < or = 55.2 Gy. One patient experienced a small bowel obstruction that required surgical intervention. There were no other severe complications. CONCLUSION: Postoperative treatment with radiotherapy using a dose > 55.0 Gy is recommended for patients with retroperitoneal sarcomas following surgical resection due to the significant likelihood of local recurrence. Innovative adjuvant radiation techniques to escalate doses to greater than 55.0 Gy including intraoperative radiation therapy, brachytherapy, or use of small bowel exclusion devices to reduce small bowel toxicity should be considered for retroperitoneal sarcomas.

Surgical resection and radiotherapy for primary retroperitoneal soft tissue sarcoma.

Gilbeau L, Kantor G, Stoeckle E, Lagarde P, Thomas L, Kind M, Richaud P, Coindre JM, Bonichon F, Bui BN.  Radiother Oncol 2002 Dec;65(3):137-43

Radiation Oncology Department, Institut Bergonie, Regional Cancer Center, 229, cours de l'Argonne, 33076, Bordeaux, France

METHODS AND MATERIALS: Forty-five patients were consecutively treated for primary retroperitoneal soft tissue sarcoma with surgery in combination with radiation therapy in the same institution. The median follow-up time was 53 months (7-108).RESULTS: Seventeen (38%) patients had clear microscopic margins (R0 resection), 26 patients (58%) had gross complete surgical excision (R1 resection) and two patients (4%) had a macroscopic residual disease (R2 resection). External radiotherapy doses ranged from 40.8 to 59.4 Gy (mean and median: 49 Gy). Seventeen patients underwent intraoperative radiation therapy (IORT). Moreover, 11 patients received chemotherapy. The overall 1-, 2-, and 5-year survival for all 45 patients were 93, 85 and 60%, respectively. The 1-, 2-, and 5-year locoregional relapse-free rate for the whole group was 91, 70 and 40%, respectively. In univariate analysis, quality of surgery was the only variable to show a significant effect for overall survival (P=0.0386) and for local control (P=0.0059). Tumor size and tumor grade had no statistically significant effect. For the patients receiving IORT+external beam radiation therapy, no difference was observed for survival or locoregional control. The most frequent acute side effects treatment complications were radiation-induced nausea or vomiting (42%) and moderate enteritis (30%). Significant late morbidity was observed for two patients.CONCLUSIONS: This study confirms the feasibility of external postoperative radiotherapy with an acceptable level of toxicity. However, the high rate of local relapses (especially in field of radiation) does not demonstrate the usefulness of radiotherapy at the level of dose used and further preferably randomized studies should be planned.

Long-term outcome of combined modality therapy in retroperitoneal and deep-trunk soft-tissue sarcoma: analysis of prognostic factors.

Youssef E, Fontanesi J, Mott M, Kraut M, Lucas D, Mekhael H, Ben-Josef E.  Int J Radiat Oncol Biol Phys 2002 Oct 1;54(2):514-9

Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

PURPOSE: To evaluate the long-term outcome of surgery and postoperative radiotherapy (RT) in retroperitoneal and deep-trunk soft-tissue sarcoma, and to identify the prognostic factors for local control, disease-free survival, and overall survival. METHODS AND MATERIALS: Between January 1980 and December 1998, 60 patients with nonmetastatic retroperitoneal and deep-trunk soft-tissue sarcoma were treated at Wayne State University using combined surgery and RT. The location was retroperitoneal in 38 patients (63%) and deep trunk in 22 (27%). Forty-six patients (76%) were treated for primary disease and 14 (24%) for recurrent disease. The resection margins were negative in 24 patients (40%), close in 3 (5%), and positive in 33 (55%; 18 microscopic and 15 macroscopic). The median tumor size was 8.6 cm (range 2-55). External beam RT (EBRT; median dose 5220 cGy) was given to 44 patients (73%) and combined EBRT (median dose 4200 cGy) and brachytherapy (median dose 1600 cGy) to 16 patients (27%). Univariate and multivariate Cox regression analyses were conducted to identify the possible associations between patient age, race, gender, tumor site, histologic features, grade, size, stage, surgical margin, RT dose, modality (EBRT vs. EBRT plus brachytherapy), and presentation (primary vs. recurrent) and disease control. RESULTS: The actuarial 5- and 10-year disease-free survival rate was 53% and 44%, respectively. Disease-free survival was significantly associated with female gender on univariate analysis (67% for female patients and 37% for male patients at 5 years, p = 0.05). On multivariate analysis, both gender and surgical margin had borderline significance (p = 0.06). The actuarial local control rate was 71% and 54% at 5 and 10 years, respectively. The median time to local relapse was 10.2 months, with 75% of all failures occurring within 29 months. The surgical margin status was significantly associated with local control (78% for patients with negative or close margins vs. 52% for patients with positive margins at 5 years, p = 0.04). Gender was borderline significant (85% for female patients vs. 54% for male patients at 5 years, p = 0.06). On multivariate analysis, only surgical margin status remained significant (p = 0.032). The distant metastasis-free survival rate at 5 and 10 years was 58% and 54%, respectively. The median time to distant metastases was 15.6 months. The lungs were the most common site of metastases. The only significant factor associated with distant metastasis-free survival was local control (73% for patients with locally controlled tumors vs. 19% for patients with local recurrence at 5 years, p = 0.0013). The actuarial 5- and 10-year overall survival rate was 56% and 47%, respectively. Gender (74% for female patients vs. 37% for male patients at 5 years), surgical margin status (66% for patients with negative or close margins vs. 48% for patients with positive margins at 5 years), and local control (64% for patients with locally controlled tumors vs. 21% for patients with uncontrolled primary tumors at 5 years) were significant predictors on both univariate and multivariate analyses (p <0.05). CONCLUSION: The results of this study demonstrate the paramount importance of local control and complete surgical resection in the management of soft-tissue sarcoma of the retroperitoneum and deep trunk.

Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution.

Lewis JJ, Leung D, Woodruff JM, Brennan MF.  Ann Surg 1998 Sep;228(3):355-65

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York City, New York 10021, USA.

OBJECTIVE: To analyze treatment and survival of a large cohort of patients with retroperitoneal soft-tissue sarcomas (STS) treated and prospectively followed at a single institution. SUMMARY BACKGROUND DATA: Retroperitoneal STS are relatively uncommon and constitute a difficult management problem. Although surgical resection is often difficult or impossible, current chemotherapy is not effective and radiation is limited by toxicity to adjacent structures. Thus, complete surgical resection remains the most effective modality for selected primary and recurrent disease. METHODS: Five hundred patients with retroperitoneal STS were admitted and treated between July 1, 1982, and September 30, 1997, and prospectively followed. Patient, tumor, and treatment variables were analyzed for disease-specific and disease-free survival. Survival was determined with the Kaplan-Meier method. Statistical significance was evaluated using the logrank test for univariate influence and Cox model stepwise regression for multivariate influence. RESULTS: Two hundred seventy-eight patients (56%) had primary disease and 222 (44%) recurrent disease. Median follow-up was 28 months (range 1 to 172 months), 40 months for survivors. Median survival was 72 months for patients with primary disease, 28 months for those with local recurrence, and 10 months for those with metastasis. For patients with primary or locally recurrent tumors, unresectable disease, incomplete resection, and high-grade tumors significantly reduced survival time. CONCLUSIONS: In this study of patients with retroperitoneal STS, stage at presentation, high histologic grade, unresectable primary tumor, and positive gross margin are strongly associated with the tumor mortality rate. Patients approached with curative intent should undergo aggressive attempts at complete surgical resection. Incomplete resection should be undertaken only for symptom relief.

Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management.

Heslin MJ, Lewis JJ, Nadler E, Newman E, Woodruff JM, Casper ES, Leung D, Brennan MF.   J Clin Oncol 1997 Aug;15(8):2832-9

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

198 adult patients were identified from our prospective soft tissue sarcoma database carrying the diagnosis of retroperitoneal soft tissue sarcoma who were eligible for > or = 5 years of follow-up. Of these, 48 patients (25%) were documented to be alive > or = 5 years from the time of operation. The recurrence rate during the follow-up period was approximately 5% per year from the time of initial operation. Of the patients who were disease-free for > or = 5 years from initial surgery, 40% recurred by 10 years. Radiation therapy was the only factor significant (P = .02) for a reduction in the risk of local recurrence. Age < or = 50 years and high-grade tumors were significant factors (P = .003 and .009, respectively) for an increased risk of distant metastasis. Incomplete gross resection was the only factor significant for an increased risk of tumor mortality (P = .003). CONCLUSION: Complete surgical resection at the time of primary presentation is likely to afford the best chance for long-term survival. With long-term follow-up, it is clear that recurrence will continue to occur, and a 5-year disease-free interval is not a cure. Patients with an incomplete initial resection, age less than 50 years, and high-grade tumors are candidates for investigational adjuvant therapy.

Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum.

Jaques DP, Coit DG, Hajdu SI, Brennan MF.   Ann Surg 1990 Jul;212(1):51-9

Department of Surgery and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

From 1982 to 1987, 114 patients underwent operation at Memorial Sloan-Kettering Cancer Center for soft-tissue sarcoma of the retroperitoneum. A retrospective analysis of these patients defines the biologic behavior, surgical management of primary and recurrent disease, predictive factors for outcome, and impact of multimodality therapy. Complete resection was possible in 65% of primary retroperitoneal sarcomas and strongly predicts outcome (p less than 0.001). The rate of complete resection was not altered by histologic type, size, or grade of tumor. These patients had a median survival of 60 months compared to 24 months for those undergoing partial resection and 12 months for those with unresectable tumors. Forty-nine per cent of completely resected patients have had local recurrence. This is the site of first recurrence in 75% of patients. These patients undergo reoperation when feasible. Complete resection of recurrent disease was performed in 39 of 88 (44%) operations, with a 41-month median survival time after reoperation. Tumor grade was a significant predictor of outcome (p less than 0.001). High-grade tumors (n = 65) were associated with a 20-month median survival time compared to 80 months for low-grade tumors (n = 49). Gender, histologic type, size, previous biopsy, and partial resection versus unresectable tumors did not predict outcome by univariate analysis. Adjuvant radiation therapy and chemotherapy could not be shown to have significant impact on survival. Concerted attempt at complete resection of both primary and recurrent retroperitoneal soft-tissue sarcoma is indicated.

Preliminary results of a randomized study of adjuvant radiation therapy in resectable adult retroperitoneal soft tissue sarcomas.

Kinsella TJ, Sindelar WF, Lack E, Glatstein E, Rosenberg SA.  J Clin Oncol 1988 Jan;6(1):18-25

Radiation Oncology Branch, National Cancer Institute, Bethesda, MD 20892.

Between January 1980 and September 1985, 35 adult patients with resectable retroperitoneal soft tissue sarcomas were entered on a randomized trial comparing two forms of adjuvant radiation therapy. Fifteen patients received the experimental therapy consisting of intraoperative radiotherapy (IORT) to 20 Gy using high-energy electrons followed by low-dose (35 to 40 Gy) postoperative external beam irradiation. Twenty patients received standard therapy consisting of high-dose (50 to 55 Gy) postoperative external beam irradiation. With a minimum follow-up of 15 months, there is no significant difference in the actuarial disease-free survival (DFS) and overall survival (OS) comparing the two groups (median DFS, 34 months; median OS, 38 months). At 5 years follow-up, approximately 40% of patients are alive and 20% of patients remain disease-free. Although there is a trend towards an improvement in in-field local control in the experimental arm, the predominant pattern of failure in both groups was locoregional within the retroperitoneum and/or peritoneal cavity. Acute and late radiation enteritis were significantly reduced in the experimental group. However, four experimental patients developed late (greater than 6 months following treatment) peripheral neuropathy believed related to the use of IORT; all four recovered. We conclude that there is no difference in the therapeutic effectiveness of the combination of IORT and low-dose external beam radiation compared with conventional high-dose radiation as adjuvant treatment in retroperitoneal sarcomas, although the former appears to be less toxic. Newer combined modality treatment strategies are discussed to improve the prognosis in these patients.

The management of retroperitoneal soft tissue sarcoma: a single institution experience with a review of the literature.   Eur J Surg Oncol 2001 Aug;27(5):491-7

Pirayesh A, Chee Y, Helliwell TR, Hershman MJ, Leinster SJ, Fordham MV, Poston GJ.

Department of Surgery, Royal Liverpool University Hospital, Prescot St., Liverpool, L7 8XP, UK.

AIM: Ten percent of soft tissue sarcomas (STS) arise in the retroperitoneal tissues. The prognosis for patients with retroperitoneal sarcoma is poor with a 5-year survival rate between 12% and 70%. Stage at presentation, high histological grade, unresectable primary tumour and incomplete resection are associated with a less favourable outcome. METHODS: Complete follow-up data were available on 22 patients who underwent surgery for retroperitoneal STS in our institution between 1990 and 2000. Patient, tumour and treatment variables were analysed including use of adjuvant therapy and survival status. RESULTS: Eighteen patients underwent surgery for primary disease, four patients were treated for recurrent disease or metastases. Ten patients presented with pain, seven with an abdominal mass, other presentation included weight loss and haematuria. Thirteen patients presented with tumours larger than 10 cm. The tumours were seven liposarcomas, six leiomyosarcomas, three malignant fibrous histiocytomas, two rhabdomyosarcomas, two malignant schwannomas and two undifferentiated sarcomas. Six primary tumours were completely excised, five patients received radiotherapy and five received chemotherapy. Local recurrence rate was 45% and recurrence-free interval for 10 patients with recurrence was 11 months. Five patients received radiotherapy and five received chemotherapy. The median survival for patients with primary tumours was 36 months, and 5-year survival was 44%. Adjuvant therapy was not associated with higher survival rates. CONCLUSION: This study re-emphasizes the poor outcome of patients with retroperitoneal STS. Adjuvant radiotherapy and chemotherapy do not appear to be any proven benefit and the single most important prognostic factor is aggressive successful en bloc resection of the primary tumour. Our resection rate and 5-year survival rates are comparable with previous reported UK series although lower than large reports from North American centres.

Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group.

Stoeckle E, Coindre JM, Bonvalot S, Kantor G, Terrier P, Bonichon F, Nguyen Bui B; French Federation of Cancer Centers Sarcoma Group.  Cancer 2001 Jul 15;92(2):359-68

Department of Surgery, Institut Bergonie, Bordeaux, France. stoeckle@bergonie.fr

BACKGROUND: Surgery is the main prognostic factor in retroperitoneal sarcoma. However, despite progress, surgery alone is rarely curative, and analysis of the causes of failures and of other prognostic factors are warranted to ascertain treatment orientations. METHODS: Data of patients treated from 1.80 to 12.94 for primary retroperitoneal sarcoma were extracted from the French Federation of Cancer Centers Sarcoma Group registry. Univariate and multivariate analysis were performed for initial local control and for local and general outcome. One hundred sixty-five patients (median age, 54 years; range, 16--82 years) were identified. Median tumor size was 15 cm (range, 2--70 cm); 31% of tumors presented with neurovascular or bone involvement. Liposarcoma, leiomyosarcoma, and malignant fibrous histiocytoma represented 66% of the tumors. Eighty-four percent of the tumors were of high or intermediate grade. Twenty patients had initial metastases. Multimodality treatment included surgery (150 patients), radiotherapy (92 patients), and chemotherapy (77 patients). Complete excision was achieved in 94 of 145 nonmetastatic patients. Median follow-up was 47 months (range, 3--160 months). RESULTS: Actuarial overall 5-year survival rate (median) was 46% (51 months). The main prognostic factors for survival were initial metastases and surgery, which represented the major treatment-linked factor. High-grade of tumors affected local recurrence, metastatic recurrence, and survival. Adjuvant radiotherapy was significantly associated with reduced local recurrence. Various evolutive patterns were observed with histologic subtypes. CONCLUSIONS: Aggressive surgery remains mandatory in retroperitoneal sarcoma, but a randomized trial is needed to evaluate the place of radiotherapy for local control.