- Email: [email protected]
The role of radiation therapy in resectable retroperitoneal sarcomas
Surgical Oncology 9 (2000) 61}65
The role of radiation therapy in resectable retroperitoneal sarcomas Cornelius J. McGinn* Department of Radiation Oncology, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0010, USA
1. Case scenario A 29 year old female presented to her primary care physician soon after she noted a palpable mass in her left lower abdomen. She was otherwise asymptomatic. An abdominal and pelvic CT revealed a 12;10;9 cm heterogenous mass arising from the psoas and extending into the pelvis (Fig. 1a). There was no evidence of ureteral or bowel obstruction. Chest CT revealed no evidence of metastases. She had no other signi"cant medical or surgical history. Exploratory laparotomy with complete gross total excision was performed. The mass was noted to be adherent to the ureter and iliac vessels. A section of the external iliac artery was resected with the mass, and repaired with an interposition graft. Surgical clips were placed to identify regions of tumor adherence. Pathological evaluation revealed a grade III liposarcoma, with close margins in several locations along the posterior aspect of the mass. She recovered from surgery without signi"cant di$culty. Adjuvant radiotherapy was recommended and she agreed to proceed. A treatment planning CT was obtained with the patient immobilized in a prone alpha cradle with a false table top (belly board) to allow displacement of the bowel [1]. A region along the psoas and iliac vessels was identi"ed, in collaboration with the surgical oncologist, that was felt to be at highest risk for local recurrence. Three dimensional treatment planning was utilized to develop a 6 "eld plan of axial beams that localized dose to the region identi"ed (Fig. 1b and c). A total dose of 54 Gy was delivered in 1.8 Gy fractions. She experienced occasional diarrhea and mild nausea, but no other signi"cant acute toxicity. Treatment was completed in 7/98. She remains without evidence of local
* Tel.: #1-313-936-9521; fax: #1-313-763-7370. E-mail address: [email protected] (C.J. Mc Ginn).
recurrence or late toxicity. She is without evidence of distant metastases as well.
2. Introduction Approximately 7800 patients are diagnosed with soft tissue sarcoma each year in the United States [2]. Of these, approximately 15% arise in the retroperitoneum. These patients present a unique set of challenges to oncologists involved in their care. The challenges relate to many factors including the extent of tumor involvement at the time of diagnosis, the location of the tumor relative to critical normal structures, the heterogeneity of tumor types and the rarity of these tumors. The low incidence rate has hampered investigation via prospective trials, making it di$cult to arrive at de"nitive conclusions regarding optimal management strategies. Indeed, the medical literature on this subject is almost entirely limited to retrospective series. The most common presenting symptoms are generally vague and have often been ignored for months preceding the diagnosis [3]. Presentation with an abdominal mass or increasing abdominal girth is frequently the only symptom [4,5]. Additional symptoms such as early satiety, nausea, vomiting, constipation and #ank or back pain relate to compression of adjacent organs. Evidence of ureteral obstruction or deep venous thrombosis is not uncommon. The majority of patients present with tumors '10 cm in size [6]. Following appropriate radiographic imaging to determine the extent of the primary tumor and presence or absence of metastases, incisional biopsy may be obtained to con"rm the diagnosis. However, en bloc resection as the initial procedure can also be considered if the diagnosis of sarcoma is likely, and the surgeon has anticipated the potential need for resection of adjacent organs. Liposarcoma and leiomyosarcoma
0960-7404/00/$ - see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 9 6 0 - 7 4 0 4 ( 0 0 ) 0 0 0 2 5 - 6
62
C.J. McGinn / Surgical Oncology 9 (2000) 61}65
Fig. 1. (a) Preoperative CT indicating the tumor extension into the pelvis. The image is inverted to compare with the treatment planning CT which was obtained in the prone position. (b) Treatment planning CT indicating the region being treated. The 100% isodose line is encompassing the region identi"ed to be at greatest risk for local recurrence. The concentration of dose in this region is indicated by the isodose lines ranging from 100% to 70%. (c) Suface contour of the patient is indicated along with contours of the skeletal anatomy and kidneys. The central axis and beam shapes of the 6 treatment "elds are seen converging on a surface contour of the target region (darker region within the pelvis), resulting in the dose distribution seen in b.
are the most common histologic subtypes, accounting for 65% of newly diagnosed cases [6] in the recent series for Memorial Sloan-Kettering. In this series, the liposarcoma histologic subtype was associated with a signi"cantly increased risk of local recurrence. In another series, liposarcoma was associated with improved survival [7]. In most series, however, there is no signi"cance associated with speci"c histologic subtypes. The most signi"cant prognostic factors for overall survival have consistently been tumor grade and margin of resection [4}8]. The rate of complete resection with negative surgical margins ranges from 5 to 65% [5}7]. This rate is generally lower in patients with locally recurrent disease. The most common sites of distant metastases are the lung and liver. Chemotherapy has been and continues to be investigated in this patient population without de"nitive
conclusion, and will not be addressed further in this review. Survival at 5 years for patients with primary disease following complete resection is approximately 70% [5,6].
3. The rationale for adjuvant radiation therapy Local recurrence following surgical resection is frequent, considering the anatomic constraints which prevent wide local excision with negative margins. It is important to note that local recurrences can occur after a protracted disease-free interval. Heslin et al. recently reported a 40% recurrence rate among a population of patients who had survived disease-free for 5 years or longer [9]. Indeed, an earlier review of the literature
C.J. McGinn / Surgical Oncology 9 (2000) 61}65
revealed a 90% local recurrence at 10 years following complete excision [3]. Thus, data from studies with median follow-up less than 5 years may not accurately re#ect the ultimate outcome. The consequence of local recurrence is apparent in the series from Memorial in which median survival after local recurrence was 28 months [6]. It is obvious, then, that additional measures to achieve local control should be considered. Radiation therapy as a surgical adjunct has been utilized by several groups in an attempt to improve local control, based on well-established data indicating a reduction of local recurrence with adjuvant radiation therapy in conjunction with limb-sparing surgery for extremity sarcomas [10}12]. Unfortunately, the selection of patients for adjuvant radiation following resection of retroperitoneal sarcoma has not generally been de"ned prospectively. In those patients receiving treatment, details regarding dose and volume are not uniform, and frequently not even reported. A wide variety of options exist as well, including preoperative external beam, intraoperative electron irradiation, brachytherapy and postoperative external beam irradiation.
4. Preoperative radiation therapy Preoperative radiation therapy has been advocated for patients with retroperitoneal sarcoma based on experience in extremity sarcoma, and additional considerations which apply in the retroperitoneum. The theoretical advantages which apply at any site include the potential for tumor response, which may improve the rate of resection with negative margins. Preoperative therapy may also reduce the risk of peritoneal or systemic seeding secondary to operative manipulation. Improved oxygenation may exist in the preoperative setting, relative to the postoperative microenvironment. Higher levels of oxygenation have been shown to increase radiosensitivity in experimental models. However, this argument may not be relevant with tumors of this size, which likely have large regions of hypoxia. Perhaps the most compelling argument for preoperative therapy relates to the presence of the mass which can displace adjacent normal tissues that would be dose-limiting in the postoperative setting. Unfortunately, it is di$cult to take advantage of this opportunity for dose escalation, since doses '50 Gy are often associated with delayed wound healing. Preoperative therapy involves delivery of radiation to the entire tumor volume. Yet this may not be necessary, particularly in regions where the tumor has simply displaced adjacent organs without invasion, and will be resected without concern for margin status at that location. Thus, the volumes irradiated preoperatively may be larger than volumes irradiated postoperatively. This is unlike the case in extremity sarcomas.
63
The most appropriate situation for preoperative radiation therapy exists in departments equipped for intraoperative radiation therapy or brachytherapy. In this way, a preoperative dose with low risk of compromised wound healing (in the range of 40}50 Gy) can be followed by directed therapy to the regions of suspected microscopic residual or known gross residual disease. If intraoperative therapy is not employed, additional dose to these regions (via external beam) cannot be delivered for several weeks. The interval between preoperative radiation therapy and postoperative radiation therapy in this scenario would likely make the postoperative therapy of limited additional bene"t, considering radiobiologic principles of tumor cell repopulation.
5. Intraoperative radiotherapy Intraoperative radiotherapy (IORT) may be delivered prior to or following external beam radiation therapy in an attempt to provide additional dose to regions at highest risk for recurrence. The procedure involves identi"cation and isolation of the tumor bed following en bloc resection. This involves retraction of mobile normal structures, most notably bowel. Ideally, the surgery takes place in a room equipped with a linear accelerator. Otherwise, the patient is transported to the linear accelerator once the tumor bed is isolated. An appropriate size applicator is then selected which covers the target volume, and is attached to the head of the linear accelerator. Lead shields are placed on any normal tissue which cannot be retracted from the treatment "eld, including ureters and peripheral nerves. An electron beam is utilized to limit the dose to the structures deep to the region treated, principally the spinal cord. A single fraction, in the range of 20 Gy, is delivered and the operative procedure is then completed. Theoretically, this approach would improve the therapeutic index of radiation since the majority of normal tissues can be excluded from the beam. In addition, there is a potential biological advantage since the e!ectiveness of a single large fraction is greater than the same dose delivered as a fractionated regimen. The value of IORT has been investigated in one of the few randomized trials in retroperitoneal sarcoma. In this study from the NCI, 35 patients were assigned to IORT (20 Gy) followed by postoperative external beam radiation therapy (35}40 Gy) versus postoperative external beam radiation therapy alone (50}55 Gy). Patients receiving IORT experienced a signi"cant reduction in local failure compared to the control group (6/15 and 16/20 with local failure, respectively) [13]. These patients experienced a higher rate of radiation-related peripheral neuropathy, which was balanced against a higher rate of radiation enteritis in those receiving the higher dose of
64
C.J. McGinn / Surgical Oncology 9 (2000) 61}65
external beam therapy alone. There was no survival di!erence. Several groups continue to investigate this technique, based on the availability of operating rooms equipped with linear accelerators. It may become more widely available, such that larger trials will be performed, with the recent development of a mobile linear accelerator which does not require a dedicated operating room [14]. These trials may provide additional insights into the value of IORT.
6. Brachytherapy Brachytherapy involves placement of afterloading catheters in the tumor bed following en bloc resection. These catheters are then loaded with radioactive seeds following a brief postoperative recovery. As with IORT, this allows delivery of an additional 15}20 Gy to the region at highest risk for recurrence, based on the opinion of the surgeon and radiation oncologist. However, exclusion of adjacent normal tissue may not be possible since the bowel may return to the region of the implant once the surgical procedure is over. This may be circumvented with the development of high dose rate remote afterloading techniques, which allow delivery of intraoperative brachytherapy. This approach has been pioneered at Memorial Sloan-Kettering with encouraging preliminary results [14].
7. Postoperative radiation therapy The use of radiation therapy following en bloc resection, alone or in combination with IORT, has been most widely studied. Obvious advantages include immediate surgical resection and full pathologic staging for grade and margin status. Other details provided, which are not available in the preoperative setting, include presence of peritoneal/liver metastases which may obviate the need for radiation therapy. The disadvantages include di$culty identifying the region at risk. This can be limited in the multidisciplinary setting by acquisition of optimal preoperative imaging and cooperation between the surgical oncologist and radiation oncologist. In our practice, the radiation oncologist routinely attends the surgical resection to observe and direct placement of surgical clips outlining the regions of concern. The greatest disadvantage relates to the return of normal tissues, particularly bowel, to the regions at highest risk for local recurrence. Frequently, these bowel loops may become "xed as a result of adhesions. This disadvantage is most signi"cant when IORT is not employed, and the entire dose needs to be delivered via external beam therapy. Concern for normal tissue toxicity has frequently limited the dose delivered in the postoperative
setting, which may be partially responsible for the limited e$cacy noted in older series. Three-dimensional treatment planning may allow delivery of higher doses with acceptable toxicity. This technology, which merges advanced computer graphics to CT scan data sets, provides three-dimensional display of anatomic information, radiation therapy beam arrangement and radiation dose distribution [15]. Treatment planning with these systems permits more accurate targeting of the region to be treated, as identi"ed on the CT scan, thus limiting the amount of adjacent normal tissue irradiated. In addition, non-axial beam arrangements can be utilized which may permit further reduction in the radiation dose to normal tissue. Finally, and perhaps most importantly, 3D planning tools provide data on the dose distribution within normal tissue. Normal tissue complication probability models have now been developed, based on both dose and volume information, which have eliminated the need for restrictions in dose prescription based on whole organ tolerance, particularly with regard to the liver [16]. The volume to be irradiated in the postoperative setting has not been clearly established. The tendency, for retroperitoneal sarcomas and other malignancies in which surgical or chemotherapy debulking has been achieved, is to include the entire preoperative/ prechemotherapy volume. However, the ability to identify the region at greatest risk through cooperation with the surgical oncologist, and the ability to target this region with 3D planning, has lead us to focus a higher dose to a more limited region, as seen in Fig. 1b and c. This approach has been suggested by other investigators as well [17]. A dose}response relationship has been suggested in several retrospective reviews. Improved rates of local control have been observed with doses '55}60 Gy [18,19]. Unfortunately, these were relatively small series ((25 patients in each), and de"nitive conclusions are not available. Our general target dose is in the range of 55 Gy. If normal tissue tolerance is not exceeded at that point, an additional boost of 5}8 Gy is considered.
8. Results As indicated above, there are no controlled randomized trials to determine the value of adjuvant radiation therapy in conjunction with surgical resection of retroperitoneal sarcomas. Data are limited to retrospective series with a broad variety of uncontrolled variables including margin status, tumor size, histologic grade, radiation technique and dose. Indeed, several series can be found to support either side of the argument. Series which indicate no advantage often fail to include critical details regarding the radiotherapy variables, making evaluation more di$cult still [4,8]. Despite these
C.J. McGinn / Surgical Oncology 9 (2000) 61}65
limitations, the trend seems to suggest that higher rates of local control are observed among patients who have received adjuvant radiation. These series include those from Princess Margaret Hospital and Roswell Park [5,7]. Interestingly, the series from Memorial Sloan-Kettering which reported on 48 patients who remained alive '5 years from the time of operation found that radiation therapy was the only factor signi"cant for reduction of local recurrence [9]. The highest rates of local control (81% at 4 years) have been observed following preoperative radiation therapy, resection and IORT [20]. Unfortunately, the largest series in the literature (also from Memorial) did not include treatment variables in the tumor control and survival analysis [6]. 9. Summary The management of patients with retroperitoneal sarcoma remains a substantial challenge. It is clear, however, that these patients should be referred to multidisciplinary clinics sta!ed by surgical oncologists with experience in techniques of en bloc resection, considering the prognostic signi"cance of resection margin. Consultation with experienced medical and radiation oncologists can be important as well, particularly if prospective trials or de"ned treatment algorithms have been established. The role of radiation therapy has not been clearly de"ned. However, the increased availability of 3D techniques for external beam radiation therapy delivery and more accessible equipment for IORT may prompt the initiation of cooperative group trials to investigate these issues further. References [1] Shanahan TG, Mehta MP, Bertelrud KL, Buchler DA, Frank LE, Gehring MA, Kubsad SS, Utrie PC, Kinsella TJ. Minimization of small bowel volume within treatment "elds utilizing customized `belly boardsa. International Journal of Radiation Oncology and Biological Physics 1990;19:469}76. [2] Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics. CA, A Cancer Journal for Clinicians (published by the American Cancer Society) 1999;49:8}31. [3] Storm FK, Mahvi DM. Diagnosis and management of retroperitoneal soft tissue sarcoma. Annals of Surgery 1991;214:2}10. [4] Kilkenny JW, Bland KI, Copeland EM. Retroperitoneal sarcoma: the University of Florida experience. Journal of the American College of Surgens 1996;182:329}39.
65
[5] Karakousis CP, Gerstenbluth R, Kontzoglou K, Driscoll DL. Retroperitoneal sarcoma and their management. Archives of Surgery 1995;130:1104}9. [6] Lewis JJ, Leung D, Woodru! JM, Brennan MF. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Annals of Surgery 1998;228:355}65. [7] Catton CN, O'Sullivan B, Kotwall C, Cummings B, Hao Y, Fornasier V. Outcome and prognosis in retroperitoneal soft tissue sarcoma. International Journal of Radiation Oncology and Biological Physics 1994;29:1005}10. [8] Singer S, Corson JM, Demetri GD, Healey EA, Marcus K, Eberlein TJ. Prognostic factors predictive of survival for truncal and retroperitoneal soft-tissue sarcoma. Annals of Surgery 1995;221:185}95. [9] Heslin MJ, Lewis JJ, Nadler E, Newman E, Woodru! JM, Casper ES, Leung D, Brennan MF. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. Journal of Clinical Oncology 1997;15:2832}9. [10] Potter DA, Kinsella T, Glatstein E, Wesley R, White DE, Seipp CA, Chang AE, Lack EE, Costa J, Rosenberg SA. High-grade soft tissue sarcomas of the extremities. Cancer 1986;58:190}205. [11] Suit HD, Mankin HJ, Wood WC, Gebhardt MC, Harmon DC, Rosenberg A, Tepper JE, Rosenthal D. Treatment of the patient with stage M0 soft tissue sarcoma. Journal of Clinical Oncology 1988;6:854}62. [12] Pisters WT, Harrison LB, Leung DHY, Woodru! JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. Journal of Clinical Oncology 1996;14:859}68. [13] Sindelar WF, Kinsella TJ, Chen PW, DeLaney TF, Tepper JE, Rosenberg SA, Glatstein E. Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Archives of Surgery 1993;128:402}10. [14] Gunderson LL, Willett CG, Harrison LB, Peterson IA, Haddock MG. Intraoperative irradiation: current and future status. Seminars in Oncology 1997;24:715}31. [15] Lichter AS, Lawrence TS. Recent advances in radiation oncology. New England Journal of Medicine 1995;32:371}9. [16] McGinn C, Ten Haken R, Ensminger W, Walker S, Wang S, Lawrence T. The treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model. Journal of Clinical Oncology 1998;16:2246}52. [17] Clark JA, Tepper JE. Role of radiation therapy in retroperitoneal sarcomas. Oncology. 1996;10:1867}72. [18] Tepper JE, Suit HD, Wood WC, Proppe KH, Harmon D, McNulty P. Radiation therapy of retroperitoneal soft tissue sarcomas. International Journal of Radiation Oncology and Biological Physics 1984;10:825}30. [19] Fein DA, Corn BW, Lanciano RM, Herbert SH, Ho!man JP, Coia LR. Management of retroperitoneal sarcomas: does dose escalation impact on locoregional control?. International Journal of Radiation Oncology and Biological Physics 1995;31:129}34. [20] Willett CG, Suit HD, Tepper JE, Mankin HJ, Convery K, Rosenberg AL, Wood WC. Intraoperative electron beam radiation therapy for retroperitoneal soft tissue sarcoma. Cancer 1991;68:278}83.
The role of radiation therapy in resectable retroperitoneal sarcomas Cornelius J. McGinn* Department of Radiation Oncology, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0010, USA
1. Case scenario A 29 year old female presented to her primary care physician soon after she noted a palpable mass in her left lower abdomen. She was otherwise asymptomatic. An abdominal and pelvic CT revealed a 12;10;9 cm heterogenous mass arising from the psoas and extending into the pelvis (Fig. 1a). There was no evidence of ureteral or bowel obstruction. Chest CT revealed no evidence of metastases. She had no other signi"cant medical or surgical history. Exploratory laparotomy with complete gross total excision was performed. The mass was noted to be adherent to the ureter and iliac vessels. A section of the external iliac artery was resected with the mass, and repaired with an interposition graft. Surgical clips were placed to identify regions of tumor adherence. Pathological evaluation revealed a grade III liposarcoma, with close margins in several locations along the posterior aspect of the mass. She recovered from surgery without signi"cant di$culty. Adjuvant radiotherapy was recommended and she agreed to proceed. A treatment planning CT was obtained with the patient immobilized in a prone alpha cradle with a false table top (belly board) to allow displacement of the bowel [1]. A region along the psoas and iliac vessels was identi"ed, in collaboration with the surgical oncologist, that was felt to be at highest risk for local recurrence. Three dimensional treatment planning was utilized to develop a 6 "eld plan of axial beams that localized dose to the region identi"ed (Fig. 1b and c). A total dose of 54 Gy was delivered in 1.8 Gy fractions. She experienced occasional diarrhea and mild nausea, but no other signi"cant acute toxicity. Treatment was completed in 7/98. She remains without evidence of local
* Tel.: #1-313-936-9521; fax: #1-313-763-7370. E-mail address: [email protected] (C.J. Mc Ginn).
recurrence or late toxicity. She is without evidence of distant metastases as well.
2. Introduction Approximately 7800 patients are diagnosed with soft tissue sarcoma each year in the United States [2]. Of these, approximately 15% arise in the retroperitoneum. These patients present a unique set of challenges to oncologists involved in their care. The challenges relate to many factors including the extent of tumor involvement at the time of diagnosis, the location of the tumor relative to critical normal structures, the heterogeneity of tumor types and the rarity of these tumors. The low incidence rate has hampered investigation via prospective trials, making it di$cult to arrive at de"nitive conclusions regarding optimal management strategies. Indeed, the medical literature on this subject is almost entirely limited to retrospective series. The most common presenting symptoms are generally vague and have often been ignored for months preceding the diagnosis [3]. Presentation with an abdominal mass or increasing abdominal girth is frequently the only symptom [4,5]. Additional symptoms such as early satiety, nausea, vomiting, constipation and #ank or back pain relate to compression of adjacent organs. Evidence of ureteral obstruction or deep venous thrombosis is not uncommon. The majority of patients present with tumors '10 cm in size [6]. Following appropriate radiographic imaging to determine the extent of the primary tumor and presence or absence of metastases, incisional biopsy may be obtained to con"rm the diagnosis. However, en bloc resection as the initial procedure can also be considered if the diagnosis of sarcoma is likely, and the surgeon has anticipated the potential need for resection of adjacent organs. Liposarcoma and leiomyosarcoma
0960-7404/00/$ - see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 9 6 0 - 7 4 0 4 ( 0 0 ) 0 0 0 2 5 - 6
62
C.J. McGinn / Surgical Oncology 9 (2000) 61}65
Fig. 1. (a) Preoperative CT indicating the tumor extension into the pelvis. The image is inverted to compare with the treatment planning CT which was obtained in the prone position. (b) Treatment planning CT indicating the region being treated. The 100% isodose line is encompassing the region identi"ed to be at greatest risk for local recurrence. The concentration of dose in this region is indicated by the isodose lines ranging from 100% to 70%. (c) Suface contour of the patient is indicated along with contours of the skeletal anatomy and kidneys. The central axis and beam shapes of the 6 treatment "elds are seen converging on a surface contour of the target region (darker region within the pelvis), resulting in the dose distribution seen in b.
are the most common histologic subtypes, accounting for 65% of newly diagnosed cases [6] in the recent series for Memorial Sloan-Kettering. In this series, the liposarcoma histologic subtype was associated with a signi"cantly increased risk of local recurrence. In another series, liposarcoma was associated with improved survival [7]. In most series, however, there is no signi"cance associated with speci"c histologic subtypes. The most signi"cant prognostic factors for overall survival have consistently been tumor grade and margin of resection [4}8]. The rate of complete resection with negative surgical margins ranges from 5 to 65% [5}7]. This rate is generally lower in patients with locally recurrent disease. The most common sites of distant metastases are the lung and liver. Chemotherapy has been and continues to be investigated in this patient population without de"nitive
conclusion, and will not be addressed further in this review. Survival at 5 years for patients with primary disease following complete resection is approximately 70% [5,6].
3. The rationale for adjuvant radiation therapy Local recurrence following surgical resection is frequent, considering the anatomic constraints which prevent wide local excision with negative margins. It is important to note that local recurrences can occur after a protracted disease-free interval. Heslin et al. recently reported a 40% recurrence rate among a population of patients who had survived disease-free for 5 years or longer [9]. Indeed, an earlier review of the literature
C.J. McGinn / Surgical Oncology 9 (2000) 61}65
revealed a 90% local recurrence at 10 years following complete excision [3]. Thus, data from studies with median follow-up less than 5 years may not accurately re#ect the ultimate outcome. The consequence of local recurrence is apparent in the series from Memorial in which median survival after local recurrence was 28 months [6]. It is obvious, then, that additional measures to achieve local control should be considered. Radiation therapy as a surgical adjunct has been utilized by several groups in an attempt to improve local control, based on well-established data indicating a reduction of local recurrence with adjuvant radiation therapy in conjunction with limb-sparing surgery for extremity sarcomas [10}12]. Unfortunately, the selection of patients for adjuvant radiation following resection of retroperitoneal sarcoma has not generally been de"ned prospectively. In those patients receiving treatment, details regarding dose and volume are not uniform, and frequently not even reported. A wide variety of options exist as well, including preoperative external beam, intraoperative electron irradiation, brachytherapy and postoperative external beam irradiation.
4. Preoperative radiation therapy Preoperative radiation therapy has been advocated for patients with retroperitoneal sarcoma based on experience in extremity sarcoma, and additional considerations which apply in the retroperitoneum. The theoretical advantages which apply at any site include the potential for tumor response, which may improve the rate of resection with negative margins. Preoperative therapy may also reduce the risk of peritoneal or systemic seeding secondary to operative manipulation. Improved oxygenation may exist in the preoperative setting, relative to the postoperative microenvironment. Higher levels of oxygenation have been shown to increase radiosensitivity in experimental models. However, this argument may not be relevant with tumors of this size, which likely have large regions of hypoxia. Perhaps the most compelling argument for preoperative therapy relates to the presence of the mass which can displace adjacent normal tissues that would be dose-limiting in the postoperative setting. Unfortunately, it is di$cult to take advantage of this opportunity for dose escalation, since doses '50 Gy are often associated with delayed wound healing. Preoperative therapy involves delivery of radiation to the entire tumor volume. Yet this may not be necessary, particularly in regions where the tumor has simply displaced adjacent organs without invasion, and will be resected without concern for margin status at that location. Thus, the volumes irradiated preoperatively may be larger than volumes irradiated postoperatively. This is unlike the case in extremity sarcomas.
63
The most appropriate situation for preoperative radiation therapy exists in departments equipped for intraoperative radiation therapy or brachytherapy. In this way, a preoperative dose with low risk of compromised wound healing (in the range of 40}50 Gy) can be followed by directed therapy to the regions of suspected microscopic residual or known gross residual disease. If intraoperative therapy is not employed, additional dose to these regions (via external beam) cannot be delivered for several weeks. The interval between preoperative radiation therapy and postoperative radiation therapy in this scenario would likely make the postoperative therapy of limited additional bene"t, considering radiobiologic principles of tumor cell repopulation.
5. Intraoperative radiotherapy Intraoperative radiotherapy (IORT) may be delivered prior to or following external beam radiation therapy in an attempt to provide additional dose to regions at highest risk for recurrence. The procedure involves identi"cation and isolation of the tumor bed following en bloc resection. This involves retraction of mobile normal structures, most notably bowel. Ideally, the surgery takes place in a room equipped with a linear accelerator. Otherwise, the patient is transported to the linear accelerator once the tumor bed is isolated. An appropriate size applicator is then selected which covers the target volume, and is attached to the head of the linear accelerator. Lead shields are placed on any normal tissue which cannot be retracted from the treatment "eld, including ureters and peripheral nerves. An electron beam is utilized to limit the dose to the structures deep to the region treated, principally the spinal cord. A single fraction, in the range of 20 Gy, is delivered and the operative procedure is then completed. Theoretically, this approach would improve the therapeutic index of radiation since the majority of normal tissues can be excluded from the beam. In addition, there is a potential biological advantage since the e!ectiveness of a single large fraction is greater than the same dose delivered as a fractionated regimen. The value of IORT has been investigated in one of the few randomized trials in retroperitoneal sarcoma. In this study from the NCI, 35 patients were assigned to IORT (20 Gy) followed by postoperative external beam radiation therapy (35}40 Gy) versus postoperative external beam radiation therapy alone (50}55 Gy). Patients receiving IORT experienced a signi"cant reduction in local failure compared to the control group (6/15 and 16/20 with local failure, respectively) [13]. These patients experienced a higher rate of radiation-related peripheral neuropathy, which was balanced against a higher rate of radiation enteritis in those receiving the higher dose of
64
C.J. McGinn / Surgical Oncology 9 (2000) 61}65
external beam therapy alone. There was no survival di!erence. Several groups continue to investigate this technique, based on the availability of operating rooms equipped with linear accelerators. It may become more widely available, such that larger trials will be performed, with the recent development of a mobile linear accelerator which does not require a dedicated operating room [14]. These trials may provide additional insights into the value of IORT.
6. Brachytherapy Brachytherapy involves placement of afterloading catheters in the tumor bed following en bloc resection. These catheters are then loaded with radioactive seeds following a brief postoperative recovery. As with IORT, this allows delivery of an additional 15}20 Gy to the region at highest risk for recurrence, based on the opinion of the surgeon and radiation oncologist. However, exclusion of adjacent normal tissue may not be possible since the bowel may return to the region of the implant once the surgical procedure is over. This may be circumvented with the development of high dose rate remote afterloading techniques, which allow delivery of intraoperative brachytherapy. This approach has been pioneered at Memorial Sloan-Kettering with encouraging preliminary results [14].
7. Postoperative radiation therapy The use of radiation therapy following en bloc resection, alone or in combination with IORT, has been most widely studied. Obvious advantages include immediate surgical resection and full pathologic staging for grade and margin status. Other details provided, which are not available in the preoperative setting, include presence of peritoneal/liver metastases which may obviate the need for radiation therapy. The disadvantages include di$culty identifying the region at risk. This can be limited in the multidisciplinary setting by acquisition of optimal preoperative imaging and cooperation between the surgical oncologist and radiation oncologist. In our practice, the radiation oncologist routinely attends the surgical resection to observe and direct placement of surgical clips outlining the regions of concern. The greatest disadvantage relates to the return of normal tissues, particularly bowel, to the regions at highest risk for local recurrence. Frequently, these bowel loops may become "xed as a result of adhesions. This disadvantage is most signi"cant when IORT is not employed, and the entire dose needs to be delivered via external beam therapy. Concern for normal tissue toxicity has frequently limited the dose delivered in the postoperative
setting, which may be partially responsible for the limited e$cacy noted in older series. Three-dimensional treatment planning may allow delivery of higher doses with acceptable toxicity. This technology, which merges advanced computer graphics to CT scan data sets, provides three-dimensional display of anatomic information, radiation therapy beam arrangement and radiation dose distribution [15]. Treatment planning with these systems permits more accurate targeting of the region to be treated, as identi"ed on the CT scan, thus limiting the amount of adjacent normal tissue irradiated. In addition, non-axial beam arrangements can be utilized which may permit further reduction in the radiation dose to normal tissue. Finally, and perhaps most importantly, 3D planning tools provide data on the dose distribution within normal tissue. Normal tissue complication probability models have now been developed, based on both dose and volume information, which have eliminated the need for restrictions in dose prescription based on whole organ tolerance, particularly with regard to the liver [16]. The volume to be irradiated in the postoperative setting has not been clearly established. The tendency, for retroperitoneal sarcomas and other malignancies in which surgical or chemotherapy debulking has been achieved, is to include the entire preoperative/ prechemotherapy volume. However, the ability to identify the region at greatest risk through cooperation with the surgical oncologist, and the ability to target this region with 3D planning, has lead us to focus a higher dose to a more limited region, as seen in Fig. 1b and c. This approach has been suggested by other investigators as well [17]. A dose}response relationship has been suggested in several retrospective reviews. Improved rates of local control have been observed with doses '55}60 Gy [18,19]. Unfortunately, these were relatively small series ((25 patients in each), and de"nitive conclusions are not available. Our general target dose is in the range of 55 Gy. If normal tissue tolerance is not exceeded at that point, an additional boost of 5}8 Gy is considered.
8. Results As indicated above, there are no controlled randomized trials to determine the value of adjuvant radiation therapy in conjunction with surgical resection of retroperitoneal sarcomas. Data are limited to retrospective series with a broad variety of uncontrolled variables including margin status, tumor size, histologic grade, radiation technique and dose. Indeed, several series can be found to support either side of the argument. Series which indicate no advantage often fail to include critical details regarding the radiotherapy variables, making evaluation more di$cult still [4,8]. Despite these
C.J. McGinn / Surgical Oncology 9 (2000) 61}65
limitations, the trend seems to suggest that higher rates of local control are observed among patients who have received adjuvant radiation. These series include those from Princess Margaret Hospital and Roswell Park [5,7]. Interestingly, the series from Memorial Sloan-Kettering which reported on 48 patients who remained alive '5 years from the time of operation found that radiation therapy was the only factor signi"cant for reduction of local recurrence [9]. The highest rates of local control (81% at 4 years) have been observed following preoperative radiation therapy, resection and IORT [20]. Unfortunately, the largest series in the literature (also from Memorial) did not include treatment variables in the tumor control and survival analysis [6]. 9. Summary The management of patients with retroperitoneal sarcoma remains a substantial challenge. It is clear, however, that these patients should be referred to multidisciplinary clinics sta!ed by surgical oncologists with experience in techniques of en bloc resection, considering the prognostic signi"cance of resection margin. Consultation with experienced medical and radiation oncologists can be important as well, particularly if prospective trials or de"ned treatment algorithms have been established. The role of radiation therapy has not been clearly de"ned. However, the increased availability of 3D techniques for external beam radiation therapy delivery and more accessible equipment for IORT may prompt the initiation of cooperative group trials to investigate these issues further. References [1] Shanahan TG, Mehta MP, Bertelrud KL, Buchler DA, Frank LE, Gehring MA, Kubsad SS, Utrie PC, Kinsella TJ. Minimization of small bowel volume within treatment "elds utilizing customized `belly boardsa. International Journal of Radiation Oncology and Biological Physics 1990;19:469}76. [2] Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics. CA, A Cancer Journal for Clinicians (published by the American Cancer Society) 1999;49:8}31. [3] Storm FK, Mahvi DM. Diagnosis and management of retroperitoneal soft tissue sarcoma. Annals of Surgery 1991;214:2}10. [4] Kilkenny JW, Bland KI, Copeland EM. Retroperitoneal sarcoma: the University of Florida experience. Journal of the American College of Surgens 1996;182:329}39.
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[5] Karakousis CP, Gerstenbluth R, Kontzoglou K, Driscoll DL. Retroperitoneal sarcoma and their management. Archives of Surgery 1995;130:1104}9. [6] Lewis JJ, Leung D, Woodru! JM, Brennan MF. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Annals of Surgery 1998;228:355}65. [7] Catton CN, O'Sullivan B, Kotwall C, Cummings B, Hao Y, Fornasier V. Outcome and prognosis in retroperitoneal soft tissue sarcoma. International Journal of Radiation Oncology and Biological Physics 1994;29:1005}10. [8] Singer S, Corson JM, Demetri GD, Healey EA, Marcus K, Eberlein TJ. Prognostic factors predictive of survival for truncal and retroperitoneal soft-tissue sarcoma. Annals of Surgery 1995;221:185}95. [9] Heslin MJ, Lewis JJ, Nadler E, Newman E, Woodru! JM, Casper ES, Leung D, Brennan MF. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. Journal of Clinical Oncology 1997;15:2832}9. [10] Potter DA, Kinsella T, Glatstein E, Wesley R, White DE, Seipp CA, Chang AE, Lack EE, Costa J, Rosenberg SA. High-grade soft tissue sarcomas of the extremities. Cancer 1986;58:190}205. [11] Suit HD, Mankin HJ, Wood WC, Gebhardt MC, Harmon DC, Rosenberg A, Tepper JE, Rosenthal D. Treatment of the patient with stage M0 soft tissue sarcoma. Journal of Clinical Oncology 1988;6:854}62. [12] Pisters WT, Harrison LB, Leung DHY, Woodru! JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. Journal of Clinical Oncology 1996;14:859}68. [13] Sindelar WF, Kinsella TJ, Chen PW, DeLaney TF, Tepper JE, Rosenberg SA, Glatstein E. Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Archives of Surgery 1993;128:402}10. [14] Gunderson LL, Willett CG, Harrison LB, Peterson IA, Haddock MG. Intraoperative irradiation: current and future status. Seminars in Oncology 1997;24:715}31. [15] Lichter AS, Lawrence TS. Recent advances in radiation oncology. New England Journal of Medicine 1995;32:371}9. [16] McGinn C, Ten Haken R, Ensminger W, Walker S, Wang S, Lawrence T. The treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model. Journal of Clinical Oncology 1998;16:2246}52. [17] Clark JA, Tepper JE. Role of radiation therapy in retroperitoneal sarcomas. Oncology. 1996;10:1867}72. [18] Tepper JE, Suit HD, Wood WC, Proppe KH, Harmon D, McNulty P. Radiation therapy of retroperitoneal soft tissue sarcomas. International Journal of Radiation Oncology and Biological Physics 1984;10:825}30. [19] Fein DA, Corn BW, Lanciano RM, Herbert SH, Ho!man JP, Coia LR. Management of retroperitoneal sarcomas: does dose escalation impact on locoregional control?. International Journal of Radiation Oncology and Biological Physics 1995;31:129}34. [20] Willett CG, Suit HD, Tepper JE, Mankin HJ, Convery K, Rosenberg AL, Wood WC. Intraoperative electron beam radiation therapy for retroperitoneal soft tissue sarcoma. Cancer 1991;68:278}83.