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© 2003 American Society for Clinical Oncology Phase I Trial of Preoperative Concurrent Doxorubicin and Radiation Therapy, Surgical Resection, and Intraoperative Electron-Beam Radiation Therapy for Patients With Localized Retroperitoneal Sarcoma
From the Multidisciplinary Sarcoma Center at the University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Peter W.T. Pisters, MD, Department of Surgical Oncology, Unit 444, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; email: ppisters{at}mdanderson.org.
Purpose: The primary objective of this phase I trial was to define the maximum-tolerated dose of external-beam radiation with concurrent fixed-dose continuous-infusion doxorubicin followed by surgical resection and electron-beam intraoperative radiation therapy (EB-IORT) for patients with localized, potentially resectable retroperitoneal sarcomas (RPS). Patients and Methods: Thirty-five patients with radiographically resectable primary or recurrent intermediate- or high-grade RPS were treated. Doxorubicin was administered each week for 4 or 5 weeks as an initial bolus (4 mg/m2) followed by a 4-day continuous infusion (4 mg/m2/d). Concurrent radiation therapy was administered in escalating doses of 18.0, 30.6, 36.0, 41.4, 46.8, or 50.4 Gy in 1.8-Gy fractions. Radiographic restaging was performed 4 to 8 weeks after chemoradiation, and patients with localized disease underwent surgical resection with EB-IORT (15 Gy). Results: Chemoradiation was completed as outpatient therapy in 31 patients (89%); four patients required hospital admission during chemoradiation or in the postchemoradiation preoperative period. At the highest radiation dose of 50.4 Gy, two (18%) of 11 patients had grade 3 or 4 nausea. Twenty-nine patients (83%) underwent laparotomy; six patients had interval disease progression and did not undergo surgery. Grossly complete resection (R0 or R1) was performed in 26 (90%) of 29 patients who had surgery. EB-IORT was feasible and successfully administered to 22 patients who had R0 or R1 resections. Conclusion: Preoperative chemoradiation, surgical resection, and EB-IORT are feasible for patients with RPS. Preoperative external-beam radiation can be administered to a total dose of 50.4 Gy with continuous-infusion doxorubicin.
THE RETROPERITONEUM is the site of origin of 15% to 20% of soft tissue sarcomas (STS).1 Patients with retroperitoneal STS often present with large, locally advanced tumors because of the general mobility of the retroperitoneal viscera and the large volume of space available for visceral displacement in the retroperitoneum and peritoneal cavity. Surgical resection remains the mainstay of treatment. Complete surgical resection is possible in 67% of patients who present with primary disease.2 Because retroperitoneal STS are often large and locally advanced at presentation, and are adjacent to vital viscera and major vascular structures, wide surgical resection with microscopically negative margins is usually not possible. Consequently, local recurrence rates are high. Randomized trials have demonstrated that the addition of radiation to surgery unequivocally improves local tumor control for patients with extremity and superficial trunk STS.2,3 This has led to considerable interest in the use of surgery plus radiation for patients with retroperitoneal STS. Although radiation was given postoperatively in the phase III trials of surgery plus radiation for extremity and superficial trunk STS, many investigators believe that patients with retroperitoneal STS will be more optimally treated with preoperative radiation.4 Radiation with the tumor in situ is a distinct advantage for retroperitoneal STS because the tumor itself displaces radiosensitive viscera (particularly the mobile small intestine) out of the radiation field. In contrast, when postoperative radiation is planned for patients with retroperitoneal STS, the treatment field almost always includes the small intestine and previously displaced viscera that migrate back after resection, and dose reduction is necessary owing to the increased risk for radiation injury and treatment-related toxicity. The concurrent administration of chemotherapy and intraoperative radiation therapy (IORT) may improve the therapeutic index of conventional external-beam radiation. Doxorubicin is one of the most active agents in STS.5 It also is a potent radiosensitizer and is therefore a reasonable choice for a concurrent chemotherapy and radiation therapy approach. Pilot studies of doxorubicin-based chemoradiation in patients with locally advanced extremity and superficial trunk STS indicate that local control rates may be 90% or greater.6–9 Furthermore, IORT may increase the therapeutic index of radiation by allowing the delivery of a single large fraction intraoperatively to the anatomic region believed to be at greatest risk of harboring microscopic residual disease while minimizing radiation to the radiosensitive viscera, which are retracted out of the intraoperative radiation field. Thus, for a disease characterized by high rates of local recurrence, chemoradiation and IORT may represent reasonable therapeutic strategies to maximize local control. Previous work had indicated that low-dose continuous-infusion doxorubicin could be safely administered at a dose of 12 mg/m2/d (for 5 days, repeated every 2 to 3 weeks) with external-beam radiation for patients with STS of the extremities.10 However, there are no data that address the dose of radiation that can be safely provided with continuous-infusion doxorubicin for patients with nonvisceral STS of the retroperitoneum—an anatomic site that may be associated with a different chemoradiation toxicity profile than the extremity. This phase I trial was designed to investigate the feasibility of preoperative chemoradiation, surgery, and IORT, and to define the maximum-tolerated dose (MTD) of radiation that can be administered with continuous-infusion doxorubicin for patients with retroperitoneal STS.
Eligibility Patients with T2 (5 to 35 cm), localized, potentially resectable intermediate- and high-grade retroperitoneal or pelvic STS were eligible for this trial. Patients with untreated primary disease and those with locally recurrent disease were eligible. Histologic or cytologic confirmation of STS was required. Determination of resectability was based on pretreatment computed tomography (CT) and multidisciplinary consultation with a sarcoma surgeon and radiation oncologist. The pretreatment evaluation included a complete history and physical examination; baseline assessment of organ function; chest x-ray; and CT scans (or magnetic resonance imaging) of the chest, abdomen, and pelvis. Patients with radiographic evidence of pulmonary metastases were excluded, but patients with four or fewer indeterminate pulmonary nodules were eligible. Additional eligibility criteria included a Karnofsky performance score of 70 or greater, an absolute granulocyte count (AGC) greater than 1,500/mL, a platelet count of at least 100,000/µL, and a serum creatinine level less than 1.6 mg/dL. Patients with a history of abdominal or pelvic irradiation that included the region of the present tumor and patients whose previous cumulative doxorubicin exposure combined with the protocol-related doxorubicin dose would result in a cumulative doxorubicin exposure of 450 mg or greater were not eligible. The trial was approved by the Institutional Review Board of the University of Texas M.D. Anderson Cancer Center. Written informed consent was obtained from all patients before initiation of therapy.
Chemoradiation
Doxorubicin dose adjustment for individual patients was based on toxicity experienced and the AGC and platelet count at the beginning of each week of treatment. A full dose was delivered if the patient had an AGC at least 500/µL, platelet count of at least 25,000/µL, and grade 2 or less mucositis. Administration of doxorubicin was postponed if the patient had an AGC less than 500/µL or significant infectious morbidity, platelet count less than 25,000/µL or any bleeding episode, or grade 3 or greater mucositis. If administration of doxorubicin was postponed, radiation therapy was also withheld. Treatment was resumed when the toxic effects had resolved to grade 2 or less. Preoperative radiation up to a total dose of 50.4 Gy was administered using 1.8-Gy daily fractions (5 d/wk). Treatment planning was done using three-dimensional CT with oral contrast to outline the gastrointestinal tract when appropriate. The gross tumor volume was the primary or recurrent tumor as defined by CT. The planning target volume was the gross tumor volume plus a variable margin to account for microscopic disease extension and tumor motion. This margin ranged from 1 to 5 cm and also was based in part on the anatomic relationships between the tumor and radiosensitive organs. The radiation dose was prescribed to the isodose line encompassing the volume of interest, which typically was 95% to 98%. If the pretreatment surgical plan included en-bloc nephrectomy, no specific attempt to protect the involved kidney was made. However, in these patients, at least 90% of the contralateral kidney was excluded from the primary beam. Spinal cord doses were limited to 35 Gy, and off–spinal-cord reductions were performed as necessary. In addition, no more than 30% of the total liver volume received more than 30 Gy. Special treatment positioning techniques were used on an individual basis. These included patient placement in the lateral decubitus or prone position and use of a belly board.
Radiation Dose Escalation
As initially designed, the protocol permitted 4 weeks of concurrent chemoradiation with a maximum external-beam radiation dose of 46.8 Gy. However, the protocol was subsequently modified (with institutional review board approval) to add a fifth week of chemoradiation to achieve an additional total radiation dose of 50.4 Gy; this modification was made because the MTD was not reached at the initial maximum dose of 46.8 Gy. The protocol revision allowed for additional patients to be treated at the 50.4-Gy dose level (if toxicities permitted) to better define the toxicity profile at this dose. The treatment schema for patients treated with the higher radiation dose is shown in Figure 1B
Surgery and IORT In a dedicated surgical suite, 15 Gy of electron-beam IORT (EB-IORT) was administered to the bed of the resected tumor. IORT was delivered through a 7- to 12-cm cone with the radiation dose prescribed to the 90% isodose line using a 9-MeV electron beam. Multiple IORT fields were not permitted. EB-IORT was omitted if, in the judgment of the operating surgeon, the operation had been of such length or complexity as to engender concern about the added operative time associated with EB-IORT.
Standardized histologic evaluation of the resected specimen was performed. Tumor size was calculated after surgical resection by measuring the maximum dimension (craniocaudad, medial-lateral, or anterior-posterior) of the tumor. The percentage of tumor necrosis (considered the histologic response) was estimated and assigned a semiquantitative value of less than 10%, 10% to 49%, 50% to 89%, or
Toxicity and Response Evaluation The radiographic response to preoperative chemoradiation was evaluated by a single radiologist (M.J.F.) by comparing pretreatment and restaging CT scans or magnetic resonance imaging studies. Radiographic responses were classified using the Response Evaluation Criteria in Solid Tumors.12
Patients and Tumors Treatment was initiated in 35 patients with retroperitoneal or pelvic STS believed to be resectable on the basis of pretreatment staging evaluation. The characteristics of these 35 patients and their tumors are listed in Table 1  . The median patient age was 55 years (range, 21 to 87 years). The median pretreatment (radiographic) tumor size was 10 cm (range, 5.7 to 31.0 cm). The distributions of histologic subtypes and histologic grades were as anticipated for retroperitoneal STS; leiomyosarcoma was the most common high-grade histologic subtype.
Feasibility and Toxicity of Chemoradiation Preoperative chemoradiation was completed as planned in 30 patients (86%). One patient was treated to a total radiation dose of 50 Gy instead of the planned 46.8 Gy, and four patients did not receive the entire planned radiation dose because of tumor proximity to the liver (one patient; 28.8 Gy received of planned 46.8 Gy), grade 3 anorexia (one patient; 45 Gy received of planned 50.4 Gy), patient refusal (one patient; 48.6 Gy received of planned 50.4 Gy), and rapid disease progression (one patient; 19.8 Gy received of planned 46.8 Gy). All treated patients were included in the toxicity analysis. Chemoradiation was completed as outpatient therapy in 31 patients (89%). Two patients required hospital admission during chemoradiation because of dehydration and anorexia. Two additional patients were admitted to the hospital in the postchemoradiation period with dehydration and gastrointestinal bleeding that required blood transfusions. On the basis of endoscopic findings and review of radiation fields, these episodes of posttreatment gastrointestinal bleeding were believed to be secondary to radiation-induced gastritis (46.8 and 50.4 Gy, respectively, were delivered to fields that included the stomach).
The frequency and distribution of grade 3 and 4 toxicities during preoperative chemoradiation are listed in Table 2
Radiographic and Histopathologic Response to Chemoradiation Radiographic response of the primary tumor to chemoradiation was assessable in 32 patients. Twenty-nine patients (91%) had stable disease, two patients (6%) had radiographic progression of the primary tumor, and one patient (3%) had a partial response. The two patients with local disease progression also had interval development of CT-definable visceral metastatic disease (lungs, one patient; liver, one patient).
The histologic responses to chemoradiation in the 27 patients who underwent complete tumor resection are outlined in Table 3
Surgery and IORT Twenty-nine (83%) of the 35 patients treated with preoperative chemoradiation underwent subsequent laparotomy for planned resection of the residual posttreatment tumor mass. Five patients did not proceed to surgery because of disease progression in the form of interval development of unequivocal pulmonary (two patients) or liver (one patient) metastases, or the development of sarcomatosis (two patients, one of whom also had new lung metastases). One patient died as a result of multisystem organ failure that developed in the postchemoradiation period. This was believed to be have been precipitated by a combination of disease- and treatment-related deconditioning and disease progression. Grossly complete surgical resection (R0 or R1) was possible in 26 (90%) of 29 patients who had surgery; two patients were found to have locally advanced, unresectable disease at laparotomy, and one patient underwent an R2 (subtotal) resection. Contiguous-organ resection was required to facilitate grossly complete resection in 20 patients. Major vascular resection and reconstruction were required in three patients. IORT (15 Gy) was administered in 22 (76%) of the 29 patients who had surgery. Seven patients did not receive IORT because it would have required unduly large fields that included major vascular structures (three patients), the field at risk for harboring microscopic disease could not be defined precisely enough (three patients), or an R2 (noncurative) resection was performed (the intent of the protocol was to treat only potential microscopic residual disease with IORT). No complications were attributable to the IORT in 21 (95%) of 22 treated patients. One patient with a pelvic sarcoma who had a pelvic IORT field that likely included both ureters developed postoperative bilateral ureteral strictures. This patient required postoperative ureteral stenting (with periodic stent exchange) for 15 months after surgery. At the time of this report, the patient remains free of disease with normal renal function. In retrospect, we believe that this patient’s postoperative ureteral strictures were related to the cumulative effects of preoperative radiation (41.4 Gy), operative dissection, and IORT.
This report demonstrates the feasibility of preoperative chemoradiation combined with surgical resection and IORT for patients with retroperitoneal STS. In a strict sense, we did not complete one of our stated objectives in that we did not define the MTD of external-beam radiation that could be safely administered with 20 mg/m2/wk doxorubicin. Given the potent radiosensitizing properties of doxorubicin and the large radiation field sizes required to treat retroperitoneal tumors, we anticipated that the MTD would be between 18.0 and 46.8 Gy. The protocol was amended after the treatment of patients with 46.8 Gy to allow for an additional dose level of 50.4 Gy, which was well tolerated. Given the known sensitivity of the abdominal viscera to radiation, we did not believe that it was appropriate to escalate the external-beam radiation dose beyond this level. In our opinion, the toxicity profile observed with preoperative doxorubicin-based chemoradiation at radiation doses up to and including 50.4 Gy was acceptable. Moreover, chemoradiation can be completed on an outpatient basis; hospital admission for toxicity was uncommon. Three other groups recently have reported feasibility and toxicity results of pilot trials13 or consecutive series14,15 of preoperative radiation with IORT for patients with retroperitoneal STS. Two of these reports focused on the use of IORT and did not include detailed toxicity data on the preoperative external-beam radiation component of the program.14,15 However, Gieschen et al14 did report that only five (14%) of 37 patients did not receive full-dose (45 to 50 Gy) preoperative radiation because of acute toxicity, disease progression, or prior radiation. Similarly, Jones et al13 completed preoperative radiation to a median dose of 45 Gy in 46 (84%) of 55 patients; the other nine patients experienced disease progression after protocol registration. None of the 46 patients treated by Jones et al experienced grade 3 or greater toxicities by Radiation Therapy Oncology Group criteria. Considering our experience with preoperative radiation as well as the existing literature, it seems that preoperative radiation can be completed as planned in 80% or more of patients who present with ostensibly localized retroperitoneal STS. Moreover, given the large treatment volumes that are required to treat these tumors, the acute toxicities of preoperative radiation seem to be acceptable. To our knowledge, this is the first report of concurrent doxorubicin and radiation for patients with retroperitoneal STS. Prior reports evaluating chemoradiation have generally been confined to patients with extremity and superficial trunk STS, and have evaluated intra-arterial or IV doxorubicin combined with shorter course, higher dose-per-fraction preoperative radiation at total doses ranging from 17 to 35 Gy.6–9,16 These prior reports have also used higher dose, shorter duration (generally 48 to 72 hours) doxorubicin infusions, generally administered once at the beginning of radiation. Our treatment schema differs considerably, and relies instead on a low-dose continuous doxorubicin infusion designed to provide for continuous radiosensitization. Although direct comparison of the toxicity profiles of these two chemoradiation strategies is difficult (particularly given the differences in tumor site), our data indicate that low doses of doxorubicin given by continuous IV infusion can be safely combined with standard preoperative radiation doses of 50.4 Gy. We also used EB-IORT to deliver an intraoperative radiation boost immediately after surgical resection. Our findings with this approach seem to be similar to those observed by other investigators in several respects.13,14 First, EB-IORT cannot be used in all patients for whom the technique is planned. We were able to deliver the IORT boost in 76% of patients who had surgery. This is somewhat higher than the 46% and 54% rates reported by Gieschen et al14 and Jones et al13 for intraoperative and postoperative (low-dose brachytherapy) boosts, respectively. Anatomic considerations, logistic issues, the boost technique itself, and the complexity of the primary tumor resection often influence the feasibility of a planned intraoperative or postoperative radiation boost. Second, complications that were believed to be related to the IORT boost were rare. One patient (5%) developed posttreatment ureteral strictures that were believed to be related in part to the IORT. Other investigators have also reported this complication.14,15 It seems reasonable to suggest that caution should be used when incorporating previously irradiated and operatively dissected ureters into an intraoperative or postoperative radiation field. We did not experience any episodes of postoperative IORT-related neuropathy, which has been reported by others.14,15,17 We speculate that this may be related to our avoidance of multiple fields and the fact that we did not use misonidazole or any other radiation sensitizer during the intraoperative boost. On the basis of our findings, and those of others, we believe that an IORT boost can be delivered safely with minimal risk for intraoperative or postoperative complications. This seems to be distinct from a postoperative radiation boost delivered by low-dose brachytherapy—a technique that is associated with a significant risk of complications. 13 We could not assess the potential therapeutic benefit of IORT. However, given the theoretical advantages, feasibility, and relative safety of an intraoperative boost, additional investigations of IORT and other strategies to increase the therapeutic index of external-beam radiation seem to be well founded. In summary, this report demonstrates the feasibility and relative safety of a combined-modality program of low-dose infusional doxorubicin with concurrent external-beam radiation to doses of 46.8 to 50.4 Gy followed by surgery and IORT for patients with retroperitoneal STS. Our report, combined with the recently published report from Jones et al,13 provides convincing evidence to support the impression that, despite the large treatment volumes required, preoperative radiation and chemoradiation are reasonably well tolerated in patients with retroperitoneal STS. These phase I data and the local control benefit seen in phase III trials of surgery plus radiation for extremity STS2,3 provide more support for a future phase III trial to more definitively address the toxicities and therapeutic benefits of preoperative combined-modality therapy for patients with retroperitoneal STS.
Supported by the University of Texas M.D. Anderson Cancer Center. There was no industry funding for this protocol.
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2. Pisters PW, Harrison LB, Leung DH, et al: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 14:859–868, 1996
3. Yang JC, Chang AE, Baker AR, et al: A randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16:197–203, 1998 4. Pisters PWT, O’Sullivan B: Retroperitoneal sarcomas: Combined-modality treatment approaches. Curr Opin Oncol 14:400–405, 2002[CrossRef][Medline] 5. O’Bryan RM, Baker LH, Gottlieb JE, et al: Dose response evaluation of adriamycin in human neoplasia. Cancer 39:1940–1948, 1977[CrossRef][Medline] 6. Eilber FR, Giuliano AE, Huth JH, et al: Neoadjuvant chemotherapy, radiation, and limited surgery for high grade soft tissue sarcoma of the extremity, in Ryan JR, Baker LO (eds): Recent Concepts in Sarcoma Treatment. Dordrecht, The Netherlands, Kluwer Academic, 1988, pp. 115–122 7. Goodnight JEJ, Bargar WL, Voegeli T, et al: Limb-sparing surgery for extremity sarcomas after preoperative intraarterial doxorubicin and radiation therapy. Am J Surg 150:109–113, 1985[CrossRef][Medline] 8. Levine EA, Trippon M, DasGupta TK: Preoperative multimodality treatment for soft tissue sarcomas. Cancer 71:3685–3689, 1993[CrossRef][Medline] 9. Wanebo HJ, Temple WJ, Popp MB, et al: Preoperative regional therapy for extremity sarcoma: A tricenter update. Cancer 75:2299–2306, 1995[CrossRef][Medline] 10. Toma S, Palumbo R, Vincente M, et al: Concomitant doxorubicin (DOXO) by continuous infusion (CI) and radiotherapy (RT) at low doses in locally advanced and/or metastatic soft tissue sarcomas (STS): Long-term results of a phase II study. Proc Am Soc Clin Oncol 14:520, 1995 (abstr 1709) 11. Lokich J, Bothe A, Zipoli T, et al: Constant infusion schedule for adriamycin: A phase I–II clinical trial of a 30-day schedule by ambulatory pump delivery system. J Clin Oncol 1:24–28, 1983[Abstract]
12. 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 92:205–216, 2000 13. Jones JJ, Catton CN, O’Sullivan B, et al: Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 9:346–354, 2002[CrossRef][Medline] 14. Gieschen HL, Spiro IJ, Suit HD, et al: Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 50:127–131, 2001[CrossRef][Medline] 15. Petersen IA, Haddock MG, Donahue JH, et al: Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys 52:469–475, 2002[CrossRef][Medline] 16. Eilber FR, Giuliano AE, Huth JF, et al: Intravenous (IV) vs. intraarterial (IA) Adriamycin, 2800 radiation and surgical excision for extremity soft tissue sarcomas: A randomized prospective trial. Proc Am Soc Clin Oncol 9:309, 1990 (abstr 1194)
17. Sindelar WF, Kinsella TJ, Chen PW, et al: Intraoperative radiotherapy in retroperitoneal sarcomas: Final results of a prospective, randomized, clinical trial. Arch Surg 128:402–410, 1993 Submitted January 23, 2003; accepted May 23, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
90%. A microscopically positive surgical margin was defined as tumor extending to the inked margin. 
