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Annals of Surgical Oncology 9:535-542 (2002)
© 2002 Society of Surgical Oncology

EDUCATIONAL REVIEW

Preoperative Chemoradiation Treatment Strategies for Localized Sarcoma

Peter W. T. Pisters, MD, Matthew T. Ballo, MD and Shreyaskumar R. Patel, MD

From the Multidisciplinary Sarcoma Center, The University of Texas M. D. Anderson Cancer Center Houston, Texas.

Correspondence: Address correspondence and reprint requests to: Peter W. T. Pisters, MD, Department of Surgical Oncology, Box 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009; Fax: 713-792-7829; E-mail: ppisters{at}mdanderson.org

ABSTRACT

Background: Over the past 2 decades, there has been increasing interest in chemoradiation treatment strategies for patients with soft tissue sarcomas. Investigators have evaluated: (1) the optimal route for chemotherapy administration (intra-arterial vs. intravenous); (2) the possible advantages of protracted infusion of the radiosensitizer versus brief infusion; (3) the efficacy and toxicity of various intravenous and oral radiation sensitizers; and (4) the efficacy of sequential versus concurrent combined modality treatment.

Methods: The English-language literature addressing chemoradiation for localized and locally advanced extremity and retroperitoneal sarcomas was reviewed.

Results: All studies have been pilot, phase I, or phase II designs. The most commonly used radiosensitizer for concurrent chemoradiation has been doxorubicin, administered intravenously in most recent reports. In the studies that have included assessment of recurrence-free survival, preoperative chemoradiation combined with surgery has resulted in favorable local control rates, often in excess of 90% for patients with localized and locally advanced extremity sarcomas.

Conclusions: The toxicities and recurrence-free outcome with chemoradiation plus surgery for soft tissue sarcoma still need to be compared to these with surgery and pre- or postoperative radiation. However, the generally favorable local control rates reported for chemoradiation justify continued investigation of preoperative chemoradiation strategies for localized sarcoma.

Key Words: Soft tissue sarcoma • Chemoradiation • External-beam radiation • Radiosensitizer • Retroperitoneal sarcoma

Over the past 2 decades, there has been evolving interest in chemoradiation treatment strategies for solid tumors, and this interest has extended to soft tissue sarcoma (STS). Several groups are investigating chemoradiation for localized and locally advanced STS. These efforts have been focused largely on the treatment of patients with extremity STS but have also included some patients with retroperitoneal sarcomas. Studies of chemoradiation and surgery for STS have been restricted to pilot, phase I, and phase II trials. To date, no phase III trials have compared this therapeutic approach with standard local therapy (surgery with pre- or postoperative radiation).

This article reviews the use of concurrent chemoradiation and sequential chemotherapy and radiation for extremity and retroperitoneal STS. Extremity and retroperitoneal sarcomas will be considered separately because the treatment and toxicity considerations for them differ substantially.

CHEMORADIATION FOR EXTREMITY STS

For patients with localized, high-risk extremity STS, the primary therapeutic goals of chemoradiation are the same as for local treatment of extremity STS: to maximize local control and to minimize amputation rates. A secondary goal is to provide initial systemic treatment of potential micrometastatic disease; patients with localized, high-risk extremity STS have an approximately 50% risk of harboring subclinical micrometastatic disease at presentation. It is believed that early treatment of micrometastases and/or improved locoregional tumor control may improve recurrence-free or even overall survival in these patients.

Historical Perspective on Preoperative Concurrent Chemoradiation
The initial experience with preoperative concurrent chemoradiation for extremity sarcoma was reported by Eilber and colleagues from the University of California, Los Angeles (UCLA).1,2 Their preliminary studies involved intra-arterial doxorubicin combined with high dose-per-fraction radiotherapy. Because those studies were done during an era when amputation rates were in the 20% to 40% range,3 the 5% amputation rate reported by Eilber and colleagues represented a substantial improvement in overall limb salvage. As a consequence of the very favorable local control and low amputation rates, this therapeutic approach was adopted by several centers, 4–7 which have subsequently reported similar treatment results using regimens similar to that of Eilber and colleagues.

The initial treatment protocol described by the UCLA group involved doxorubicin (20 to 30 mg/day over 3 days) delivered by continuous intra-arterial infusion.1 External-beam radiotherapy at a total dose of 35 Gy was provided concurrently using a fractionation scheme (10 fractions) that has subsequently been termed "rapid fractionation" because of the combination of a higher dose per fraction, reduced total number of fractions, and reduced length of treatment compared with standard-fractionation radiation regimens.8,9 Seventy-seven patients with high-risk disease (84% grade 3, 22% locally recurrent disease) were treated. Following preoperative chemoradiation, only three patients (4%) required amputation. With a median follow-up of 8 years, only four patients (5%) experienced local tumor recurrence. However, toxicity was substantial, with 33 patients (43%) experiencing treatment-related complications. In 18 patients (23%), a second operation was required to treat the complications. Complications included wound slough in 15 patients (19%) and adjacent long bone fracture in eight patients (10%). These toxicity rates were believed to be unacceptably high, and a subsequent treatment protocol was developed that reduced the radiation dose by 50%.

In a follow-up study from UCLA, 137 patients were treated with the same intra-arterial doxorubicin regimen combined with a lower dose of 17.5 Gy (5 fractions) of concurrent external-beam radiotherapy.1 The toxicity of the therapy was substantially reduced compared with that of the earlier treatment protocol, with 35 (26%) of 137 patients developing major complications. Only eight patients (6%) required reoperation for complications, and two patients (1%) experienced fractures of adjacent long bones. However, with a median follow-up of 48 months, 17 patients (12%) developed a local recurrence. This local recurrence rate was statistically and significantly inferior to the previously noted 5% local recurrence rate for the group treated with 35 Gy, suggesting that the reduction in the external-beam radiation dose compromised local control. For this reason, subsequent patients treated with chemoradiation at UCLA have received 28 Gy.

Efficacy
On the basis of the encouraging limb salvage and local control rates reported by Eilber and colleagues, other investigators have modified the UCLA chemoradiation regimen and reported results with meaningful follow-up (Table 1).4–7,10


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  		TABLE 1. TABLE 1. Local failure with doxorubicin-based concurrent chemoradiation for extremity STS
 
In one study, investigators from the University of Illinois treated 55 patients with a 10-day preoperative regimen of intra-arterial doxorubicin (10 mg/m2/day) with concurrent external-beam radiotherapy (25 Gy in 10 fractions).5 The local failure rate for this cohort was 15%, quite similar to that reported by Eilber et al. using the 17.5-Gy regimen. Other groups have continued to use radiation doses of 30 Gy or higher in response to the nonrandomized data suggesting inferior local control with lower radiation dose approaches. Three reports (two may contain overlapping patients)6,7 have observed local failure rates of <5% using concurrent chemoradiation regimens similar to the original UCLA regimen (i.e., radiation doses >=30 Gy).4,6,7 This local control rate of more than 95% seems more favorable than the expected 60% to 90% range of local control rates for patients with locally advanced STS.11,12 Whether the favorable local control rates reported with chemoradiation plus surgery are due to selection bias, a bona fide difference in treatment efficacy, or a combination of these factors is uncertain.

Toxicity
Local toxicities of chemoradiation depend on a number of factors, including the specific chemotherapeutic agent, route of chemotherapy administration, and radiation dose/fractionation regimen. Tumor-related factors, especially anatomic site and tumor size, may also impact local complication rates.

The postoperative wound complication rates associated with preoperative intra-arterial doxorubicin and rapid-fractionation radiotherapy regimens are high. In the UCLA experience, major complications occurred in 26% of patients who received 17.5 Gy and required further operative management in 6%.1 The majority of these complications were wound complications that often required reoperation and occasionally required secondary amputation. However, this wound complication rate needs to be interpreted in the context of the period during which the studies were performed. Multidisciplinary surgical resection with reconstruction by rotational or free transfer of autologous tissue may not have been universally available during the 1970s and early 1980s, so wound complication rates may have been higher than they would be in most specialty centers today.

Technical Issues in Chemoradiation Regimen Design
Several issues related to the design of chemoradiation treatment schemas merit comment. These include the route of chemotherapy administration, duration of chemotherapy infusion (brief vs. extended), and the sequencing strategy for administration of chemotherapy and radiation (concurrent vs. sequential).

Intravenous Versus Intra-Arterial Route
Intravenous administration of the chemotherapeutic agents has been examined as a way to minimize the complications associated with arterial infusion. The comparative efficacy and complication rates associated with intra-arterial versus intravenous concurrent chemoradiation were evaluated in a phase III study performed by the UCLA group.2 Ninety-six patients with localized, high-risk extremity STS were randomly assigned to receive intra-arterial doxorubicin (30 mg/day by continuous infusion for 3 days) or intravenous doxorubicin (30 mg/day by continuous infusion for 3 days). Both groups received concurrent rapid-fractionation external-beam radiotherapy (28 Gy in 8 fractions). There were no significant differences in the rates of limb salvage, local recurrence, complications, or histologically evident necrosis between the two treatment groups (median follow-up, 3 years). The investigators concluded that there was no advantage to intra-arterial therapy, which is more complicated to deliver and has greater potential morbidity than intravenous therapy. On the basis of these results, most groups have switched to intravenous administra-tion of chemotherapeutic agents during concurrent chemoradiation.

Brief Versus Extended Chemotherapy Infusion
The majority of published clinical research investigating concurrent chemoradiation has involved a short duration (typically 3 days) of intra-arterial or intravenous doxorubicin infusion combined with concurrent rapid-fractionation radiotherapy (Table 1). This approach relies predominantly on the cytotoxic effect of doxorubicin at therapeutic doses but also provides a limited period of doxorubicin-based radiosensitization. The half-life of doxorubicin is on the order of 24 hours, thereby limiting the window of radiosensitization to approximately 4 days using a 3-day doxorubicin infusion.

Continuous intravenous infusion is an alternative treatment strategy that maximizes the duration of radiosensitization by providing the drug at a lower daily dose for the entire duration of radiotherapy. This approach was employed by investigators at the University of Genoa in a recently reported phase II study for patients with locally advanced STS.10 Doxorubicin (12 mg/m2/day) was provided by continuous infusion over 5 days concomitantly with external-beam radiotherapy (7.5 to 10 Gy in 5 fractions). This 5-day cycle was repeated every 2 to 3 weeks for 2 or 3 cycles. Toxicity was acceptable, with no patients experiencing grade 3 or 4 leukopenia or symptomatic cumulative cardiotoxicity. The overall objective response rate was 56% (19 of 34 patients), with three complete (9%) and 16 partial responses (47%). No patient experienced disease progression with this regimen. These preliminary response rates are quite encouraging and certainly approach the response rates reported for multiagent high-dose chemotherapy regimens that are associated with substantially more toxicity.13,14 Based on this report and the general adoption of completely concurrent chemoradiation regimens for many gastrointestinal cancers, continuous infusion concurrent chemoradiation is being actively pursued for patients with localized and locally advanced STS in a number of centers.

Sequential Chemotherapy and Radiotherapy
The Radiation Therapy Oncology Group recently completed a phase II multi-institutional trial (RTOG 95–14) of preoperative sequential chemotherapy and split-course radiation for patients with localized high-risk extremity STS.15 The study was based on encouraging single-institution results with sequential treatment.16 The RTOG trial evaluated a preoperative combined-modality regimen consisting of 3 cycles of doxorubicin, ifosfamide, dacarbazine, and mesna; the first 2 cycles were alternated with two 22-Gy courses of radiation (11 fractions each), for a total preoperative radiation dose of 44 Gy. This was followed by surgical resection with microscopic assessment of margins. An additional 16-Gy boost dose was delivered for microscopically positive surgical margins. Sixty-six patients were treated on this protocol; toxicity results have been reported in a subset of 41 patients.15 Observed toxicities were significant, with 27 (66%) and 12 (29%) of 41 patients experiencing grade 4 neutropenia and thrombocytopenia, respectively. Notwithstanding these toxicities, 88% of patients completed preoperative chemotherapy, and 93% completed preoperative radiotherapy. The 2-year actuarial overall survival rate was 95% at a median follow-up of 2.4 years. Although this preliminary report will require further follow-up, the encouraging survival data support additional studies of sequential chemoradiation for patients with localized, high-risk sarcoma.

Novel Radiosensitizers: Idoxuridine, Razoxane, and Ifosfamide
The majority of published reports of concurrent chemoradiation for STS have involved doxorubicin as the radiosensitizer. However, investigators have evaluated other radiosensitizing agents, including idoxuridine (IdUrd), razoxane, and ifosfamide in patients with extremity and nonextremity sarcomas.

IdUrd is a thymidine analogue that is incorporated into the DNA of proliferating cells in place of thymidine, increasing the susceptibility of those cells to the cytotoxicity of ionizing radiation. The evaluation of this agent as a radiosensitizer in the combined-modality treatment of patients with sarcoma was based on data in other tumor types17,18 and preliminary studies of IdUrd with hyperfractionated radiotherapy in patients with locally advanced sarcomas.19 Sondak and colleagues at the University of Michigan have reported results of a phase I/II trial of preoperative IdUrd plus radiotherapy for patients with high-risk STS.20 Tumors were located in the extremities (n = 13), retroperitoneum (n = 20), head or neck (n = 2), or mediastinum (n = 2). Thirty-seven patients were treated with 3 or 5 cycles of intravenous IdUrd infusions (1000 to 1600 mg/m2/day for 5 days) alternating weekly with twice-daily (hyperfractionated) radiation (1.25 to 1.5 Gy per fraction) and were then evaluated for resection. The total preoperative radiation dose ranged from 62.5 to 75.0 Gy. The dose-limiting toxicity was stomatitis, which was encountered at the 1600 mg/m2/day dose but not at lower doses. Five patients (14%) had partial responses, and 28 patients (76%) underwent successful resection of the postchemoradiation tumor mass. With a median follow-up of 5.8 years, local control was achieved in 19 (68%) of 28 patients who underwent resection. In addition, histologically negative margins were achieved in 13 (46%) of the patients who underwent resection (70% of patients with extremity tumors who underwent resection) despite the fact that patients were entered into this study on the basis of pretreatment imaging studies that were believed to indicate that resection with negative margins was not possible.

Another agent studied for its radiosensitizing effect is razoxane, an oral radiosensitizer that arrests dividing cells in the G2 or G2/M phase of the cell cycle, the phase most sensitive to irradiation.21 In addition, razoxane shows a strong angiogenic effect on the developing tumor vasculature in animal models. This effect could lead to improved oxygenation of tumor tissue, a factor known to enhance radiation-related cytotoxicity. The efficacy of razoxane as a radiosensitizer in the treatment of STS was evaluated in a recent multicenter phase III trial performed in a heterogeneous group of patients with STS that had undergone gross complete resection (n = 48) or had unresectable or residual gross disease (n = 82).22 Patients were randomly assigned to receive radiotherapy alone or radiotherapy plus razoxane. Patients in the razoxane group received 150 mg/m2 razoxane daily by mouth beginning 5 days before the first radiation dose and continuing until completion of radiotherapy. The results were stratified by whether patients received adjuvant treatment following complete resection or received treatment for gross residual disease after surgery. Among the 48 patients who received postoperative therapy after gross complete resection, there were no substantial differences in local control or survival between the patients who did or did not receive razoxane. In the subset of 82 patients treated for gross residual disease, treatment with radiotherapy and razoxane was associated with an increased response rate (74% vs. 49%) and improved local control rate (64% vs. 30%; P < .05) compared with radiotherapy alone. Hematologic toxicities were more common in the razoxane group as a result of razoxane-mediated bone marrow suppression. Unfortunately, the trial design did not adequately stratify for known prognostic factors, and thus there was a maldistribution of prognostic factors between the treatment and control groups that obscures interpretation of the results. Therefore, no specific recommendations can be made regarding razoxane-based concurrent chemoradiation. However, further studies of this agent are warranted on the basis of the findings in patients with gross residual disease.

Another agent under evaluation is ifosfamide, which has well-defined activity against many types of STS and is known to have radiosensitizing properties.23,24 Several groups have investigated ifosfamide and concurrent irradiation treatment (Table 2).23,25–29 The majority of these studies have been in patients with small-cell sarcomas or in pediatric patients with rhabdomyosarcoma (as part of the Intergroup rhabdomyosarcoma studies). As a result, most patients were treated with additional chemotherapy, often including doxorubicin or vincristine. Nevertheless, the findings provide evidence that ifosfamide can be administered together with radiation with an acceptable overall toxicity profile and encouraging pathologic response rates.


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  		TABLE 2. TABLE 2. Ifosfamide and concurrent radiation for STS
 
Cormier and colleagues from The University of Texas M. D. Anderson Cancer Center recently reported toxicities and response rates for ifosfamide-based chemoradiation in 43 patients with STS or bone sarcomas.29 Treatment consisted of external-beam radiotherapy (median dose, 50.4 Gy) with concomitant intravenous ifosfamide (median dose per cycle, 10.2 g/m2); a subset of 14 patients underwent subsequent surgical resection. Twenty-six patients (60%) received 2 or more cycles of ifosfamide; 17 patients (40%) were treated with 1 cycle of ifosfamide and irradiation. The incidences of World Health Organization grade 3 and grade 4 toxicities were 29% (21 of 73 cycles) and 22% (16 of 73 cycles), respectively. Grade 4 systemic toxicities included leukopenia (n = 14), neurotoxicity (suicidal ideation, n = 1), and diarrhea (n = 1). Confluent moist desquamation (grade 3) occurred in nine patients in the treatment field; no patient experienced grade 4 local toxicity. Among 14 patients who underwent subsequent surgical resection, two (14%) had pathologic complete responses, and six (43%) had pathologic near-complete responses (>=90% necrosis). In this retrospective report, local and systemic toxicities following the administration of therapeutic doses of ifosfamide with concomitant external-beam radiotherapy seemed comparable with those observed with either treatment alone. These results thus support the general impression that systemic doses (3.0 to 10.2 g/m2) of ifosfamide can be given with concurrent radiation to doses of 50 Gy or more in pediatric and adult patients. On the basis of these data, additional studies of ifosfamide-based chemoradiation are warranted.

PREOPERATIVE CHEMORADIATION FOR RETROPERITONEAL STS

For patients with localized retroperitoneal STS, complete tumor resection remains the single most important prognostic factor for long-term survival.30 However, owing to the large size of most retroperitoneal STS and the proximity of retroperitoneal and intraperitoneal viscera that make it difficult to achieve satisfactory surgical margins, local recurrence remains the most common form of treatment failure. Given the high risk for local recurrence and the established local control advantage demonstrated for patients with extremity and superficial trunk STS treated with surgery plus radiotherapy,31,32 there is considerable interest in preoperative radiation and chemoradiation for patients with retroperitoneal STS.

Preoperative radiation is favored more than postoperative radiation for patients with retroperitoneal STS because preoperative treatment allows the tumor to be precisely anatomically outlined for radiation planning and because radiosensitive viscera (particularly bowel) are usually displaced outside the treatment field by the tumor mass (Fig. 1). In contrast, when postoperative treatment for similar lesions is contemplated, the bowel and other radiosensitive viscera migrate into the space formerly occupied by the tumor, and this volume is encompassed in the postoperative radiation field. In addition, the small bowel often becomes fixed in location by adhesions, losing its normal mobility and trapping loops of bowel within the intended radiation field. These factors combine to induce dose-limiting toxicity at radiation doses below those believed to be effective in eradicating microscopic residual sarcoma. As a consequence, most combined-modality approaches for retroperitoneal STS involve preoperative radiation.33,34



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  		FIG. 1. Radiotherapy treatment plan for a patient with a large retroperitoneal myxoid liposarcoma. The mass closely abutted the left external iliac vein and displaced the bladder and small bowel to the right. Radiotherapy was delivered to a dose of 50.4 Gy in 28 fractions using anterior and posterior 18 MV photons. As illustrated by this image, the tumor (T) displaced the majority of radiosensitive viscera out of the radiation field allowing the patient to receive radiotherapy without significant toxicity.

 
Investigators from the University of Michigan have reported on 16 patients with large (median, 17 cm) retroperitoneal STS who were treated preoperatively with 3 to 5 14-day cycles of IdUrd (1000 to 1600 mg/m2 by continuous intravenous infusion on days 1 to 5) with sequential twice-daily external-beam radiotherapy (1.25 Gy per fraction on days 8 to 12).35 The only grade 4 acute toxicity noted was vomiting, which occurred in three patients. Eleven patients underwent surgical resection, grossly complete resection in eight patients and subtotal resection in three. Local control was achieved in 3 of 4 patients with microscopically negative surgical margins, 2 of 4 patients with microscopically positive surgical margins, and 1 of 3 patients who underwent subtotal excision. The investigators concluded that 1600 mg/m2 represented the optimal dose of IdUrd and that local control was possible for patients in whom a negative-margin resection could be achieved.

Preliminary reports of doxorubicin-based concurrent chemoradiation for retroperitoneal STS have been reported from UCLA36 and the M. D. Anderson Cancer Center.37 Eilber and colleagues36 at UCLA have treated 23 patients with retroperitoneal STS using high-dose intravenous ifosfamide, doxorubicin, and cisplatin with concurrent radiotherapy (28 Gy). Although details of this study have not been published, a recent review indicated that 6 of 23 (26%) patients have achieved pathologic complete responses with no residual tumor in the subsequently resected specimen.36 At the M. D. Anderson Cancer Center, investigators have reported preliminary results of a phase I study of preoperative doxorubicin-based concurrent chemoradiation with intraoperative radiotherapy for patients with resectable retroperitoneal STS.37 This study was designed to evaluate the toxicities of continuous-infusion intravenous doxorubicin (20 mg/m2/week for 3 weeks) combined with external-beam radiotherapy. The external-beam dose has been escalated from 18 to 50.4 Gy (P.W.T. P., unpublished data, 2002) with minimal treatment-related toxicities.

Preoperative chemoradiation for patients with retroperitoneal STS remains investigational. However, the cumulative experience reported with preoperative chemoradiation combined with additional pilot reports confirming the safety and feasibility of preoperative radiation for patients with retroperitoneal STS33,34 has led to increased interest in this treatment approach. The RTOG has initiated a multi-institutional Intergroup phase II trial of preoperative chemotherapy followed by preoperative radiotherapy and then by surgical resection with an intra- or postoperative radiation boost (RTOG S0124; Fig. 2; www.RTOG.org) for patients with intermediate- or high-grade retroperitoneal STS. This trial will provide important information on the feasibility and toxicities of this treatment approach in a multi-institutional setting. The accrual rates to and results of this trial will help to determine the feasibility of a phase III trial of preoperative combined-modality treatment for patients with retroperitoneal STS.



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  		FIG. 2. Treatment schema for Radiation Therapy Oncology Group (RTOG) S0124, an Intergroup study of preoperative sequential chemoradiation for patients with intermediate-and high-grade retroperitoneal STS. STS, soft tissue sarcoma; Dox, doxorubicin; Ifos, ifosfamide; IO EB-IORT, intraoperative electron-beam radiotherapy; IO HD BRT, intraoperative high-dose brachytherapy; PO HD BRT, postoperative high-dose brachytherapy; PO LD BRT, postoperative low-dose brachytherapy; PO EBRT, postoperative low-dose external-beam radiotherapy.

 
CONCLUSIONS

Despite nearly 2 decades of research, chemoradiation treatment strategies for localized STS remain investigational. Further investigation of these approaches is supported by: (1) the favorable response rates and acceptable toxicity profiles in preliminary reports of extended-duration infusion chemotherapy with concurrent radiation; (2) local control rates in excess of 95% with concurrent (intravenous or intra-arterial) doxorubicin-based chemoradiation for locally advanced STS; and (3) the favorable preliminary survival data from RTOG 95–14. On this basis, studies by several cooperative groups and individual institutions are currently focused on chemoradiation strategies for patients with localized STS. It is hoped that these phase II trials will serve as stepping-stones to a new era of collaborative research for this rare disease.

Received for publication January 9, 2002. Accepted for publication April 25, 2002.

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