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10.1245/s10434-006-9248-9
Annals of Surgical Oncology 14:577-582 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Complications Associated with Neoadjuvant Radiotherapy in the Multidisciplinary Treatment of Retroperitoneal Sarcomas

Abigail S. Caudle, MD1, Joel E. Tepper, MD2, Benjamin F. Calvo, MD1, Michael O. Meyers, MD1, Lav K. Goyal, MD2, William G. Cance, MD3 and Hong Jin Kim, MD1

1 Department of Surgery, Division of Surgical Oncology, University of North Carolina School of Medicine, 3010 Old Clinic Building, CB #7213, Chapel Hill, NC 27599, USA
2 Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
3 Department of Surgery, University of Florida, Gainesville, FL 32610-0286, USA

Correspondence: Address correspondence and reprint requests to: Hong Jin Kim, MD; E-mail: kimhj{at}med.unc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Introduction: Retroperitoneal sarcomas (RPS) remain a therapeutic challenge due to high local recurrence rates. Preoperative RT offers theoretical advantages in the multidisciplinary care of RPS. The purpose of our study was to evaluate our experience using preoperative radiotherapy (PRT) in the treatment of RPS.

Methods: This is a single-institution review of patients with RPS treated with PRT from 1994 until 2004. Three radiation oncologists and four surgical oncologists were involved. Medical records, tumor registries, and death records were reviewed.

Results: Fourteen patients were included; nine were treated for primary presentation and five for recurrent disease. Histologic grade was grade I (n = 3), grade II (n = 3), and grade III (n = 8). Five patients received additional IORT. Radiotherapy complications were generally mild, including nausea (n = 3), diarrhea (n = 1), dehydration (n = 1), anemia (n = 1), and skin changes (n = 1); one required early cessation due to nausea. Thirteen patients had gross negative margins; while 7/13 had negative microscopic margins. Operative complications included anastomotic bleeding (n = 1), fluid collections (n = 2), ileus (n = 3), ascites (n = 2), temporary leg weakness (n = 1), and uncomplicated wound infections (n = 2). In patients with R0 or R1 resections, one and two year local control rates were 64 and 50%. Overall survival for all patients was 90% at 1 year and 74% at 2 years with median survival of 21 months.

Conclusion: PRT and IORT can be administered effectively in carefully selected patients with resectable RPS. Larger multi-center studies are needed to delineate the role of PRT and IORT to improve local recurrence and survival rates in the treatment of RPS.

Key Words: Retroperitoneal sarcoma • Radiotherapy • Complications


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Retroperitoneal sarcomas (RPS) represent a therapeutic challenge to clinicians for many reasons. Complete resection remains the mainstay of treatment, but this is complicated by the fact that patients often present with large tumors encroaching on other vital organs making it difficult or impossible to attain negative surgical margins. The juxtaposition of tumor and normal structures also makes adjuvant locoregional modalities such as radiotherapy (RT) challenging. Given these constraints, it is not surprising that local recurrence rates are high. Because of the small numbers of patients and the variability in histology, it has been difficult to conduct well-designed, prospective trials of adjuvant therapies. Postoperative radiotherapy is not routinely used since the small single-institutional studies evaluating postoperative radiation in RPS have given mixed results and high complication rates.1–4 Randomized trials have shown the benefit of radiotherapy in extremity soft tissue sarcomas by allowing higher limb salvage rates and lower local recurrence rates,5,6 but this has not been established in abdominal locations.

Preoperative RT has several theoretical advantages in the management of these patients. Treating the field before resection allows for improved tissue oxygenation and theoretically may reduce the risk of tumor seeding during surgery. Most importantly, having the large tumor in situ displacing normal structures allows the radiation oncologist to more accurately plan the radiation fields with a lower dose delivered to normal tissues. Concerns about impaired wound healing and the delay to surgery have hindered the widespread acceptance of this treatment algorithm. A prospective, randomized, multi-institutional trial, ACOSOG Z9031, was established in an effort to delineate the role of preoperative radiotherapy in the care of these patients. Despite early enthusiasm, however, the trial was closed secondary to slow accrual. The focus of our study was to determine the feasibility and morbidity of preoperative radiation plus resection in patients with large, marginally resectable RPS.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This is a single institution retrospective review of patients with retroperitoneal sarcomas treated with preoperative external beam RT in addition to surgical resection. Approval was granted by our institutional review board before initiation of the study. Four fellowship-trained surgical oncologists and three radiation oncologists were involved. Patients were identified by reviewing operative case logs, the North Carolina Tumor Registry, and radiation databases. Clinic notes, operative reports, hospital medical records, pathology and radiology reports, and social security death records were reviewed. Factors analyzed include age, sex, past medical history, primary or secondary presentation, radiation and chemotherapy toxicities, operative details, intraoperative radiation details, margin status, histopathologic findings, and postoperative complications. Therapeutic plans were determined by a multidisciplinary tumor board, which includes surgical oncology, radiation oncology, medical oncology, radiology, and pathology.

Preoperative RT was designed using three-dimensional CT scans. Target volume was gross tumor volume plus a margin that varied according to tumor anatomic associations. Emphasis was placed on coverage of the area of retroperitoneal origin of the tumor and other areas of local invasion. If a kidney was in the planned radiation field, a renal scan was performed before initiation of therapy to determine the contralateral renal function. If this scan demonstrated adequate function, and the involved kidney was going to be resected, it was not protected from the radiation field. A total goal of 4,500–5,040 cGy in 180 cGy fractions was used. The dose was adjusted as needed for toxicities.

Patients were taken to surgery 4–6 weeks after completion of external beam RT with the goal to remove all gross disease in an en-bloc resection. Involved viscera were removed as required with the assistance of other surgical specialties such as urology, vascular, and plastic surgery as appropriate.

Intraoperative RT (IORT) was added to the treatment plan at the discretion of the treating team. One thousand two hundred and fifty to 1,500 cGy was administered to the tumor bed after resection with care to exclude normal organs. A Mobetron (IntraOp Medical, Santa Clara, CA, USA) linear accelerator in a dedicated surgical suite was used.

All specimens were evaluated by a surgical pathologist with results reviewed weekly by our multidisciplinary tumor board. Patients were followed postoperatively in the surgical and radiation oncology clinics at intervals determined by the treating physician.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fourteen patients were included in this study. Fifty-seven percent were male and 43% female with a mean age of 53 years (range 45–68). Nine patients were treated for their primary presentation and five for recurrent disease. One of the patients in the primary group was referred after an incomplete resection. Co-morbid conditions included a history of Stage IIB Hodgkins lymphoma (n = 1), Raynaud’s syndrome (n = 1), Hashimoto’s thyroiditis (n = 1), coronary artery disease (n = 1), diabetes mellitus (n = 1), ulcerative colitis (n = 1), drug abuse (n = 1), and hepatitis C (n = 1). Three patients received chemotherapy prior to their surgery. (Table 1Go)


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  		TABLE 1. Demographics
 
Six patients reported toxicities related to their preoperative RT, with one requiring early cessation of radiotherapy. These included mild nausea (n = 2), nausea limiting therapy (n = 1), diarrhea (n = 1), dehydration requiring intravenous fluids as an outpatient (n = 1), anemia requiring transfusion (n = 1), and skin changes (n = 1). Five patients received IORT in addition to their preoperative RT in doses ranging from 1,250 to 1,500 cGy. Two additional patients were scheduled for IORT but did not receive it because their disease was thought to be too extensive.

At the time of operation, thirteen patients had grossly negative margins with one having a R2 resection. Of the patients with grossly negative margins, six had microscopically positive margins. Organs resected during surgery include small bowel (n = 2), colon (n = 4), duodenum (n = 3), pancreas (n = 2), kidney (n = 9), liver (n = 2), spleen (n = 3), IVC (n = 3), and iliac vessels (n = 1). Median tumor size was 16.9 cm (8–34). The tumors were classified as liposarcoma (n = 6), leiomyosarcoma (n = 6), rhabdomyosarcoma (n = 1), and adenosarcoma (n = 1). Histologic grade was grade III (n = 8), grade II (n = 3), and grade I (n = 3) (Table 2Go).


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  		TABLE 2. Histopathology
 
Average hospital stay was 8.9 days (range 6–16). Post-operative complications occurred in ten patients. These included ileus requiring re-admission (n = 3), anastomotic bleed requiring transfusion (n = 1), fluid collections treated with percutaneously placed drain (n = 2), ascites requiring shunt placement (n = 1), chylous ascites managed as an outpatient with bowel rest and total parenteral nutrition (n = 1), leg weakness which improved with physical therapy (n = 1), and wound infections which healed with wound packing (n = 2). There were no perioperative deaths (Table 3Go).


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  		TABLE 3. Complications
 
Though there is limited follow-up, the data is promising. In patients with R0 or R1 resections, 1 and 2 year local control rates were 64 and 50%. Six patients are currently NED at median follow-up of 11 months. Of the patients with known recurrence, time to recurrence was 17 months for primary disease and 8 months for those treated for recurrent disease. Overall survival for all patients was 90% at 1 year and 74% at 2 years with a median survival of 21 months. Nine patients are still alive at a median of 19 months follow-up (Table 4Go).


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  		TABLE 4. Outcomes
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Known prognostic factors for RPS include surgical resectability, histologic grade, size, and gross/microscopic margin status.7–10 While histologic grade is a fixed constant, efforts to improve margin status should improve local recurrence rates and presumably survival. Adjuvant radiation is a logical adjunct to surgical resection to improve local recurrence rates with several studies showing reduced local failure rates with the addition of radiation treatments.8,11 Several adjuvant regimens have been studied including preoperative, intraoperative, post-operative, external beam radiation as well as brachytherapy. While there may be an advantage to post-operative EBRT,12 this benefit is only seen when high doses can be administered.1 Unfortunately, in the post-operative setting, delivering high doses to the tumor bed is limited by tolerance of normal structures in that space such as small intestine, kidneys, and spinal cord. Intraoperative radiotherapy has been added in an attempt to overcome these dose limitations.13,14

Preoperative RT has several theoretical advantages. The tumor acts as a natural tissue expander displacing normal organs out of the radiation field, which allows for more accurate dose targeting and higher dose administration. This is especially critical with mobile small bowel that would be particularly vulnerable to the toxic effects of radiation in the treatment field. Treating the tumor in situ clearly facilitates planning of the treatment field. With the vasculature undisturbed by surgical resection, there may also be improved tissue oxygenation in the pre-operative setting, a key in maximizing the effects of radiotherapy. Another consideration is that preoperative therapy can convert unresectable tumors into resectable as shown by one study in which four of a total of fourteen patients who had been deemed unresectable at first exploration were able to be completely resected after radiation.15 Finally, the ability to measure responses to therapy in situ enables us to gather valuable information regarding the biology of the disease, as well as the opportunity to obtain tissue for translational scientific studies. Because of these benefits, there has been increased interest in evaluating preoperative XRT.16–19

There is a clear precedent that neoadjuvant strategies in other malignancies does not result in significantly increased perioperative morbidity or mortality rates. Certainly, this has become the standard of care for locally-advanced rectal cancer. Preoperative chemoradiation for rectal cancer is associated with decreased acute toxicity when compared to postoperative treatments.20 Chessin et al.21 found an operative complication rate of 33% in their group of 297 patients with the most common ones being bowel obstruction (11%), and wound infection (10%). The German Rectal Cancer Study Group22 actually reported a lower rate of grade 3 or 4 radiation toxicities in the preoperative chemoradiation group, with no difference in postoperative morbidity or mortality. Similarly, there is emerging data supporting the neoadjuvant approach in the treatment of resectable or marginally-resectable pancreatic adenocarcinomas. Several prospective neoadjuvant chemoradiation trials have been completed at the M.D. Anderson Cancer Center; although there was significant toxicity and hospitalization rates associated with the various neoadjuvant approaches, there was no significant increases in the perioperative complication rates for those undergoing resection.23–25 In patients undergoing neoadjuvant chemoradiation for periampullary malignancies (n = 79), operative mortality (3.8%) compared favorably to comparable patients undergoing resection alone (4.5%).26 In fact, a recent study from Duke University found a lower incidence of anastomotic leaks and abcesses after pancreaticoduodenectomy in the group that underwent neoadjuvant chemoradiation.27 Given the acceptable morbidity in these similar abdominal sites, it is reasonable to apply this approach to the treatment of retroperitoneal sarcomas.

The purpose of our study was to evaluate the feasibility and safety of administering RT in the preoperative setting. Several centers have reported their results with different regimens. Pisters et al.18 have reported a Phase I study of preoperative chemoradiotherapy and IORT in 35 patients. Their study used doxorubicin as a radiosensitizer with escalating doses of 18, 30.6, 41.4, 46.8, or 50.4 Gy in 1.8-Gy fractions. Radiation toxicities increased with dose escalation including four patients who required hospitalization for dehydration or bleeding. Minimal complications were seen in those receiving 18–46.8 Gy, but this rose at the maximum dose with 18% of the 11 treated with 50.4 Gy experiencing grade 3 or 4 nausea and 27% with grade 3 or 4 hematologic toxicities. Eighty-nine percent completed the treatment planned, and only one postoperative complication was noted: ureteral stricture in a patient who received IORT in addition to the preoperative regimen. Another study from the University of Michigan used a neoadjuvant regimen of dose-escalation iododeoxyuridine and concurrent radiotherapy with a goal dose of 62.5 Gy administered in 1.25 Gy fractions twice daily. Seventy-five percent received the maximum radiation doses and an additional patient completed a planned lower dose because of the tumor location. Of note, only one of the three remaining patients had early cessation of this high dose secondary to toxicities. Dose reduction of the chemotherapy, however, was much more common. Long term complications included biliary stricture, ureteral obstruction, small bowel obstruction, and CSF leak.19 Jones et al.16 also found that preoperative RT doses of 42–50 Gy were well tolerated in their 55 patients with no patients requiring hospitalization or early cessation of treatment. Their postoperative complications are difficult to compare to our study because of the addition of brachytherapy in their regimen, which added marked morbidity and mortality with three deaths and seven patients suffering life-threatening illnesses. Gieschen et al.17 describes complications in four patients who received IORT including neuropathy, vaginal fistula, uretero-arterial fistulas, and hydronephrosis, but do not specify complications in patients treated with external beam RT alone. A recent study from the University of Florida comparing patients who received preoperative versus postoperative RT found that the postoperative group had more significant complications than the preoperative group.3

Most of the complications and toxicities in our patients were minor. In the preoperative phase, over 90% were able to complete the prescribed therapy. Two patients required some sort of intervention (one for IVF and one for transfusion), but none required hospitalization. Postoperative complications were also predominantly mild. Only one patient required another operation (shunt for ascites). Four patients required additional hospitalization: three for dehydration, and one for percutaneous drainage of a peripancreatic fluid collection. The wound infections were easily treated with simple packing. Though our numbers are small, early follow-up results are in line with other published reports. We plan to continue to follow these patients in an effort to make future comments concerning survival and local recurrence rates.

We conclude that preoperative radiation has several theoretical advantages in the management of patients with large, marginally resectable RPS. This neoadjuvant approach can be administered effectively, with reasonable complications rates.

Received for publication August 8, 2006. Accepted for publication August 31, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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