Role of Radiation Therapy in Retroperitoneal Sarcoma

Authors: Kilian E. Salerno MD1 and Elizabeth H. Baldini MD, MPH2,3
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  • 1 Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and
  • | 2 Harvard Medical School, and
  • | 3 Sarcoma Center, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, Massachusetts.

Retroperitoneal sarcoma comprises a small subset of all soft tissue sarcoma and includes various histopathologic subtypes, each with unique patterns of behavior and differential risks for local recurrence and hematogenous metastatic spread. The primary treatment modality is surgery, although even with complete macroscopic resection, recurrence is common. The rationale for the addition of radiotherapy to resection is to improve local control; however, the use of radiation therapy for retroperitoneal sarcoma is controversial, and existing data are suboptimal to guide management. Treatment decisions should be determined with multidisciplinary input and shared decision-making. When used in selected patients, radiation therapy should be delivered preoperatively; postoperative treatment is not recommended.

Retroperitoneal Sarcoma

Retroperitoneal sarcoma (RPS) comprises a small subset of all soft tissue sarcoma (STS) and includes various histopathologic subtypes, each with unique patterns of behavior.1,2 Histopathologic subtype and grade significantly influence natural history, prognosis, and risk for local recurrence and hematogenous distant metastatic spread.24 Additional prognostic factors include tumor size and multifocality, patient age and comorbidities, and treatment variables including completeness of resection.2 The pattern of distant spread differs from extremity and truncal sarcoma, as the liver and peritoneum, in addition to lung, are common sites of metastases. The most common histologic subtypes are well-differentiated and dedifferentiated liposarcoma (WDLPS and DDLPS, respectively) and leiomyosarcoma. WDLPS is associated with a high risk of local recurrence and very low risk of distant recurrence, DDLPS is associated with moderate risks of both local recurrence and distance recurrence, and leiomyosarcoma is associated with a high risk of distant recurrence and low risk of local recurrence.2,3

As for all STS, multidisciplinary evaluation prior to treatment initiation by care providers with expertise in sarcoma is recommended for optimal outcomes.512 Multidisciplinary input is recommended to consider the role for radiotherapy (RT) and systemic therapy in addition to resection, and the timing and sequence of such treatments when used.57 Options for local therapy should be assessed jointly by both surgical and radiation oncology. The role of systemic therapy, especially for high-grade tumors and specific histopathologic subtypes (eg, leiomyosarcoma), should be assessed in conjunction with medical oncology.

Surgical Resection

The primary treatment for RPS is surgical resection. Given the complex anatomy of the retroperitoneal space and numerous adjacent critical normal tissues, achieving wide negative margins at resection is often impossible. The intent is for macroscopically complete resection (R0/R1), which may require en bloc removal of tumor with adjacent viscera.5,13,14 The appropriate balance between preservation of organ function and risk of local recurrence is a key consideration in local therapy decision-making, including extent of resection and use of RT. Local recurrence is frequent even with complete macroscopic resection, particularly for WDLPS and DDLPS.24,13,14 Incomplete resections (R2) are not curative.5 The addition of RT does not counter the negative impact of incomplete resection on outcome, and reresection should be considered if feasible.

Rationale for RT

Outcomes for RPS, including overall survival, are determined by distant hematogenous metastatic disease as in extremity and truncal STS, and also significantly impacted by local recurrence and intrabdominal spread. As local recurrence following resection is common, particularly with certain histopathologic subtypes (ie, WDLPS and DDLPS), there is rationale for additional therapeutic options to improve local control. The rationale for RT in the treatment of RPS is extrapolated from the clear local control benefit of RT in addition to resection for extremity and truncal STS.15,16

Despite this rationale, the addition of RT to resection for RPS remains controversial. Given the rarity of RPS, there are limited prospective randomized data to inform decision-making. Nonrandomized prospective studies, multicenter and single-institutional retrospective reports, and large database-derived series have shown conflicting results regarding the role of RT.1723 Some report improved local control with surgery and RT versus surgery alone, whereas others have shown no benefit. Existing studies are heterogeneous, do not stratify by histologic subtype, include both preoperative and postoperative RT, and use various treatment modalities, such as external-beam RT (EBRT), brachytherapy, and intraoperative RT. Meta-analyses evaluating RT for RPS demonstrated improvement in local control, recurrence-free survival, and overall survival with the addition of RT to surgery.24,25

On a trial conducted at the National Cancer Institute (NCI), 35 patients with resected RPS were randomized to either higher-dose postoperative EBRT (5,000–5,500 cGy) or intraoperative electron RT (2,000 cGy) and lower-dose postoperative EBRT (3,500–4,000 cGy).26 Fewer local recurrences occurred on the combined intraoperative and lower-dose RT arm (6 of 15 patients) versus the higher-dose RT arm (16 of 20 patients) (P<.001). Median survival was similar between arms; however, toxicity profiles differed. Significant radiation-related enteritis was more common with higher-dose postoperative RT, and peripheral neuropathy was more common in the combined intraoperative and lower-dose RT group.

The NCI randomized trial remains of historical interest and provides data on local control and postoperative RT toxicity patterns. However, because both arms included RT, this study cannot address the addition of RT to surgery versus surgery alone. Two subsequent prospective randomized studies were initiated to evaluate the role for preoperative RT with resection but were closed prematurely due to poor accrual (RTOG 0124 and ACOSOG Z9031; ClinicalTrials.gov identifiers: NCT00017160 and NCT00091351, respectively).

The EORTC STRASS trial is the only completed randomized controlled trial of preoperative RT and resection versus resection alone (n=266 patients).27 Surgery involved multivisceral en bloc resection with intent for macroscopic negative margins. Preoperative RT was delivered to 5,040 cGy in 28 fractions. The primary outcome was abdominal recurrence-free survival, defined as local, abdominal, or distant progressive disease during RT; tumor or patient becoming inoperable; peritoneal sarcomatosis found at surgery; R2 resection; or local relapse after macroscopically complete resection. With a median follow-up of 43.1 months, the STRASS trial did not show a statistically significant difference in 3-year abdominal recurrence-free survival rate for RT and surgery (60%; 95% CI, 51%–68%) versus surgery alone (59%; 95% CI, 50%–67%) (hazard ratio, 1.01; log-rank P=.95). Unplanned sensitivity analyses were performed, with local progression during RT excluded as an event when patients were able to proceed to macroscopically complete resection. Post hoc analysis by histopathologic subtype and grade suggested a potential improvement in abdominal recurrence-free survival with preoperative RT for liposarcoma and low-grade sarcoma, without similar improvement observed for leiomyosarcoma and high-grade sarcoma. The follow-up is relatively short, especially for WDLPS, in which late recurrence is common. Although the STRASS data do not support routine use of preoperative RT for all patients with RPS, with shared decision-making, preoperative RT and resection may be appropriate in selected circumstances (eg, patients with WDLPS).

Use of RT With Resection

The decision regarding whether or when to add RT to surgery for selected patients should be based on multidisciplinary evaluation and assessment of the relative risks for local recurrence and distant metastatic spread. These risks are influenced by histopathologic subtype, grade, and other prognostic factors. Indication for RT to improve local control is most appropriate in patients with predominant risk for local only recurrence (eg, WDLPS). When used, EBRT should be delivered preoperatively; postoperative RT is generally not recommended given its higher toxicity profile.57,28

Preoperative RT

Preoperative RT may reduce risk of tumor seeding and intraperitoneal dissemination at surgery. The presence of the tumor in situ improves target delineation for planning and often displaces small bowel out of the treatment volume, reducing associated toxicity (Figure 1). Potential disadvantages of preoperative RT include limited histologic sampling and delay to surgery.

Figure 1.
Figure 1.

Preoperative radiotherapy plan to 5,000 cGy for a patient with a large retroperitoneal liposarcoma. The tumor in situ is displacing bowel (turquoise contour) out of the treatment field.

Abbreviation: PTV, planning target volume.

Citation: Journal of the National Comprehensive Cancer Network 20, 7; 10.6004/jnccn.2022.7035

When preoperative RT is used, a patient must have a tumor amenable for macroscopic complete resection, not have symptoms requiring immediate surgery (eg, bowel obstruction), and be able to tolerate RT with acceptable toxicity. Each patient should be counseled regarding rationale for consideration of preoperative RT, risks, and alternatives, including resection alone, for shared decision-making.

The dose for preoperative RT is 5,000 to 5,040 cGy in 25 to 28 fractions.6,27,28 Simulation using motion management techniques such as 4D-CT is recommended for tumors above the pelvic brim.6,28 Intensity-modulated techniques are generally preferred over 3D conformal RT given the complex anatomy and many adjacent normal tissues.5,6,2830 It is important that the plan for resection, especially anticipated ipsilateral nephrectomy or partial hepatic resection, be reviewed jointly by the surgeon and radiation oncologist, as extent of resection impacts RT planning and dose constraints to preserve organ function.6,28 Assessment of adequate renal function is essential if the ipsilateral kidney will be resected, and the contralateral kidney must be maximally spared in RT planning (Figure 2). Similarly, when partial hepatic resection is planned, dose to the remaining liver should be minimized. Comprehensive guidelines for RT planning considerations, including planning volume definitions and dose constraints for organs at risk, have been published elsewhere.6,28

Figure 2.
Figure 2.

Contrast-enhanced CT axial image of a retroperitoneal well-differentiated liposarcoma surrounding the right kidney. Discussion of plan for nephrectomy and evaluation of contralateral renal function are necessary for preoperative radiotherapy planning.

Citation: Journal of the National Comprehensive Cancer Network 20, 7; 10.6004/jnccn.2022.7035

Studies have evaluated treating only a high-risk posterior target volume or dose escalation to margins at high risk for recurrence with simultaneous integrated boost (Figure 3).3134 These high-risk volumes should be defined jointly by the surgeon and radiation oncologist.33 A prospective multi-institutional phase II trial using simultaneous integrated boost to treat the high-risk margin to 6,300 cGy and the tumor to 5,040 cGy is ongoing (ClinicalTrials.gov identifier: NCT01659203). These approaches are intriguing, but efficacy has not yet been demonstrated. As such, they are best used only in the setting of clinical trials.

Figure 3.
Figure 3.

Preoperative radiotherapy target volumes with a simultaneous integrated boost to the high-risk margin. The conventional GTV is outlined in red. The high-risk GTV boost volume, as defined jointly by the radiation oncologist and surgeon, is shown in magenta along the posterior retroperitoneal musculature and ipsilateral paravertebral space.

Abbreviation: GTV, gross tumor volume.

Citation: Journal of the National Comprehensive Cancer Network 20, 7; 10.6004/jnccn.2022.7035

Postoperative RT

Postoperative RT is generally not recommended because the appropriate treatment dose (6,000–6,600 cGy) exceeds adjacent normal tissue tolerances (eg, small bowel, kidney, liver, and spinal cord).57,28 Furthermore, the appropriate postoperative RT treatment volume is typically large given the need to encompass the initial extent of disease and entire surgical bed, and often contains multiple loops of bowel. Higher RT-related complications and gastrointestinal toxicity have been observed with appropriate doses of postoperative RT.19,26 Most sarcoma experts do not routinely offer postoperative RT and favor close surveillance after resection, with possible use of preoperative RT at the time of recurrence.6,28 However, highly selective use of postoperative RT may be considered in circumstances when the area at risk is well-defined and recurrence would be associated with significant morbidity or limited options for resection.6,7 In such cases, coordination between the surgeon and radiation oncologist is important for defining areas at risk and potential use of techniques to displace the bowel out of the anticipated treatment field.35,36

Conclusions

RPS is a rare subset of STS, comprising heterogeneous histopathologic subtypes with different behaviors. Risk of recurrence, local and distant, is influenced by histologic subtype and grade. The primary treatment modality is macroscopic complete resection. The appropriate role of RT is not defined, largely due to insufficient high-quality data appropriately stratified by prognostic factors, such as histologic subtype. Selected use of preoperative EBRT may be considered in patients with high risk for local recurrence. Postoperative RT is not recommended. Given the rarity of RPS and heterogeneity of tumor biology, enrollment on prospective trials is necessary to better ascertain optimal treatment paradigms and improve outcomes.

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    • PubMed
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Submitted February 25, 2022; final revision received May 19, 2022; accepted for publication May 19, 2022.

Disclosures: Dr. Baldini has disclosed receiving royalties from UpToDate, Inc. Dr. Salerno has disclosed having no financial interests, arrangements, affiliations, or commercial interests with manufacturers of any products discussed in this article or their competitors.

Correspondence: Kilian E. Salerno, MD, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10 CCR, Room B2-3500, Bethesda, MD 20892. Email: kilian.salerno@nih.gov
  • View in gallery

    Preoperative radiotherapy plan to 5,000 cGy for a patient with a large retroperitoneal liposarcoma. The tumor in situ is displacing bowel (turquoise contour) out of the treatment field.

    Abbreviation: PTV, planning target volume.

  • View in gallery

    Contrast-enhanced CT axial image of a retroperitoneal well-differentiated liposarcoma surrounding the right kidney. Discussion of plan for nephrectomy and evaluation of contralateral renal function are necessary for preoperative radiotherapy planning.

  • View in gallery

    Preoperative radiotherapy target volumes with a simultaneous integrated boost to the high-risk margin. The conventional GTV is outlined in red. The high-risk GTV boost volume, as defined jointly by the radiation oncologist and surgeon, is shown in magenta along the posterior retroperitoneal musculature and ipsilateral paravertebral space.

    Abbreviation: GTV, gross tumor volume.

  • 1.

    WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone, 5th ed. Lyon, France: IARC Publications; 2020.

    • Search Google Scholar
    • Export Citation
  • 2.

    Gronchi A, Strauss DC, Miceli R, et al. Variability in patterns of recurrence after resection of primary retroperitoneal sarcoma (RPS): a report on 1007 patients from the multi-institutional collaborative RPS working group. Ann Surg 2016;263:10021009.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Tan MCB, Brennan MF, Kuk D, et al. Histology-based classification predicts pattern of recurrence and improves risk stratification in primary retroperitoneal sarcoma. Ann Surg 2016;263:593600.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Tseng W, Martinez SR, Tamurian RM, et al. Histologic type predicts survival in patients with retroperitoneal soft tissue sarcoma. J Surg Res 2012;172:123130.

  • 5.

    Swallow CJ, Strauss DC, Bonvalot S, et al. Management of primary retroperitoneal sarcoma (RPS) in the adult: an updated consensus approach from the Transatlantic Australasian RPS Working Group. Ann Surg Oncol 2021;28:78737888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Salerno KE, Alektiar KM, Baldini EH, et al. Radiation therapy for treatment of soft tissue sarcoma in adults: executive summary of an ASTRO clinical practice guideline. Pract Radiat Oncol 2021;11:339351.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Gronchi A, Miah AB, Dei Tos AP, et al. Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021;32:13481365.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Callegaro D, Raut CP, Ng D, et al. Has the outcome for patients who undergo resection of primary retroperitoneal sarcoma changed over time? A study of time trends during the past 15 years. Ann Surg Oncol 2021;28:17001709.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Bonvalot S, Gaignard E, Stoeckle E, et al. Survival benefit of the surgical management of retroperitoneal sarcoma in a reference center: a nationwide study of the French Sarcoma Group from the NetSarc Database. Ann Surg Oncol 2019;26:22862293.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Martin-Broto J, Hindi N, Cruz J, et al. Relevance of reference centers in sarcoma care and quality item evaluation: results from the prospective registry of the Spanish Group for Research in Sarcoma (GEIS). Oncologist 2019;24:e338346.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Blay JY, Honoré C, Stoeckle E, et al. Surgery in reference centers improves survival of sarcoma patients: a nationwide study. Ann Oncol 2019;30:11431153.

  • 12.

    Blay JY, Soibinet P, Penel N, et al. Improved survival using specialized multidisciplinary board in sarcoma patients. Ann Oncol 2017;28:28522859.

  • 13.

    Gronchi A, Lo Vullo S, Fiore M, et al. Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol 2009;27:2430.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Bonvalot S, Rivoire M, Castaing M, et al. Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. J Clin Oncol 2009;27:3137.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft- tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305315.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197203.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Haas RLM, Bonvalot S, Miceli R, et al. Radiotherapy for retroperitoneal liposarcoma: a report from the Transatlantic Retroperitoneal Sarcoma Working Group. Cancer 2019;125:12901300.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Kelly KJ, Yoon SS, Kuk D, et al. Comparison of perioperative radiation therapy and surgery versus surgery alone in 204 patients with primary retroperitoneal sarcoma: a retrospective 2-institution study. Ann Surg 2015;262:156162.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Bishop AJ, Zagars GK, Torres KE, et al. Combined modality management of retroperitoneal sarcomas: a single-institution series of 121 patients. Int J Radiat Oncol Biol Phys 2015;93:158165.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Le Péchoux C, Musat E, Baey C, et al. Should adjuvant radiotherapy be administered in addition to front-line aggressive surgery (FAS) in patients with primary retroperitoneal sarcoma? Ann Oncol 2013;24:832837.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Pawlik TM, Pisters PWT, Mikula L, et al. Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol 2006;13:508517.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Chouliaras K, Senehi R, Ethun CG, et al. Role of radiation therapy for retroperitoneal sarcomas: an eight-institution study from the US Sarcoma Collaborative. J Surg Oncol 2019;120:12271234.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Nussbaum DP, Speicher PJ, Gulack BC, et al. Long-term oncologic outcomes after neoadjuvant radiation therapy for retroperitoneal sarcomas. Ann Surg 2015;262:163170.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Diamantis A, Baloyiannis I, Magouliotis DE, et al. Perioperative radiotherapy versus surgery alone for retroperitoneal sarcomas: a systematic review and meta-analysis. Radiol Oncol 2020;54:1421.

    • Crossref
    • PubMed
    • Search Google Scholar
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