A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

A systematic review of the role of chemotherapy in retroperitoneal sarcoma by the Australia and New Zealand sarcoma association clinical practice guidelines working party.

BACKGROUND: In primary localised resectable retroperitoneal sarcoma (RPS), loco-regional and distant relapse occur frequently despite optimal surgical management. The role of chemotherapy in improving outcomes is unclear. METHODS: A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether neoadjuvant or adjuvant chemotherapy improve outcomes in adults with primary localised resectable RPS. Medline, Embase and Cochrane Central were queried for publications from 1946 to June 2022 that evaluated recurrence free survival, overall survival, and post operative complications. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Twenty three studies were identified; one meta-analysis of retrospective studies and 22 retrospective studies including three with propensity matched cohorts. Most studies did not analyse outcomes by histology, detail treatment regimens, provide baseline characteristics or selection criteria for those receiving chemotherapy. Evidence of selection bias was illustrated in several studies. Newcastle-Ottawa quality of retrospective cohort studies was good for 12 studies and poor for 10 studies. All studies were assessed as Level III-2 evidence by the Australian NHMRC hierarchy. Overall, the addition of neoadjuvant or adjuvant chemotherapy to surgery was not associated with improvement in local recurrence, metastasis free survival, disease free survival or overall survival in primary localised resectable RPS. There is some evidence of an association of chemotherapy with worse overall survival. One single centre study showed that neoadjuvant chemotherapy was not associated with increased post operative complications compared to surgery alone in primary localised resectable RPS. CONCLUSIONS: There is currently no evidence that demonstrates the addition of chemotherapy to surgery improves outcomes in adult patients with primary localised resectable RPS. Available evidence is limited by its retrospective nature and high likelihood of selection bias with chemotherapy generally administered to patients at higher risk of recurrence and many patients not receiving care in high volume sarcoma centres. Randomised trials are required to conclusively determine the role of chemotherapy in primary localised resectable RPS.

Neoadjuvant Chemotherapy in Retroperitoneal Sarcoma: A National Cohort Study.

INTRODUCTION: Management of retroperitoneal sarcoma (RPS) remains controversial, with the mainstay of treatment being surgery. While neoadjuvant radiation demonstrated no improvement in recurrence-free survival in a prospective randomized trial (STRASS), the role of neoadjuvant chemotherapy (NCT) remains unknown and is the subject of ongoing study (STRASS2). METHODS: Patients who underwent surgical resection of high-grade RP leiomyosarcoma (LMS) or dedifferentiated liposarcoma (DDLS) were identified from the National Cancer Database (2006-2019). Predictors of NCT were analyzed using univariate and multivariate logistic regression analyses. Differences in 5-year survival were examined using the Kaplan-Meier (KM) method and by Cox proportional hazard modeling. RESULTS: A total of 2656 patients met inclusion criteria. Fifty-seven percent of patients had DDLS and 43.5% had LMS. Six percent of patients underwent NCT. Patients who received NCT were younger (median age 60 vs 64 years, p < 0.001) and more likely to have LMS (OR 1.4, p = 0.04). In comparing NCT with no-NCT patients, there was no difference in 5-year overall survival (OS) on KM analysis (57.3% vs 52.8%, p = 0.38), nor was any difference seen after propensity matching (54.9% vs 49.1%, p = 0.48, N = 144 per group). When stratified by histology, there was no difference in OS based on receipt of NCT (LMS: 59.8% for NCT group, 56.6% for no-NCT, p = 0.34; DDLS: 54.2% for NCT group, 50.1% for no-NCT, p = 0.99). CONCLUSION: In patients undergoing surgical resection of RP LMS or DDLS, NCT does not appear to confer an OS advantage. Prospective randomized data from STRASS2 will confirm or refute these retrospective data.

Is Hypoglycemia Secondary to Metastatic Retroperitoneal Sarcoma - A Therapeutic Challenge? Case Report and Review of Literature.

Most soft tissue sarcomas afflict the extremities; however, the retro peritoneum can also be affected rarely. Retroperitoneal sarcomas are relatively asymptomatic. Although tumor-induced hypoglycemia is rare in tumors other than insulinomas, extrapancreatic tumors are a subset that displays this phenomenon. The occurrence of hypo-insulinemic hypoglycemia with low GH and IGF-1 should prompt consideration of the secretion of a hypoglycemic substance impeding the secretion of insulin and GH, such as IGF-2 or one of its related substances. The present case report is of a 38-year-old male with retroperitoneal round cell sarcoma with liver metastasis with severe symptomatic hypoglycemia who was managed with multipronged symptomatic therapy and oncological management after which he had shown significant improvement in hypoglycemic episodes and symptom profile. A literature review revealed our case report to be the first reported case of a young male (preponderance in the older population) with hypoglycemia associated with retroperitoneal sarcoma which presented with liver metastasis and the only one treated with Gemcitabine /Docetaxel. The presence of these features might point toward a poorer prognosis in a disease with an already dismal course. All these points towards the need for further research regarding intensified oncological treatment after evidence-based prognostication of high-risk groups and modalities for the management of symptomatic hypoglycemia such as Somatostatin analogs and glucagon which aid in symptom control.

Adjuvant Palbociclib May be Associated with Delayed Recurrence in Completely Resected Retroperitoneal Liposarcoma: Results of a Single-Institution Retrospective Cohort Study.

BACKGROUND: Retroperitoneal liposarcomas are locally aggressive and frequently recur following complete surgical resection. Palbociclib, a cyclin-dependent kinase (CDK) 4/CDK6 inhibitor, is effective in the treatment of metastatic or unresectable liposarcoma. OBJECTIVE: The purpose of this study was to describe our initial experience using adjuvant palbociclib to delay recurrence. METHODS: Patients with resected RPS were identified from a prospectively maintained institutional database. In 2017, we began offering adjuvant palbociclib to patients following complete gross resection. Treatment interval, defined as the time between surgical resection and re-resection or change in systemic therapy, was compared between patients selected for adjuvant palbociclib or observation. RESULTS: Between 2017 and 2020, 12 patients underwent a total of 14 operations (14 patient cases) and were selected for adjuvant palbociclib for recurrence prevention. These patients were compared with 14 patients who, since 2010, underwent a total of 20 operations (20 patient cases) and were selected for observation. Histology was primarily dedifferentiated liposarcoma for both groups (observation: 70% [14/20]; adjuvant palbociclib: 64% [9/14]). All patients underwent complete gross resection. Neither age, number of previous surgeries, histologic grade, or Eastern Cooperative Oncology Group (ECOG) performance status differed between groups (p > 0.05 for all). Patients selected for adjuvant palbociclib experienced a longer treatment interval than those selected for observation, although it did not reach statistical significance (20.5 months vs. 13.1 months, p = 0.08, log rank). CONCLUSION: Adjuvant palbociclib may be associated with a prolonged interval between liposarcoma resection and the need for re-resection or other systemic therapy. Palbociclib may be effective in delaying liposarcoma recurrence, and its use for this indication warrants prospective study.

Primary Retroperitoneal Mucinous Cystadenocarcinoma during Long-term Administration of Infliximab for the Treatment of Crohn's Disease.

We herein report a rare case of primary retroperitoneal mucinous cystadenocarcinoma (PRMC) in a 60-year-old man. The patient, who had been treated with infliximab for Crohn's disease of the colon for 13 years, was referred to our hospital for lower back pain. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging revealed multiple cystic lesions in the right retroperitoneum, the calcification of the cyst, and bone lesions. Bone and CT-assisted biopsies of the retroperitoneal lesions revealed poorly differentiated adenocarcinoma. The patient was diagnosed with PRMC with bone metastases using immunohistochemical staining and positron emission tomography/CT.

Next questions in the management of retroperitoneal sarcoma.

PURPOSE OF REVIEW: Retroperitoneal soft-tissue sarcomas (RPS) are a group of rare, histologically distinct tumours with variable recurrence patterns depending on histological type. This review will discuss the growing body of evidence supporting histology-specific, multidisciplinary management and highlight areas of future research for patients with RPS. RECENT FINDINGS: Histology-tailored surgery is the cornerstone of management in patients with localized RPS. Further efforts to develop resectability criteria and identify patients who will benefit from neoadjuvant treatment strategies will help standardize the treatment of patients with localized RPS. Surgery for local recurrence is well tolerated in selected patients and re-iterative surgery in liposarcoma (LPS) may be beneficial at the time of local recurrence. The management of advanced RPS holds promise with several trials currently investigating systemic treatment beyond conventional chemotherapy. SUMMARY: The management of RPS has made significant progress over the past decade owing to international collaboration. Ongoing efforts to identify patients who will derive the most benefit from all treatment strategies will continue to advance the field of RPS.

Excision of Postchemotherapy Residual Retroperitoneal Mass in Testicular Cancer.

In this study, patients, who underwent excision of retroperitoneal mass following chemotherapy for testicular cancers from 2006 to 2016, were studied and followed till 2021. The clinical and oncological outcomes were measured. Among 338 patients, who were treated for TC during the entire study period, 38 (11.2%) underwent excision of the residual retroperitoneal mass. The mean age of these patients was 26.9±6.3 years. The majority were stage 3 testicular cancer. Complete resection with negative microscopic margins was achieved in the majority of cases i.e. 31 (81.6%). Damage to the collateral structures was seen in 12 (31.6%) cases. On histopathological examination, teratoma was seen in 18 (47.4%) of the cases followed by necrosis in 10 (26.3%). Complications were recorded in 12 (31.5%) cases, most were low grades. At five years of follow-up, 19 (50%) were disease-free, 25 (65.8%) were alive, and 9 (23.6%) were lost to follow-up. Five-year survival rates are lower than standard template-based retroperitoneal dissection, however, complications rates are comparable. Such complex surgeries should only be performed in high-volume centres. Key Words: Testicular neoplasms, Lymph node excision, Seminoma, Germ cell and embryonal.

A long-term survivor of advanced retroperitoneal dedifferentiated liposarcoma: a successful multimodal approach with extended resection and chemotherapy.

Surgical resection is the mainstay of treatment for retroperitoneal liposarcoma (RPLS). Herein, we describe a case of dedifferentiated RPLS successfully treated with an extended surgical approach with adjuvant chemotherapy. A 61-year-old male was referred to our hospital with a chief complaint of chest tightness. Abdominal computed tomography revealed a large retroperitoneal tumor, 11 cm in diameter, extensively invading the surrounding organs: the celiac axis, the splenic artery, the pancreatic body and tail, the lesser curvature of the stomach and the left adrenal gland. Endoscopic ultrasound-guided fine-needle aspiration biopsy confirmed dedifferentiated liposarcoma, suggesting aggressive tumor biology. We performed total gastrectomy combined with distal pancreatectomy with celiac axis and left adrenal gland resection with a curative intent. The postoperative course was almost uneventful. As the pathological findings indicated a positive margin with a well-differentiated liposarcoma component, we added adjuvant chemotherapy with four cycles of doxorubicin and ifosfamide (AI). Five years after primary surgery, regular follow-up CT demonstrated a pulmonary hilar lymph node enlargement and a tumor at paraesophageal locations. After downsizing chemotherapy with eribulin followed by pazopanib, he underwent partial esophagectomy with dissection of the paraesophageal tumor. The pathological findings indicated recurrence of dedifferentiated liposarcoma with a tumor-free surgical margin. He is currently alive without any evidence of recurrence almost 7 years after the first surgery and 15 months after the second surgery. The long-term survival gained in this patient indicates that extended resections and adjuvant chemotherapy could prolong survival in patients even with RPLS with dedifferentiated tumor histology.

[Medicinal treatment of retroperitoneal soft tissue sarcomas]. / Medikamentöse Therapie retroperitonealer Weichteilsarkome.

Retroperitoneal soft tissue sarcomas represent extreme challenges for interdisciplinary treatment teams. The sarcoma-specific experience of surgeons has the greatest impact on the survival of patients; however, too many patients still die despite optimal local treatment. The role of chemotherapy is undisputed only for patients with highly malignant bone sarcomas or rhabdomyosarcomas. For soft tissue sarcomas in adult patients, especially liposarcomas and leiomyosarcomas, the evidence situation is very unsatisfactory. This overview article discusses the complex data situation and controversial aspects that are relevant for current treatment decisions in interdisciplinary treatment teams.

[A Case of Primary Neuroendocrine Carcinoma of the Retroperitoneum].

In this case report, we describe a case of primary retroperitoneal neuroendocrine carcinoma. An 85- year-old man presented with a 3-week history of left back pain. Contrast-enhanced computed tomography showed an 8×5 cm mass to the left of the aorta and multiple hepatic metastases. Immunohistochemistry staining of the tumor cells showed positivity for the neuroendocrine marker synaptophysin and a very high Ki67 proliferation index. He was treated with carboplatin and etoposide. After 2 courses of chemotherapy, the mass had decreased in size, confirming that the treatment was effective. We plan to administer a total of 6 courses of chemotherapy.

Advanced germ cell tumor patients undergoing post-chemotherapy retroperitoneal lymph node dissection: Impact of residual teratoma on prognosis.

OBJECTIVES: To evaluate the histologic findings and clinical outcomes of post-chemotherapy retroperitoneal lymph node dissection for advanced germ cell tumor. METHODS: We analyzed the medical records of 66 patients who underwent post-chemotherapy retroperitoneal lymph node dissection between 2005 and 2019 at Tsukuba University Hospital. RESULTS: The proportions of necrosis, teratoma, and viable germ cell tumor in the specimens were 62.1%, 36.4%, and 1.5%, respectively. The 5-year progression-free and overall survival rates were 82.3% and 91.3%, respectively. The 5-year overall survival rate of patients with residual teratoma was significantly worse than that of patients with necrosis only (74.1% vs 100%). Overall, three patients died: one from cancer and two from teratoma with somatic-type malignancy. Of these, two patients relapsed after incomplete resection of residual teratoma. When limited to patients with completely resected teratoma, the 5-year overall survival rate was 91.7%, which did not differ from that for patients with necrosis only. Multivariate analysis showed that presence of teratoma in the primary site and decrease in retroperitoneal lymph node mass to less than 50% of the initial tumor size were independent factors for residual teratoma. However, the absence of these factors could not reliably predict necrosis only in retroperitoneal lymph node dissection specimens. CONCLUSIONS: In our series, 98% of post-chemotherapy retroperitoneal lymph node dissection pathology was either necrosis or teratoma, with viable germ cell tumor only found in 2% of patients. Residual teratoma was associated with poorer prognosis, especially in cases of incomplete resection.

What is the standard indication of adjuvant or neoadjuvant chemotherapy in localized soft-tissue sarcoma?

PURPOSE OF REVIEW: The aim is to bring latest evidence of the role of perioperative chemotherapy in localized soft-tissue sarcomas (STS) of limbs and to review the risk classification systems of retroperitoneal and extremity STS. RECENT FINDINGS: High-risk subset of localized STS of limbs and trunk-wall, defined with classic prognostic factors, consistently obtained 5-year overall survival ranging from 69 to 76% in randomized patients treated with full-dose of anthracycline and ifosfamide. Validated nomograms accurately predict, on individual basis, the risk of death and recurrence in localized STS of retroperitoneum and limbs, enabling a better selection of high-risk patients (usually those with death risk of ≥40%) that potentially could benefit with perioperative systemic treatment. Nomograms have virtually converted a negative large perioperative trial into a positive, favouring chemotherapy arm in the high-risk selection. SUMMARY: Perioperative three cycles of full-dose of anthracycline and ifosfamide should be proposed on an individual basis, in reference sarcoma centres, to high-risk localized STS of limbs or trunk-wall in certain histologies.

Modern multimodality management of patients with caval leiomyosarcoma: New treatment paradigms and potential molecular insights.

BACKGROUND AND OBJECTIVES: Caval leiomyosarcomas (cLMS) are rare soft tissue sarcomas historically associated with high recurrence rates and poor prognosis. While radical resection remains the mainstay of therapy for cLMS, new systemic therapies have presented opportunities for multimodality treatment. We examined the clinical outcomes of patients with cLMS treated with modern, multimodality approaches, and compared their outcomes to those of patients with noncaval retroperitoneal LMS (ncLMS). METHODS: A retrospective, single-institution review identified all patients diagnosed with primary retroperitoneal LMS from 2012 to 2018. Radiographic and pathologic review distinguished patients with cLMS and ncLMS. Standard clinicopathologic variables and response to chemotherapy (when applicable) were analyzed. Primary endpoints were overall (OS) and progression-free survival (PFS). RESULTS: Eleven patients with cLMS were identified. Median tumor size was 7.5 cm (IQR, 5.0-14.3 cm); all patients had Stage II/III disease. Seven patients received neoadjuvant chemotherapy. Nine cLMS patients underwent R0/R1 resection; two did not complete resection. Six patients received adjuvant systemic therapy. Twenty patients with ncLMS were treated during the same period. No statistical intergroup differences were noted in tumor size, pathologic grade, stage, or resection margin status. Patients with ncLMS were less likely to receive neoadjuvant (10% vs. 64%) and adjuvant chemotherapy (30% vs. 55%). Two-year OS (81% vs. 78%; p = NS) and PFS (55% vs. 46%; p = NS) were comparable between cLMS and ncLMS patients. CONCLUSIONS: Multimodality treatment with systemic therapy and aggressive surgical resection may achieve equivalent survival outcomes for patients with cLMS versus similar ncLMS. We recommend that all patients with cLMS be evaluated for multidisciplinary treatment. Genomic and proteomic expression profiling may identify novel or targetable mutations.

Blood testis barrier revisited-Analysis of post-chemotherapy germ cell tumor orchidectomy and retroperitoneal lymph node dissection specimens.

OBJECTIVE: To assess the response of chemotherapy on the primary tumor, compare it with the response in retroperitoneal disease, and study factors associated with pathological complete response. METHODS: We conducted a retrospective audit of all high inguinal orchidectomies (HIOs) performed after chemotherapy between 2012 and 2019 at a tertiary cancer center in India. Patient characteristics and histopathological response were extracted from electronic medical records, and predictors of testicular disease response were assessed. RESULTS: Of the 260 retroperitoneal lymph node dissections (RPLNDs) performed in the study period, 37 HIOs (14.23%) were carried out after chemotherapy. The median age of presentation was 28 years (16-41). Histopathology was divided into a viable tumor, mature teratoma, and necrosis/scarring. Residual disease was seen in 17 RPLND (46.0%) and 18 HIO (48.6%) specimens respectively. Of these 18, three patients had a residual viable tumor in the testis, and the remaining had a mature teratoma. Clinico-radiological assessment showed an average reduction of 61% in testicular disease size following chemotherapy. On orchidectomy histopathological assessment, the median tumor size was 9, 4, and 1.5 cm in specimens with a viable tumor, mature teratoma, and necrosis/scarring, respectively. CONCLUSIONS: A low threshold for upfront chemotherapy in patients with a high disease burden may be considered as tumors within the testis respond to chemotherapy in more than half of the patients. Discordance rates of residual cancer in RPLND and HIO specimens exist but post-chemotherapy tumor size in testis correlates with the presence of a residual viable tumor.

Pegylated liposomal doxorubicin-induced renal toxicity in retroperitoneal liposarcoma: a case report and literature review.

Doxorubicin is one of the most active drugs for sarcoma. Pegylated liposomal doxorubicin (PLD) is a unique formulation of doxorubicin, which carries a more favorable toxicity profile in comparison with free doxorubicin. The main toxicity of PLD is hand-foot syndrome. Unlike free doxorubicin, PLD is unlikely to cause alopecia, nausea, myelosuppression, or cardiotoxicity. Additionally, no premedications are required. We describe the case of a 50-year-old man with advanced retroperitoneal liposarcoma who developed irreversible PLD-associated progressive renal failure requiring chronic hemodialysis due to a thrombotic microangiopathy. No cardiotoxicity was noted 84 months after he initiated PLD. This case describes a lesser known toxicity of PLD and may be a toxicity of long-term treatment with other liposomal drugs.

Defining the role of neoadjuvant systemic therapy in high-risk retroperitoneal sarcoma: A multi-institutional study from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: In patients with retroperitoneal sarcoma (RPS), the incidence of recurrence after surgery remains high. Novel treatment approaches are needed. This retrospective study evaluated patients with primary, high-risk RPS who received neoadjuvant systemic therapy followed by surgery to 1) determine the frequency and potential predictors of radiologic tumor responses and 2) assess clinical outcomes. METHODS: Clinicopathologic data were collected for eligible patients treated at 13 sarcoma referral centers from 2008 to 2018. Univariable and multivariable logistic models were performed to assess the association between clinical predictors and response. Overall survival (OS) and crude cumulative incidences of local recurrence and distant metastasis were compared. RESULTS: Data on 158 patients were analyzed. A median of 3 cycles of neoadjuvant systemic therapy (interquartile range, 2-4 cycles) were given. The regimens were mostly anthracycline based; however, there was significant heterogeneity. No patients demonstrated a complete response, 37 (23%) demonstrated a partial response (PR), 88 (56%) demonstrated stable disease, and 33 (21%) demonstrated progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Only a higher number of cycles given was positively associated with PR (P = .005). All patients underwent complete resection, regardless of the tumor response. Overall, patients whose tumors demonstrated PD before surgery showed markedly worse OS (P = .005). An indication of a better clinical outcome was seen in specific regimens given for grade 3 dedifferentiated liposarcoma and leiomyosarcoma. CONCLUSIONS: In patients with high-risk RPS, the response to neoadjuvant systemic therapy is fair overall. Disease progression on therapy may be used to predict survival after surgery. Subtype-specific regimens should be further validated.