A multicentre retrospective study on extra-thoracic solitary fibrous tumour: preoperative MRI findings predict intraoperative findings and postoperative prognosis.

OBJECTIVE: The present study investigated the relationships between the preoperative and operative findings of solitary fibrous tumour (SFT) and between preoperative findings and prognosis. METHODS: We reviewed 50 SFT patients treated at our musculoskeletal oncology hospital group. We analyzed preoperative clinical findings, particularly MRI imaging findings, and intraoperative information as well as the relationship between preoperative findings and outcomes. RESULTS: Mean age was 48.9 years and the mean follow-up was 51.8 months. Prior to surgery, needle biopsy was performed on 27 patients and open biopsy on 14. T2-weighted images showed a high signal intensity in 24 patients and heterogeneous signal intensity in 20. Tumours had polylobular contours in 17 patients and smooth and round contours in 27. Collateral feeding vessels were detected in 22 patients. Gd-enhanced MRI was performed on 23 patients, and showed 15 with homogeneous enhancement and 8 with heterogeneous enhancement. Surgical times were significantly longer in patients with a retroperitoneal origin, a tumour of 10 cm or more, and polylobular-type tumours. Intraoperative blood loss was significantly greater in patients with a retroperitoneal origin and heterogeneous Gd-MRI-enhanced tumours. In histopathological evaluations, surgical margins were positive in 12 patients. Local recurrence was observed in one patient. Distant metastasis was noted in eight patients, four of whom had pulmonary metastases. Positive surgical margins were more common in polylobular-type tumours. Distant metastases were more likely to appear in patients with observable collateral feeding vessels and heterogeneous Gd-MRI enhancement. CONCLUSION: The present results suggest that preoperative clinical findings in SFT patients predict longer surgical times and the risk of increased intraoperative blood loss. Moreover, the risk of a positive surgical margin and postoperative distant metastases may be predicted based on preoperative MRI.

Histological markers, sickle-shaped blood vessels, myxoid area, and infiltrating growth pattern help stratify the prognosis of patients with myxofibrosarcoma/undifferentiated sarcoma.

Myxofibrosarcoma (MFS) and undifferentiated sarcoma (US) have been considered as tumors of the same lineage based on genetic/epigenetic profiling. Although MFS shows a notably better prognosis than US, there are no clear criteria for distinguishing between them. Here, we examined 85 patients with MFS/US and found that tumors with infiltrative growth patterns tended to have more myxoid areas and higher local recurrence rates but fewer distant metastases and better overall survival. Morphologically characteristic sickle-shaped blood vessels, which tended to have fewer αSMA-positive cells, were also observed in these tumors, compared with normal vessels. Based on the incidence of these sickle-shaped blood vessels, we subdivided conventionally diagnosed US into two groups. This stratification was significantly correlated with metastasis and prognosis. RNA sequencing of 24 tumors (9 MFS and 15 US tumors) demonstrated that the proteasome, NF-kB, and VEGF pathways were differentially regulated among these tumors. Expression levels of KDR and NFATC4, which encode a transcription factor responsible for the neuritin-insulin receptor angiogenic signaling, were elevated in the sickle-shaped blood vessel-rich US tumors. These findings indicate that further analyses may help elucidate the malignant potential of MFS/US tumors as well as the development of therapeutic strategies for such tumors.

Fluorodeoxyglucose positron emission tomography (FDG/PET) shows the effect of carbon-ion radiotherapy (CIRT); with pathologic confirmation.

Response evaluation of carbon-ion radiotherapy poses a diagnostic challenge. Due to its functional aspects, fluorodeoxyglucose positron emission tomography (FDG/PET) has a role in the diagnosis of photon radiation therapy. In addition, several studies suggested that FDG/PET may be useful to select the optimal site for performing a diagnostic biopsy. Here, we report a 73-year-old female in which FDG/PET was effective in determining the recurrence of liposarcoma and the therapeutic effect. Based on the results of FDG/PET, we could make a pathologic definitive diagnosis and selectively performing carbon-ion radiotherapy for active tumors.

Bone marrow adipocytes induce cancer-associated fibroblasts and immune evasion, enhancing invasion and drug resistance.

Bone metastasis occurs frequently in cancer patients. Conventional therapies have limited therapeutic outcomes, and thus, exploring the mechanisms of cancer progression in bone metastasis is important to develop new effective therapies. In the bone microenvironment, adipocytes are the major stromal cells that interact with cancer cells during bone metastasis. However, the comprehensive functions of bone marrow adipocytes in cancer progression are not yet fully understood. To address this, we investigated the role of bone marrow adipocytes on cancer cells, by focusing on an invasive front that reflects the direct effects of stromal cells on cancer. In comprehensive histopathological and genetic analysis using bone metastasis specimens, we examined invasive fronts in bone metastasis and compared invasive fronts with adipocyte-rich bone marrow (adipo-BM) to those with hematopoietic cell-rich bone marrow (hemato-BM) as a normal counterpart of adipocytes. We found morphological complexity of the invasive front with adipo-BM was significantly higher than that with hemato-BM. Based on immunohistochemistry, the invasive front with adipo-BM comparatively had a significantly increased cancer-associated fibroblast (CAF) marker-positive area and lower density of CD8+ lymphocytes compared to that with hemato-BM. RNA sequencing analysis of primary and bone metastasis cancer revealed that bone metastasized cancer cells acquired drug resistance-related gene expression phenotypes. Clearly, these findings indicate that bone marrow adipocytes provide a favorable tumor microenvironment for cancer invasion and therapeutic resistance of bone metastasized cancers through CAF induction and immune evasion, providing a potential target for the treatment of bone metastasis.

Differential diagnosis of uterine adenosarcoma: identification of JAZF1-BCORL1 rearrangement by comprehensive cancer genomic profiling.

BACKGROUND: Uterine adenosarcoma is a rare malignant tumor that accounts for 8% of all uterine sarcomas, and less than 0.2% of all uterine malignancies. However, it is frequently misdiagnosed in clinical examinations, including pathological diagnosis, and imaging studies owing to its rare and non-specific nature, which is further compounded by the lack of specific diagnostic markers. CASE PRESENTATION: We report a case of uterine adenosarcoma for which a comprehensive genomic profiling (CGP) test provided a chance to reach the proper diagnosis. The patient, a woman in her 60s with a history of uterine leiomyoma was diagnosed with an intra-abdominal mass post presentation with abdominal distention and loss of appetite. She was suspected to have gastrointestinal stromal tumor (GIST); the laparotomically excised mass was found to comprise uniform spindle-shaped cells that grew in bundles with a herringbone architecture, and occasional myxomatous stroma. Immunostaining revealed no specific findings, and the tumor was diagnosed as a spindle cell tumor/suspicious adult fibrosarcoma. The tumor relapsed during postoperative follow-up, and showed size reduction with chemotherapy, prior to regrowth. CGP was performed to identify a possible treatment, which resulted in detection of a JAZF1-BCORL1 rearrangement. Since the rearrangement has been reported in uterine sarcomas, we reevaluated specimens of the preceding uterine leiomyoma, which revealed the presence of adenosarcoma components in the corpus uteri. Furthermore, both the uterine adenosarcoma and intra-abdominal mass were partially positive for CD10 and BCOR staining. CONCLUSION: These results led to the conclusive identification of the abdominal tumor as a metastasis of the uterine adenosarcoma. The JAZF1-BCORL1 rearrangement is predominantly associated with uterine stromal sarcomas; thus far, ours is the second report of the same in an adenosarcoma. Adenosarcomas are rare and difficult to diagnose, especially in atypical cases with scarce glandular epithelial components. Identification of rearrangements involving BCOR or BCORL1, will encourage BCOR staining analysis, thereby potentially resulting in better diagnostic outcomes. Given that platinum-based chemotherapy was proposed as the treatment choice for this patient post diagnosis with adenosarcoma, CGP also indirectly contributed to the designing of the best-suited treatment protocol.

Clinical analysis of multimodal treatment for localized synovial sarcoma: A multicenter retrospective study.

INTRODUCTION: Several prognostic factors for survival in synovial sarcoma have been proposed, but the role of adjuvant chemotherapy and radiotherapy is a matter of debate. The study aim was to clarify the effect of high-dose ifosfamide-containing chemotherapy and adjuvant radiotherapy for patients with localized synovial sarcoma. MATERIALS AND METHODS: Five tertiary musculoskeletal oncology hospitals participated in this retrospective study. The records of the patient diagnosed with synovial sarcoma without metastasis at diagnosis from 1990 to 2011 have been collected and reviewed. Overall, distant failure-free, and local failure-free survivals were calculated, and prognostic factors for each survival were evaluated by performing univariate and multivariate analyses. RESULTS: A total of 162 patients were enrolled in this study with a median follow-up period of 67 months (range, 5-267 months) for all surviving patients. The 5-year overall, distant failure-free, and local failure-free survival rates were 79.7%, 66.3%, and 98.4%, respectively. Univariate analyses demonstrated that high-dose ifosfamide-containing chemotherapy was significantly associated with better overall (p = 0.014) and distant failure-free survival (p = 0.0043) than that of low-dose or no ifosfamide-containing chemotherapy if we analyzed only patients with tumors >5 cm in size. Addition of radiotherapy was not a significant prognostic factor for overall survival in the univariate and multivariate analyses, but it did improve the overall survival of the patients with R1 resection (p = 0.053). CONCLUSION: Patients with localized synovial sarcoma >5 cm in size had better overall and distant failure-free survival after receiving adjuvant chemotherapy containing high-dose ifosfamide comparing to low-dose or no ifosfamide-containing chemotherapy. The addition of adjuvant radiotherapy was beneficial for the patients who received R1 resection. Alternatively, adjuvant radiotherapy could be avoided for patients who achieved an R0 margin.

Intraoperative extracorporeal irradiation for giant sarcoma-infiltrated calvarium: a case report.

Large bone defects that occur after resection of calvarial tumours are commonly remedied using titanium meshes or bone prostheses. However, these methods have several problems. While intraoperative extracorporeal radiotherapy for bone flaps could avoid these problems, there have been only a few reports wherein meningiomas were treated with 120 Gy irradiation. Moreover, no reports are available on calvarial metastasis of sarcoma, and the therapeutic radiation dose remains uncertain. Here, we report a case of giant calvarial metastasis of myxoid liposarcoma treated with intraoperative extracorporeal radiotherapy at a dose of 50 Gy. The treatment resulted in successful tumour control followed by favourable bone reconstruction.

Effect of Tranilast on the Frequency of Invasive Treatment for Extra-Abdominal Desmoid Fibromatosis.

BACKGROUND: Active surveillance (AS) has been suggested for managing extra-abdominal desmoid fibromatosis (EADF), but a substantial percentage of such patients transitioned to invasive secondary treatments. The anti-keloid medication tranilast is frequently used in Japan but its effectiveness for EADF is not well understood. METHODS: We retrospectively analyzed the medical records of EADF patients treated with tranilast between January 2009 and March 2021. EADF has been reported to shrink spontaneously, so the effects of all drugs must be compared with AS. To assess the effect of tranilast, we compared the clinical courses of patients receiving tranilast with those managed by AS (as identified in a systematic review). A systematic review of AS outcomes was conducted on July 22, 2021, in accordance with PRISMA guidelines. The primary endpoint was rate of conversion to secondary treatment. Secondary endpoints were progression-free survival, objective response rate (ORR), disease control rate (DCR), and adverse events. The rates of conversion to secondary treatment, ORRs, and DCRs were compared between the two groups by using the Fisher exact test. RESULTS: Eighteen patients who received tranilast as initial treatment for EADF were included. Two patients (11.1%) underwent surgical resection for treatment of tumor growth and persistent pain. The rate of conversion to secondary treatment was significantly lower for tranilast than for a pure AS approach (40.1%; p = 0.01). ORR and DCR did not differ between groups. CONCLUSIONS: Tranilast was better than AS for initial management of EADF.

Clinical Outcomes of Scanning Carbon-ion Radiotherapy for Soft Tissue Sarcoma of the Extremities.

BACKGROUND/AIM: Carbon-ion radiotherapy (CIRT) has been reported to obtain favorable results in the treatment of bone and soft tissue malignancies; however, studies on CIRT for soft tissue sarcomas (STS) of the extremities are limited. Here, we have retrospectively evaluated the therapeutic efficacy and adverse events associated with scanning CIRT (sCIRT) for STS of the extremities at our institution. PATIENTS AND METHODS: Thirteen consecutive patients with STS who underwent sCIRT between January 2017 and January 2020 were included in the study. The total dose of sCIRT was set at 67.2-70.4 Gy (RBE), which was provided in 16 fractions. Overall survival (OS), progression-free survival (PFS), and local control (LC) were estimated using the Kaplan-Meier method. Toxicity was evaluated using Common Terminology Criteria for Adverse Events v5.0. RESULTS: The cohort consisted of 10 males and 3 females with a median age of 69 years (range=38-95 years). Median duration of observation was 31.8 months (range=7.4-56.4 months). Tumors were localized to the upper extremity in 2 cases and to the lower extremity in 11 cases. Median maximum tumor diameter was 11.7 cm (range=3.0-36.6 cm), while 3-year OS, PFS, and LC were 61.5%, 44.9%, and 79.1%, respectively. Acute toxicity of grade 3 or higher was not observed. Late toxicity included grade 3 peripheral nerve palsy and decreased range of motion in 1 and 1 patient each. Late toxicity of Grade 4 or higher was not observed. CONCLUSION: sCIRT for STS of the extremities demonstrates favorable therapeutic results with acceptable toxicity.

Perioperative Adriamycin plus ifosfamide vs. gemcitabine plus docetaxel for high-risk soft tissue sarcomas: randomised, phase II/III study JCOG1306.

BACKGROUND: This randomised phase II/III trial aimed to determine whether perioperative chemotherapy with gemcitabine plus docetaxel (GD) is non-inferior to the standard Adriamycin plus ifosfamide (AI) in terms of overall survival (OS) in patients with soft tissue sarcoma (STS). METHODS: Patients with localised high-risk STS in the extremities or trunk were randomised to receive AI or GD. The treatments were repeated for three preoperative and two postoperative courses. The primary endpoint was OS. RESULTS: Among 143 enrolled patients who received AI (70 patients) compared to GD (73 patients), the estimated 3-year OS was 91.4% for AI and 79.2% for GD (hazard ratio 2.55, 95% confidence interval: 0.80-8.14, P = 0.78), exceeding the prespecified non-inferiority margin in the second interim analysis. The estimated 3-year progression-free survival was 79.1% for AI and 59.1% for GD. The most common Grade 3-4 adverse events in the preoperative period were neutropenia (88.4%), anaemia (49.3%), and febrile neutropenia (36.2%) for AI and neutropenia (79.5%) and febrile neutropenia (17.8%) for GD. CONCLUSIONS: Although GD had relatively mild toxicity, the regimen-as administered in this study-should not be considered a standard treatment of perioperative chemotherapy for high-risk STS in the extremities and trunk. CLINICAL TRIAL REGISTRATION: jRCTs031180003.

A randomized phase III trial of denosumab before curettage for giant cell tumor of bone. JCOG1610.

OBJECTIVES: The aim of JCOG1610 (randomized controlled phase III trial) was to confirm the superiority of preoperative denosumab to curettage with adjuvant local therapy for patients with giant cell tumor of bone without possible post-operative large bone defect. METHODS: The primary endpoint was relapse-free survival and the total sample size was set at 106 patients. Patient accrual began in October 2017. However, the accrual was terminated in December 2020 due to a recommendation from the Data and Safety Monitoring Committee because of poor patient accrual. Now, we report the descriptive results obtained in this study. RESULTS: A total of 18 patients had been registered from 13 Japanese institutions at the time of termination on December 2020. Eleven patients were assigned to Arm A (curettage and adjuvant local therapy) and 7 to Arm B (preoperative denosumab, curettage and adjuvant local therapy). Median follow-up period was 1.6 (range: 0.5-2.8) years. Protocol treatment was completed in all but one patient in Arm A who had a pathological fracture before surgery. All patients in Arm B were treated with five courses of preoperative denosumab. Relapse-free survival proportions in Arm A and B were 90.0% (95% confidence interval: 47.3-98.5) and 100% (100-100) at 1 year, and 60.0% (19.0-85.5) and 62.5% (14.2-89.3) at 2 years, respectively [hazard ratio (95% confidence interval): 1.51 (0.24-9.41)]. CONCLUSION: In terms of relapse-free survival, the superiority of preoperative denosumab was not observed in patients with giant cell tumor of bone without possible post-operative large bone defect.

Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas.

BACKGROUND: Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis. METHODS: Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board. RESULTS: A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893-18.188, p = 0.070). CONCLUSION: The standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

Differential diagnosis of lipoma and atypical lipomatous tumor/well-differentiated liposarcoma by cytological analysis.

BACKGROUND: Adipocytic tumors are the most common soft tissue tumors, with lipomas and atypical lipomatous tumor/well-differentiated liposarcomas (ALT/WDL), which comprise most cases. Preoperative differential diagnosis of lipoma or ALT/WDL can provide important information for decisions regarding treatment. We evaluated the cytological findings of 20 cases of lipoma and ALT/WDL. METHODS: Fluorescence in situ hybridization (FISH) was performed on formalin-fixed paraffin-embedded specimens (FFPE) to examine mouse double minute 2 homolog (MDM2) amplification in all cases. Tissue samples were collected from the center of the surgical materials, stained with Pap, and evaluated for 12 cytological parameters by six cytotechnologists. RESULTS: The findings regarding large atypical cells, multinucleated cells, and nuclear pleomorphism were highly concordant among the cytotechnologists and were associated with MDM2 amplification. Large atypical cells, considered a highly specific feature of ALT/WDL, were not observed in lipoma cases. However, the sensitivity of the large atypical cell findings was not high (67%); therefore, comprehensive evaluation of multinucleated cells and pleomorphism is crucial for predicting ALT/WDL diagnosis. FISH of MDM2 on Pap-stained specimens was performed in four cases. In two, the results were similar to those of MDM2 FISH performed on FFPE sections and were reproducible, whereas in the other two, the signal could not be evaluated because of the strong background coloration. CONCLUSIONS: Cytology specimens may be useful for the preoperative diagnosis of adipocytic tumors, particularly if the FISH conditions for Pap-stained specimens and the detection accuracy of MDM2 amplification can be improved.

Transitional changes of spacer materials used in carbon-ion radiation therapy.

PURPOSE: To evaluate the imaging findings and transitional changes in spacer materials used in carbon-ion radiation therapy MATERIALS: Medical records were retrospectively reviewed, and the maximum thickness, volume, and CT value of spacers were calculated from CT scans. Procedure-related complications were recorded. RESULTS: A spacer was surgically placed in six patients in retroperitoneal, presacral, or peritoneal sites. The spacer material was polyglycolic acid (PGA) in four patients and expanded polytetrafluoroethylene (ePTFE) in two patients. The thickness of PGA spacers showed no changes in any patients within 4 weeks, but increased within 6 weeks in one patient and was unchanged or decreased in the remaining patients. PGA spacer volume decreased gradually after placement in three of four patients; this was observed at 4 months in two patients and at 6 months in one patient. The mean CT value of PGA spacers was 83 HU just after placement, and decreased gradually thereafter. Air was seen in the PGA spacers of two patients. Neither ePTFE spacer showed volume changes over time, and the mean CT value was low (mean, -53.7 HU) just after placement but increased rapidly to 145 HU at 2 months. CONCLUSION: Spacer imaging findings may vary according to type and may change over time. Familiarity with these features is beneficial for diagnostic radiologists.

Time lapse analysis of tumor response in patients with soft tissue sarcoma treated with trabectedin: A pooled analysis of two phase II clinical trials.

The time course of the response to each drug is important to avoid inappropriate termination of treatment by misjudging tumor progression; however, little is known about soft tissue sarcoma (STS) regarding this matter. This study aimed to perform a time-lapse analysis of tumor response in patients with STS treated with trabectedin from 2 phase II clinical trials. We examined 66 patients with translocation-related sarcoma registered in 2 Japanese phase II clinical trials. All patients previously received standard therapy before the administration of trabectedin at 1.2 mg/m2 every 3 weeks. Imaging evaluation was performed according to the study protocol. The sum of the maximum diameters of the target lesions was calculated and analyzed over time. Among the 66 patients, 9 (13.6%) showed partial response (PR) to trabectedin. Histological diagnoses of these 9 responders comprised 6 myxoid liposarcoma, 2 synovial sarcoma, and a mesenchymal chondrosarcoma. The median period from treatment initiation to the first PR was 123 (range, 34-328) days. The pattern of tumor response to trabectedin showed an increasing tendency in size in the initial stage, usually followed by a size decrease with repeated administration. STS response to trabectedin was characterized as delayed and potentially persistent. Clinicians treating STS with trabectedin should know the features of the response pattern to avoid interrupting the treatment before maximal efficacy is achieved.

Publisher Correction: Integrated exome and RNA sequencing of dedifferentiated liposarcoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

[A CASE OF EXTRASKELETAL EWING'S SARCOMA IN THE RETROPERITONEUM].

A 23-year-old man was admitted to our hospital with a huge pelvic tumor. MRI showed a tumor mixed with a solid component and polycystic cyst with maximum diameter of about 20 cm. Percutaneous tumor needle biopsy was performed and diagnosis was Ewing sarcoma. At that time, operation is extremely difficult, so the neoadjuvant chemotherapy with ifosfamide, etoposide, Adriamycin, and vincristine were administered. After 6 courses, MRI showed tumor reduction to maximum diameter of 10 cm. We planned tumor resection with total cystectomy for radical resection, but we also tried to preserve bladder considering the young age and quality of life. Although the bladder was partially resected, tumor resection was succeeded without removing surrounding organs. Histopathological examination revealed viable cells remained, but more than 95% was disappeared and the surgical margins were negative. Here we report a case of extra skeletal Ewing sarcoma in the retroperitoneum that was treated with chemotherapy and surgery without scarifying surrounding organs.

Integrated exome and RNA sequencing of dedifferentiated liposarcoma.

The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management.

Ten-year follow-up results of perioperative chemotherapy with doxorubicin and ifosfamide for high-grade soft-tissue sarcoma of the extremities: Japan Clinical Oncology Group study JCOG0304.

BACKGROUND: Soft-tissue sarcomas (STS) are rare malignant tumors those are resistant to chemotherapy. We have previously reported the 3-year follow-up result on the efficacy of perioperative chemotherapy with doxorubicin (DXR) and ifosfamide (IFM) for high-risk STS of the extremities (JCOG0304). In the present study, we analyzed the 10-year follow-up results of JCOG0304. METHODS: Patients with operable, high-risk STS (T2bN0M0, AJCC 6th edition) of the extremities were treated with 3 courses of preoperative and 2 courses of postoperative chemotherapy, which consisted of 60 mg/m2 of DXR plus 10 g/m2 of IFM over a 3-week interval. The primary study endpoint was progression-free survival (PFS) estimated by Kaplan-Meier methods. Prognostic factors were evaluated by univariable and multivariable Cox proportional hazards model. RESULTS: A total of 72 patients were enrolled between March 2004 and September 2008, with 70 of these patients being eligible. The median follow-up period was 10.0 years for all eligible patients. Local recurrence and distant metastasis were observed in 5 and 19 patients, respectively. The 10-year PFS was 65.7% (95% CI: 53.4-75.5%) with no PFS events being detected during the last 5 years of follow-up. The 10-year overall survival was 78.1% (95% CI: 66.3-86.2%). Secondary malignancy was detected in 6 patients. The subgroup analysis demonstrated that there was significant difference in survival with regard to primary tumor size. CONCLUSIONS: Only a few long-term results of clinical trials for perioperative chemotherapy treatment of STS have been reported. Our results demonstrate that the 10-year outcome of JCOG0304 for patients with operable, high-risk STS of the extremities was stable and remained favorable during the last 5 years of follow-up. TRIAL REGISTRATION: This trial was registered at the UMIN Clinical Trials Registry as C000000096 on August 30, 2005.

Prospective comparison of various radiological response criteria and pathological response to preoperative chemotherapy and survival in operable high-grade soft tissue sarcomas in the Japan Clinical Oncology Group study JCOG0304.

BACKGROUND: Soft tissue sarcomas (STS) are rare malignant tumors. The efficacy of preoperative chemotherapy for STS is evaluated using various tumor size-based radiological response criteria. However, it is still unclear which set of criteria would show the best association with pathological response and survival of the patients with STS. METHODS: We compared radiological responses to preoperative chemotherapy for operable STS by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST, World Health Organization criteria, Japanese Orthopaedic Association criteria, and modified Choi criteria and analyzed the association with pathological response and survival using the data from the Japan Clinical Oncology Group (JCOG) study JCOG0304, a phase II clinical trial evaluating the efficacy of perioperative chemotherapy for STS in the extremities. RESULTS: Seventy eligible patients in JCOG0304 were analyzed. The results demonstrated that none of the size-based radiological response criteria showed significant association with pathological response to preoperative chemotherapy for STS. The difference between overall survival of the patients assessed as partial response and stable disease/progressive disease by RECIST was not significant (hazard ratio 1.37, p = 0.63), and calculated C-index was 0.50. All other response criteria also could not exhibit significant association between radiological responses and survival. CONCLUSION: In the present study, none of the radiological response criteria analyzed demonstrated association of response to preoperative chemotherapy with pathological response or survival of the patients with operable STS. Further prospective investigation is required to develop criteria to evaluate not only tumor shrinkage but biological effects of preoperative chemotherapy for the patients with localized STS. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).