Preventative effect of celecoxib in dimethylbenz[a]anthracene-induced ovarian cancer in rats.

PURPOSE: The present study investigated the preventive effect of the cyclooxygenase (COX)-2 inhibitor, celecoxib, in 7,12-dimethylbenz[a]anthracene (DMBA)-induced ovarian cancer in a rat model. METHODS: A diet containing celecoxib (1500 ppm) was started 2 weeks before the introduction of DMBA. DMBA-soaked cotton threads were surgically applied to induce ovarian cancer in female Wistar rats. Tumor growth and survival were observed for 24 weeks. RESULTS: During the study period, an overall tumor incidence of 97.5% was observed and 65% of tumors were ovarian adenocarcinoma. The celecoxib diet significantly reduced the incidence and size of DMBA-induced ovarian cancers and significantly improved survival of tumor-bearing rats. The preventive effect of celecoxib was associated with increased apoptosis. CONCLUSION: DMBA-induced ovarian cancer in rats recapitulates many pathophysiological features of the human counterpart. Our results provide supportive evidence that celecoxib has a preventive effect on development of ovarian cancer in a rat model.

Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors-A Scandinavian Sarcoma Group study (SSG XX).

PURPOSE: To investigate the outcome following adjuvant doxorubicin and ifosfamide in a prospective non-randomised study based on a soft tissue sarcoma (STS) patient subgroup defined by specific morphological characteristics previously shown to be at a high-risk of metastatic relapse. The expected 5-year cumulative incidence of metastases in patients with this risk profile has previously been reported to be about 50% without adjuvant chemotherapy. METHODS: High-risk STS was defined as high-grade morphology (according to the Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade II-III) and either vascular invasion or at least two of the following criteria: tumour size ≥8.0 cm, infiltrative growth and necrosis. Six cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2) were given. Postoperative accelerated radiotherapy was applied and scheduled between cycles 3 and 4. RESULTS: For the 150 eligible patients, median follow-up time for metastases-free survival was 3.9 years (range 0.2-8.7). Five-year metastases-free survival (MFS) was 70.4% (95% confidence interval [CI]: 63.1-78.4) with a local recurrence rate of 14.0% (95% CI: 7.8-20.2). For overall survival (OS), the median follow-up time was 4.4 years (range: 0.2-8.7). The five-year OS was 76.1% (95% CI: 68.8-84.2). Tumour size, deep location and reduced dose intensity (<80%) had a negative impact on survival. Toxicity was moderate with no treatment-related death. CONCLUSIONS: A benefit of adjuvant chemotherapy, compared to similar historical control groups, was demonstrated in STS patients with defined poor prognostic factors. Vascular invasion, tumour size, growth pattern and necrosis may identify patients in need of adjuvant chemotherapy.

Prevention of Feline Injection-Site Sarcomas: Is There a Scientific Foundation for Vaccine Recommendations at This Time?

Recently published guidelines have made specific vaccine recommendations purported to potentially reduce the incidence of feline injection-site sarcomas (FISS). These recommendations have largely been based on experimental models of inflammation under different vaccine formulations. In none of these studies did sarcomas occur. It is scientifically untenable to address FISS risk based on propensity of vaccines to elicit differential inflammatory responses if none of those responses led to sarcoma development. Although the recommendations may ultimately be found to be prescient and valid, it will take considerable additional research before this can happen. Until then, such guidelines must be regarded with skepticism.

Neem leaf glycoprotein generates superior tumor specific central memory CD8+ T cells than cyclophosphamide that averts post-surgery solid sarcoma recurrence.

The success of cancer vaccines is limited as most of them induce corrupted CD8+ T cell memory populations. We reported earlier that a natural immunomodulator, neem leaf glycoprotein (NLGP), therapeutically restricts tumor growth in a CD8+ T cell-dependent manner. Here, our objective is to study whether memory CD8+ T cell population is generated in sarcoma hosts after therapeutic NLGP treatment and their role in prevention of post-surgery tumor recurrence, in comparison to the immunostimulatory metronomic cyclophosphamide (CTX) treatment. We found that therapeutic NLGP and CTX treatment generates central memory CD8+ T (TCM) cells with characteristic CD44+CD62LhighCCR7highIL-2high phenotypes. But these TCM cells are functionally impaired to prevent re-appearance of tumors along with compromised proliferative, IL-2 secretive and cytotoxic status. This might be due to the presence of tumor load, even a small one in the host, which serves as a persistent source of tumor antigens thereby corrupting the TCM cells so generated. Surgical removal of the persisting tumors from the host restored the functional characteristics of memory CD8+ T cells, preventing tumor recurrence after surgery till end of the experiment. Moreover, we observed that generation of superior TCM cells in NLGP treated surgically removed tumor hosts is related to the activation of Wnt signalling in memory CD8+ T cells with concomitant inhibition of GSK-3ß and stabilisation of ß-catenin, which ultimately activates transcription of Wnt target genes, like, eomesodermin, a signature molecule of CD8+ TCM cells.

Intracranial Inflammatory Myofibroblastic Tumor with Sarcomatous Local Recurrence.

CASE DESCRIPTION: A 20-year-old woman presented with a rare intracranial inflammatory myofibroblastic tumor (IMT) manifesting as headache and insomnia. Magnetic resonance imaging showed a tumorous lesion with heterogeneous enhancement at the right temporal lobe, as well as perifocal edema with midline shift. The tumor was totally resected with the margin free. Pathologic examination showed IMT with myofibroblastic cells admixed with collagen fibers. Sarcomatous change in morphology was observed in tumor recurrence within 7 months. CONCLUSIONS: Surgical resection and whole brain radiation are recommended in patients with IMT.

The University of Michigan Sarcoma Survivorship Clinic: Preventing, Diagnosing, and Treating Chronic Illness for Improved Survival and Long-Term Health.

The Children's Cancer Survivorship Study reports more chronic illnesses in sarcoma survivors than other pediatric cancers. Chemotherapy and radiation put survivors at risk for developing chronic illnesses, including heart disease, diabetes, hypertension, and kidney failure. Sarcoma survivors may have a reduced life expectancy and signs of heart disease in their 30s and 40s. Since these medical problems occur much later in the general population, they often go undetected or misdiagnosed in sarcoma survivors, creating delays in intervention and treatment. The good news is that these chronic illnesses can often be prevented or minimized. The most common adverse effect of chemotherapy and radiation is coronary artery disease (CAD). CAD has a number of risk factors, including hypertension, diabetes, obesity, and dyslipidemia. These risk factors are modifiable with lifestyle changes, including diet and exercise, and/or pharmacological intervention. By identifying and managing risk factors like hypertension early, we in turn reduce the risk for CAD and prolong survival. This is well established in the general population; there is no reason a priori not to apply it to sarcoma survivors. Sarcoma survivors should be followed by physicians who understand the late effects and outcomes of sarcoma treatment. The University of Michigan Sarcoma Survivorship Clinic provides long-term care for sarcoma survivors by preventing, diagnosing, and treating the adverse long-term physical and psychological effects associated with sarcoma survivorship.

NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression.

Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNß, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression.

The importance of surgical margins in retroperitoneal sarcoma.

Surgery is the "gold-standard" treatment for retroperitoneal sarcomas, but local recurrence is common, and can cause disease-related death. Complete gross resection is associated with improved survival, but debate exists as to whether resection of adjacent organs to improve margins or prescription of neoadjuvant radiation leads to better outcomes. This review summarizes data addressing prognostic value of margin, extent of surgery necessary to optimize treatment of retroperitoneal sarcomas, and role of histology in optimizing therapy.

Cytoreductive Surgery and HIPEC as a Treatment Option for Laparoscopic Resection of Uterine Leiomyosarcoma with Morcellation: Early Results.

BACKGROUND: A new and frequently utilized treatment option for symptomatic uterine leiomyoma is laparoscopic resection with morcellation so the specimen can be extracted through a small abdominal incision or through the vagina. Some of these tumors (approximately 0.2 %) have malignant foci of uterine leiomyosarcoma (ULMS) that is widely disseminated in the process of resection. These patients are in need of effective additional treatments. METHODS: Patients with ULMS were treated with a standardized cytoreductive surgery (CRS), hyperthermic perioperative chemotherapy (HIPEC), and early postoperative intraperitoneal chemotherapy (EPIC) specifically designed for sarcomatosis. Distribution of disease by Peritoneal Cancer Index was recorded by preoperative computed tomography or magnetic resonance imaging and at the time of CRS. Completeness of cytoreduction score was determined after completion of CRS. Morbidity and mortality, as well as interval to start systemic chemotherapy, were prospectively recorded. RESULTS: Six patients with disseminated ULMS after morcellation or slicing underwent CRS and HIPEC plus EPIC. All six patients had complete visible clearing of sarcoma prior to perioperative chemotherapy. Early intervention after morcellation was associated with a lesser extent of disease. No serious morbidity or mortality was observed in early referral patients, and patients eligible for systemic chemotherapy were treated with perioperative chemotherapy within 6 weeks of the CRS. CONCLUSIONS: The future use of laparoscopic resection of ULMS with morcellation is currently under debate. However, patients after laparoscopic resection and morcellation have CRS and HIPEC plus EPIC as a treatment option. Results regarding short-term benefit are suggested by these early data, especially with early referral.

The role of margins in extremity soft tissue sarcoma.

For extremity soft tissue sarcomas, limb salvage is now standard of care. The extent of surgical margins is balanced with functionality of the resected limb. Although negative margins are the goal, the necessary width is unclear. Additional considerations for margin adequacy include presence of anatomic barriers such as fascia and periosteum, proximity of critical structures, receipt of adjuvant and neoadjuvant therapies, and histologic subtype. Multidisciplinary team discussion is critical for treatment planning.

Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA.

Sarcomas are malignant tumors accounting for a high percentage of cancer morbidity and mortality in children and young adults. Surgery and radiation therapy are the accepted treatments for most sarcomas; however, patients with metastatic disease are treated with systemic chemotherapy. Many tumors display marginal levels of chemoresponsiveness and new treatment approaches are needed. Deregulation of the G1 checkpoint is crucial for various oncogenic transformation processes, suggesting that many cancer cell types depend on CDK4/6 activity. Thus, CDK4/6 activity appears to represent a promising therapeutic target for cancer treatment. In the present work, we explore the efficacy of CDK4 inhibition using palbociclib (PD0332991), a highly selective inhibitor of CDK4/6, in a panel of sarcoma cell lines and sarcoma tumor xenografts (PDXs). Palbociclib induces senescence in these cell lines and the responsiveness of these cell lines correlated with their levels of CDK4 mRNA. Palbociclib is also active in vivo against sarcomas displaying high levels of CDK4 but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a. The analysis of tumors growing after palbociclib showed a clear decrease in the CDK4 levels, indicating that clonal selection occurred in these treated tumors. In summary, our data support the efficacy of CDK4 inhibitors against sarcomas displaying increased CDK4 levels, particularly fibrosarcomas and MPNST. Our results also suggest that high levels of p16ink4a may indicate poor efficacy of CDK4 inhibitors.

Elevated expression of HSP90 and the antitumor effect of an HSP90 inhibitor via inactivation of the Akt/mTOR pathway in undifferentiated pleomorphic sarcoma.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a heterogeneous tumor group, and little is known about molecular target therapy for UPS. Heat shock protein 90 (HSP90) is an expressed chaperone that refolds certain denatured proteins under stress conditions. One of these proteins is Akt. The disruption of Akt signaling plays an important role in tumor progression. The present study's purpose was to analyze the HSP90 expression, Akt/mTOR pathway activation and the correlation between HSP90 expression and its pathway activation in UPS. METHODS: The status of HSP90 and the profiles of the Akt/ mTOR pathway were assessed by immunohistochemistry in 79 samples of UPS, and these data were compared with clinicopathological and histopathological findings. The expressions of indicated proteins were assessed by Western blotting in five frozen samples. After treating UPS cells with the HSP90 inhibitor, we assessed the antitumor effect of the inhibitor. RESULTS: Immunohistochemically, phosphorylated Akt (p-Akt), p-mTOR, p-S6RP and p-4EBP were positive in 57.3, 51.9, 54.5 and 57.1% of the UPS samples, respectively. The expressions of those phosphorylated proteins were correlated with each other. HSP90 expression was elevated in 56.4% of the samples and was correlated with p-Akt, p-mTOR and p-S6RP. The immunohistochemical results were confirmed by Western blotting. The HSP90 inhibitor led to decreased viability and invasiveness of the cells and inactivated the AKT/mTOR pathway in vitro. CONCLUSION: Elevated expression of HSP90 is a poor-prognosis factor and is involved in the activation of the Akt/mTOR pathway in UPS. HSP90 inhibition is a potential treatment option for UPS.

Update for ASCO 2015 sarcoma sessions.

There were over 75 oral or poster presentations in last Spring's American Society for Clinical Oncology (ASCO) sarcoma sessions. These presentations included investigations studying new medical therapy regimens for soft tissue sarcoma (STS) patients with advanced disease, research studies on the relative value of aggressive local therapies for certain histologies of STS, and innovative investigations evaluating prognostic (and potentially therapeutic) implications of next generation sequencing of tumors and circulating tumor DNA. This paper serves to review select presentations from the sessions in the meeting.

Management of sporadic desmoid-type fibromatosis: a European consensus approach based on patients' and professionals' expertise - a sarcoma patients EuroNet and European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group initiative.

Desmoid-type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. It may affect nearly all parts of the body including extremities, trunk and abdomen. Considering the variable clinical presentations, anatomic locations and biological behaviours, an individualised treatment approach is required. No established or evidence-based approach for the treatment of this neoplasm is available as of today. Therefore, we propose a consensus treatment algorithm based on a round table meeting bringing together sarcoma experts from the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) with patient advocates from Sarcoma Patients EuroNet (SPAEN). The aim of the meeting was to develop - for the first time ever - a consensus approach based on professionals' AND patients' expertise. As a fundamental prerequisite, all patients should be discussed in a multidisciplinary setting in centres or professional networks with a specific expertise in the disease.

Patient preferences for clinical follow-up after primary treatment for soft tissue sarcoma: a cross-sectional survey and discrete choice experiment.

BACKGROUND: Patients treated for soft tissue sarcoma (STS) require long-term follow-up to detect recurrent or metastatic disease, yet marked differences exist in clinical approaches to the length of follow-up, frequency of consultations and investigations undertaken at follow-up visits. There has been no published work assessing patient expectations or the acceptability of post-treatment follow-up strategies. This study aimed to assess the patient acceptability of different follow-up strategies following curative surgery for soft tissue sarcoma and to investigate the hypothetical levels of recurrence risk at which different follow-up regimes were acceptable. METHODS: Patients were recruited from the Royal Orthopaedic Hospital in Birmingham. The study used a cross-sectional survey incorporating a best-worst scaling discrete choice experiment to assess patient preferences regarding different aspects of follow-up. RESULTS: 132 patients participated (47% response). The nature of investigations undertaken during follow-up was the most important aspect of post-surgical care. Patients typically preferred appointments routinely consisting of clinical examination and chest X-ray, and for follow-up to remain in secondary care rather than general practice. CONCLUSION: Clear protocols for STS patient follow-up can improve consistency and equity of care. In determining the optimum follow-up plan for STS patients from the patient perspective, this study provides valuable information that should be considered alongside the clinical effectiveness of follow-up strategies to maximise patient outcomes and use NHS resources appropriately.

[Role of radiotherapy in the treatment of retroperitoneal soft tissue sarcomas]. / A sugárterápia szerepe a retroperitoneális lágyrészszarkómák kezelésében.

Soft tissue sarcomas are rare tumors, composing 1% of all malignancies. Fifteen percent of them are situated in the retroperitoneal region. The primary curative treatment for this group of patients is complete surgical resection. In most cases, due to their large size and localization at diagnoses, complete resection (R0) is not feasible. The main cause of disease-specific death is local recurrence. Therefore, improved local control by radiotherapy (RT) may contribute to better survival results. Based on international studies, despite the frequent positive surgical margins, only 25% of the patients with retroperitoneal sarcoma (RPS) receive perioperative RT. We performed a literature review based on the available data on the role of RT in the management of RPS. The 5-year local recurrence-free survival after surgery alone, and surgery + RT has been reported in the range of 23-54% and 40-62%, respectively. The respective 5-year rate of overall survival was of 33-49% and 48-64%. There are no available results from prospective randomized studies comparing surgery to surgery + RT. The majority of studies were retrospective and the treatments were performed over a time span of several decades. The total dose, technique and timing of RT were not standardized. Gastrointestinal and genitourinary side effects of RT are common, but their incidence and severity can be significantly reduced by using modern techniques. Based on the currently available studies, RT improves local control and it may play a role in the prolongation of overall survival as well. However, prospective randomized studies are needed to clarify the role of RT in the multidisciplinary management of RPS.

Use of intraoperative radiotherapy for upper-extremity soft-tissue sarcomas: analysis of disease outcomes and toxicity.

OBJECTIVES: To review outcomes for patients who received intraoperative radiotherapy (IORT) for upper-extremity sarcoma. METHODS: We identified patients with upper-extremity tumors who were treated with external beam radiotherapy, surgery, and IORT, with or without chemotherapy. Kaplan-Meier estimates for overall survival (OS), central control (CC), local control (LC), and distant control (DC) were obtained. RESULTS: Sixty-one patients were identified. Median age was 50 years (range, 13 to 95 y). Median follow-up was 5.9 years. Eleven patients had gross (R2; n=1) or microscopic (R1; n=10) disease at the time of IORT. IORT doses ranged from 7.50 to 20.00 Gy. External beam radiotherapy doses ranged from 19.80 to 54.00 Gy. OS at 5 and 10 years was 72% and 58%, respectively. LC at 5 and 10 years was 91% and 88%, respectively. DC at 5 and 10 years was 80% and 77%, respectively. Patients treated for recurrent disease had inferior 5-year OS compared with patients with first diagnoses (63% vs. 74%; P=0.02) and lower 5-year LC (67% vs. 94%; P<0.01). For patients with R1 or R2 resections, LC at 5 and 10 years was 100% and 86%, respectively; for patients with R0 resections, LC was 89% at both 5 and 10 years (P=0.98). Severe toxicity attributable to treatment was noted for 4 patients (7%). CONCLUSIONS: For upper-extremity sarcoma, treatment including IORT was associated with excellent LC, limb preservation, and survival. LC rates were excellent for patients with positive margins after resection. Patients with recurrent disease had worse outcomes, but limb preservation was achievable for most patients.

Non-melanoma skin cancer incidence and impact of skin cancer screening on incidence.

Non-melanoma skin cancer (NMSC) is the most common malignancy, whose public health significance is often unrecognized. This analysis has two objectives: first, to provide up-to-date incidence estimates by sex, age group, histological type, and body site; and second, to study the impact of skin cancer screening. The impact of screening on NMSC incidence in Schleswig-Holstein, Germany, is analyzed by comparing four time periods of different screening settings (no screening (1998-2000), pilot project (Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany, SCREEN, 2003-2004), after SCREEN (2004-2008), and nation-wide skin cancer screening (2008-2010)) to a reference region (Saarland, Germany). Age-standardized (Europe) NMSC incidence was 119/100,000 for women and 145/100,000 for men in the most recent screening period in Schleswig-Holstein (2008-2010). During implementation of SCREEN (2003-2004), incidence increased from 81.5/100,000 to 111.5/100,000 (1998-2000) by 47% for women and 34% for men. All age groups in women were affected by the increase, but increases for men were mostly limited to the older age groups. Incidence in Saarland first increased slowly, but increased steeply with the introduction of the nation-wide skin cancer screening in 2008 (+47% for women and +40% for men, reference 2004-2008). Observed changes are most likely attributed to screening activities.

Soft-tissue sarcomas in the Asia-Pacific region: a systematic review.

BACKGROUND: Soft-tissue sarcomas require tailored and multidisciplinary treatment and management. However, little is known about how sarcomas are treated and managed throughout the Asia-Pacific region. MATERIALS AND METHODS: MEDLINE was systematically searched using prespecified criteria. Publications (previous 10 years) that reported tumour characteristics, treatment patterns, survival outcomes, and/or safety outcomes of patients with soft-tissue sarcoma were selected. Exclusion criteria were studies of patients <18 years of age; ≤ 10 patients; countries other than Australia, Hong Kong, Indonesia, Korea, Malaysia, New Zealand, Philippines, Singapore, Taiwan, or Thailand; >20% benign tumours; sarcomas located in bones or joints; gastrointestinal stromal tumour; Kaposi's sarcoma; or not reporting relevant outcomes. RESULTS: Of the 1,822 publications retrieved, 35 (32 studies) were included. Nearly all patients (98%, 1,992/2,024; 31 studies) were treated with surgery, and more studies used adjuvant radiotherapy than chemotherapy (24 vs 17 studies). Survival outcomes and recurrence rates varied among the studies because of the different histotypes, sites, and disease stages assessed. Only 5 studies reported safety findings. CONCLUSIONS: These findings highlight the lack of specific data available about soft-tissue sarcomas in the Asia-Pacific region. Better efforts to understand how the sarcoma is managed and treated will help improve patient outcomes in the region.

[Surgery and postoperative radiation therapy in primary retroperitoneal sarcomas: experience of the cancer centre Alexis-Vautrin]. / Intérêt de la radiothérapie postopératoire dans la prise en charge des sarcomes rétropéritonéaux primitifs : expérience du centre Alexis-Vautrin.

PURPOSE: Surgical resection remains the standard treatment for patients with resectable retroperitoneal sarcomas. The aim of this study was to retrospectively analyse the outcomes of patients with primary retroperitoneal sarcoma. PATIENTS AND METHODS: We analysed data of 50 patients with primary retroperitoneal sarcoma who underwent curative-intent resection from 1975 to 2008. External beam radiotherapy and chemotherapy were delivered postoperatively. Demographics, surgical, pathological variables and chemo/radiation therapy were analysed as prognosis factors. RESULTS: There were 22 males and 28 females (mean age 54 ± 13 years). Surgery required visceral resections in 30 patients. There were 16 leiomyosarcomas, 25 liposarcomas and eight other sub-types. Twenty-one patients had clear surgical margins. Twenty-eight patients received postoperative external beam radiotherapy (median 45 Gy) and 15 received chemotherapy. At the end of the follow-up (median 55 months), local recurrence occurred in 39% (n=14) among R0/R1 resection group (n=36). Postoperative external beam radiotherapy tends to increase the time of local recurrence from surgery (27 vs. 13 months, P=0.05). The overall survival rates were 81%, 55% and 46% at 1, 3 and 5 years, respectively. Although R0 resection (P=0.01), well tumour differentiation (P=0.004) and postoperative external beam radiotherapy (P=0.02) significantly influenced overall survival in univariate analysis, only R0 resection was an independent prognostic factor in a multivariate analysis. CONCLUSION: We confirm the pre-eminence of radical surgery with negative margins as major prognostic factor and the benefit of postoperative radiotherapy.