Occupation and soft-tissue sarcoma in northeastern Italy

The influence of occupation and exposure to different agents on the risk of developing soft-tissue sarcoma (STS) was assessed in a case-control study based on 93 cases of STS (53 men and 40 women) and 721 controls (371 men and 350 women), conducted in northeastern Italy. No risk elevation was found in subjects employed in agriculture (odds ratio [OR] for > 10 years = 0.8,95 percent confidence interval [CI]=0.4–1.5), nor in those who reported exposure to pesticides or herbicides (OR=0.4, CI=0.1–1.2). Similarly, neither occupation in the furniture, upholstery, and mechanics industries, nor exposure to livestock or meat processing, wood dust, metal dust, and dyes or paints were associated with STS risk. Workers who reported exposure to chemical agents or to benzene or other solvents for more than 10 years had, respectively, a 1.8-fold (CI=0.7–4.4) and a 2.2-fold (CI=0.9-5.5) higher risk of developing STS. Although the small number of STS cases limits the interpretation of the study results, these findings weigh against the hyphothesis that pesticides, herbicides, or other exposures related to agriculture, play an important role in the etiology of STS. The direct associations with exposure to chemical agents and benzene or other solvents, albeit not statistically significant, may provide a useful hint for future investigations.Drs Serraino and Franceschi are with the Epidemiology Unit, and Dr Carbone is with the Department of Pathology at the Aviano Cancer Center, Aviano, Italy. Dr La Vecchia is with the Mario Negri Institute for Pharmacological Research, Milan, Italy and the Institute of Social and Preventive Medicine, Lausanne, Switzerland. Address correspondence to Dr Serraino at the Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ. 33081 Aviano (PN), Italy. The work was supported by the contribution of the Italian Association for Cancer Research, Milan, and the Italian National Research Council (CNR Applied Project Clinical Application of Oncological Research, Contract 87.01544.44).     

Body weight and risk of soft-tissue sarcoma.

The relation between body mass (BMI) and soft-tissue sarcoma (STS) risk was evaluated in a case-control study from Northern Italy based on 217 incident STS and 1297 hospital controls. The risk of STS rose with BMI, with multivariate odds ratios of 3.49 (95% confidence interval (CI) 1.06-11.55) among men and 3.26 (95% CI 1.27-8.35) among women with a BMI > 30 kg m(-2) compared to those with BMI < or = 20 kg m(-2).     

Increased risk of malignancies in a population-based study of 818 soft-tissue sarcoma patients

Soft-tissue sarcomas (STS) have been associated with various rare cancer syndromes and occur at increased frequencies in survivors of childhood cancer. Also adult patients with STS have been suggested to be at an increased risk of additional malignancies. After exclusion of syndrome-associated and radiation-induced sarcomas, we studied multiple primary malignancies in a population-based cohort of 818 patients with primary STS of the extremities and the trunk wall. In total, 203 other malignancies developed in 164 (20%) patients median 10 (0-32) years before and median 4 (0-35) years after the sarcoma diagnosis. Standardised morbidity ratios (SMRs) were determined for primary malignancies following a STS. Hereby individuals who had developed a STS were identified to be at increased risk of second primary malignancies (SMR for all malignant tumours=1.3; 95% CI=1.0-1.5; P=0.02) with STS being the only specific tumour type that occurred at an increased risk (SMR=17.6; 95% CI=8.1-33.5; P<0.001). Hence, this population-based series demonstrates a high frequency of second primary tumours among STS patients and indicates a particularly increased risk of developing a new STS.     

A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma

Background:

Preoperative radiotherapy (RT) is commonly used to treat localised soft-tissue sarcomas (STS). Hypoxia is an important determinant of radioresistance. Whether antiangiogenic therapy can ‘normalise'' tumour vasculature, thereby improving oxygenation, remains unknown.

Methods:

Two cohorts were prospectively enrolled. Cohort A evaluated the implications of hypoxia in STS, using the hypoxic tracer ¹⁸F-azomycin arabinoside (FAZA-PET). In cohort B, sunitinib was added to preoperative RT in a dose-finding phase 1b/2 design.

Results:

In cohort A, 13 out of 23 tumours were hypoxic (FAZA-PET), correlating with metabolic activity (r²=0.85; P<0.001). Two-year progression-free (PFS) and overall (OS) survival were 61% (95% CI: 0.44–0.84) and 87% (95% CI: 0.74–1.00), respectively. Hypoxia was associated with radioresistance (P=0.012), higher local recurrence (Hazard ratio (HR): 10.2; P=0.02), PFS (HR: 8.4; P=0.02), and OS (HR: 41.4; P<0.04). In Cohort B, seven patients received sunitinib at dose level (DL): 0 (50 mg per day for 2 weeks before RT; 25 mg per day during RT) and two patients received DL: −1 (37.5 mg per day for entire period). Dose-limiting toxicities were observed in 4 out of 7 patients at DL 0 and 2 out of 2 patients at DL −1, resulting in premature study closure. Although there was no difference in PFS or OS, patients receiving sunitinib had higher local failure (HR: 8.1; P=0.004).

Conclusion:

In STS, hypoxia is associated with adverse outcomes. The combination of sunitinib with preoperative RT resulted in unacceptable toxicities, and higher local relapse rates.     

A case-control study of stomach cancer and its relation to diet,cigarettes, and alcohol consumption in Saitama Prefecture,Japan

A case-control study of stomach cancer in relation to dietary, smoking, and drinking habits was undertaken in Saitama Prefectur, Japan. The study was based on 294 cases of newly diagnosed adenocarcinoma of the stomach at a single institution, 294 general population controls (matched by sex, age, and administrative division), and 202 hospital controls. Dietary habits were investigated based on the intake of 12 separate foods and 12 food groups in a food frequency questionnaire, together with individual food preferences. The consumption of raw vegetables was inversely related to the risk of stomach cancer, with a dose-response relation observed consistently in the comparisons with both sets of controls. Current cigarette smokers (1–29/day) had an increased risk (relative risk = 1.8,95 percent confidence interval = 1.1–3.0) compared with nonsmokers in the general population controls, but no dose-response effect with heavier cigarette smoking. Alcohol use did not affect the risk of stomach cancer. In the multiple logistic regression, the comsumption of raw vegetables showed a protective effect on stomach cancer while cigarette smoking had no significant association, in both sets of controls.Drs Hoshiyama and Sasaba are in the Department of Epidemiology, Saitama Cancer Center Research Institute, Japan. Address correspondence to Dr Hoshiyama, Komuro 818, Ina, Saitama 362, Japan.     

Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients

Background:

The concept of the involvement of systemic inflammation in cancer progression and metastases has gained attraction within the past decade. C-reactive protein (CRP), a non-specific blood-based marker of the systemic inflammatory response, has been associated with decreased survival in several cancer types. The aim of the present study was to validate the prognostic value of pre-operative plasma CRP levels on clinical outcome in a large cohort of soft-tissue sarcoma (STS) patients.

Methods:

Three hundred and four STS patients, operated between 1998 and 2010, were retrospectively evaluated. CRP levels and the impact on cancer-specific survival (CSS), disease-free survival (DFS) and overall survival (OS) were assessed using Kaplan–Meier curves and univariate as well as multivariate Cox proportional models. Additionally, we developed a nomogram by supplementing the plasma CRP level to the well-established Kattan nomogram and evaluated the improvement of predictive accuracy of this novel nomogram by applying calibration and Harrell''s concordance index (c-index).

Results:

An elevated plasma CRP level was significantly associated with established prognostic factors, including age, tumour grade, size and depth (P<0.05). In multivariate analysis, increased CRP levels were significantly associated with a poor outcome for CSS (HR=2.05; 95% CI=1.13–3.74; P=0.019) and DFS (HR=1.88; 95% CI=1.07–3.34; P=0.029). The estimated c-index was 0.74 using the original Kattan nomogram and 0.77 when the plasma CRP level was added.

Conclusion:

An elevated pre-operative CRP level represents an independent prognostic factor that predicts poor prognosis and improves the predictive ability of the Kattan nomogram in STS patients. Our data suggest to further prospectively validate its potential utility for individual risk stratification and clinical management of STS patients.     

Clinical significance of margin status in postoperative radiotherapy for extremity and truncal soft-tissue sarcoma

PURPOSE: To evaluate whether adjuvant radiotherapy (RT) in extremity and truncal soft-tissue sarcoma (STS) patients with microscopically positive or close margins after excision can achieve comparable local control to that of excision with negative margin plus RT. METHODS AND MATERIALS: A total of 150 patients (111 extremity and 39 trunk cases) treated with conserving surgery and adjuvant RT was analyzed. All surgical margins were classified as being a negative margin or a positive or close margin based on pathologic margin width. RT was delivered with a shrinking-field technique in 150 patients (median, 63 Gy). RESULTS: All patients were divided into two groups: (A) excision with negative margins plus RT (n = 56) and (B) excision with positive or close margins plus RT (n = 94). Overall, the 5-year local failure-free survival in all patients was 72.9%, and no significant differences were found between the two groups (Group A, 74.7%; Group B, 71.6%). High tumor grade was found to be a significant predictor of local failure. However, Group A was superior to Group B in distant metastasis-free survival (p = 0.02). No significant differences were shown in overall survival between the two groups. CONCLUSIONS: In our series, margin status did not predict for LF when adjuvant RT was used. We believe that when adjuvant RT is used, re-resection may not be necessary for selected patients with positive or close pathologic margins in the management of extremity and truncal STS patients.     

Cost-effectiveness of pazopanib in advanced soft-tissue sarcoma in Canada

Background

In the phase iii palette trial of pazopanib compared with placebo in patients with advanced or metastatic soft-tissue sarcoma (sts) who had received prior chemotherapy, pazopanib treatment was associated with improved progression-free survival (pfs). We used an economic model and data from palette and other sources to evaluate the cost-effectiveness of pazopanib in patients with advanced sts who had already received chemotherapy.

Methods

We developed a multistate model to estimate expected pfs, overall survival (os), lifetime sts treatment costs, and quality-adjusted life-years (qalys) for patients receiving pazopanib or placebo as second-line therapy for advanced sts. Cost-effectiveness was calculated alternatively from the health care system and societal perspectives for the province of Quebec. Estimated pfs, os, incidence of adverse events, and utilities values for pazopanib and placebo were derived from the palette trial. Costs were obtained from published sources.

Results

Compared with placebo, pazopanib is estimated to increase qalys by 0.128. The incremental cost of pazopanib compared with placebo is CA$20,840 from the health care system perspective and CA$15,821 from the societal perspective. The cost per qaly gained with pazopanib in that comparison is CA$163,336 from the health care system perspective and CA$124,001 from the societal perspective.

Conclusions

Compared with placebo, pazopanib might be cost-effective from the Canadian health care system and societal perspectives depending on the threshold value used by reimbursement authorities to assess novel cancer therapies. Given the unmet need for effective treatments for advanced sts, pazopanib might nevertheless be an appropriate alternative to currently used treatments.     

New medical treatment options and strategies to assess clinical outcome in soft-tissue sarcoma

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignant tumors predominantly arising from the embryonic mesoderm. The mainstay of curative therapy is the complete surgical resection of all tumor manifestations with negative histological margins. However, up to 50% of patients will develop distant metastases during the course of their disease. The prognosis for those patients is grim with a 5-year overall survival of less than 10%. First-line systemic therapy with ifosfamide and doxorubicin results in overall response rates of only 20% by conventional response evaluation criteria in solid tumors (RECIST). However, stabilization of disease can be seen in a greater proportion. Therefore, the role of the RECIST criteria has been questioned and the implementation of new imaging studies (e.g., FDG-PET) has shown promising results in assessing early tumor response to therapy. Furthermore, a broader insight into the molecular pathways of sarcomagenesis has been gained in recent years, revealing intriguing targets for new therapeutic approaches (e.g., VEGF, VEGF receptor, IGF receptor, EGF receptor, mTOR and cyclin-dependent kinases). In addition, a growing body of evidence is linking specific genetic aberrations with clinical outcome (e.g., SYT–SXX translocation in synovial sarcoma). With further insight into the biology of STS and the combination of new treatment options with modern imaging techniques, we will most certainly be able to improve clinical outcome in patients with STS in the upcoming years.     

Perioperative chemotherapy in patients undergoing pulmonary resection for metastatic soft-tissue sarcoma of the extremity : a retrospective analysis

BACKGROUND: The benefit of chemotherapy in the treatment of primary soft-tissue sarcoma (STS) is controversial. To the authors' knowledge, few studies to date have examined the effect of chemotherapy in patients undergoing pulmonary resection for metastatic STS of the extremity. METHODS: Between 1990 and 2005, 1897 patients with extremity STS were treated and prospectively followed at a single institution. In all, 508 patients (27%) developed lung metastases as the first site of distant recurrence, and 138 (7%) were treated with pulmonary resection. RESULTS: Perioperative chemotherapy was administered to 53 patients (38%). Age at diagnosis and disease-free interval were significantly different between patients who received perioperative chemotherapy and those who did not, whereas sex, grade, size of the primary tumor, depth, histology, number and size of lung metastases, and rate of complete resection were not. The median postmetastasis disease-specific survival was 24 months in patients who were treated with surgery and chemotherapy compared with 33 months in patients who were treated with surgery alone (P = .19). The median postmetastasis pulmonary progression-free survival in the 2 groups was 10 months and 11 months, respectively (P = .63). Multivariate Cox proportional hazards modeling and propensity score analysis revealed no association between perioperative chemotherapy and disease-specific, overall, or pulmonary progression-free survival. CONCLUSIONS: Although it is difficult to completely control for the effects of selection bias on outcome in this highly selected cohort of patients, data from the current study suggest that systemic chemotherapy has minimal, if any, long-term impact on the outcome of patients undergoing pulmonary resection for metastatic STS of the extremity.     

Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients

Background:

Recent data indicate that tumour microenvironment, which is influenced by inflammatory cells, has a crucial role in cancer progression and clinical outcome of patients. In the present study, we investigated the prognostic relevance of preoperative neutrophil/lymphocyte (N/L) ratio on time to tumour recurrence (TTR) and overall survival (OS) in soft-tissue sarcoma (STS) patients who underwent curative surgical resection.

Methods:

In all, 260 STS patients were included in this retrospective study. Kaplan–Meier curves and multivariate Cox proportional models were calculated for TTR and OS.

Results:

In univariate analysis, elevated N/L ratio was significantly associated with decreased TTR (hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.30–4.14; P=0.005) and remained significant in the multivariate analysis (HR, 1.98; 95%CI, 1.05–3.71; P=0.035). Patients with elevated N/L ratio showed a median TTR of 77.9 months. In contrast, patients with low N/L ratio had a median TTR of 99.1 months. Regarding OS, elevated N/L ratio was also significantly associated with decreased survival in univariate analysis (HR, 2.90; 95%CI, 1.82–4.61; P=0.001) and remained significant in multivariate analysis (HR, 1.88; 95%CI, 1.14–3.12; P=0.014).

Conclusion:

In conclusion, our findings suggest that an elevated preoperative N/L ratio predicts poor clinical outcome in STS patients and may serve as a cost-effective and broadly available independent prognostic biomarker.     

Combined modalities approach for localized adult extremity soft-tissue sarcoma

Extremity soft-tissue sarcomas are a heterogeneous group of rare neoplasms, characterized by a broad spectrum of biological aggressiveness and a uniform tendency for local failure if not adequately treated. Surgery is the mainstay of therapy, and the availability of multidisciplinary surgical skills allows adequate margins with acceptable morbidity to be obtained. Local therapies, such as radiation therapy or isolated limb perfusion, alone or in combination with systemic agents, may help to further improve local control, especially in difficult presentations. The possible impact of systemic treatment on survival is still a matter of debate, and the agents used so far have not provided a major breakthrough, even in selected populations at high risk of disease spread. Nevertheless, soft-tissue sarcomas are no longer considered a unique disease. More than 50 different histotypes can now be well recognized, with distinct biological and molecular characteristics, which lead to different clinical behavior and a potentially different sensitivity to targeted agents. Therefore, it is more essential than ever for treatment of these patients to be delivered in referral centers, where a dedicated multidisciplinary team is able to administer histology and clinically driven approaches. The employment of combined modalities will be able to maximize the chance of local cure even in difficult presentations, and possibly improve survival, especially in high-risk disease.     

Surgical margins and handling of soft-tissue sarcoma in extremities: a clinical practice guideline

Questions

1. In limb salvage surgery for extremity soft-tissue sarcoma (sts), what is an adequate surgical margin?
2. What is the appropriate number of samples to take from the margins of a surgical resection specimen?
3. What is the appropriate handling of surgical resection specimens?

Background

Surgery is the primary treatment for extremity sts. The combination of radiotherapy with surgery allows for limb salvage by using radiation to biologically “sterilize” microscopic extensions of tumour and to spare neurovascular and osseous structures. Adjuvant chemotherapy in sts—except for rhabdomyosarcoma and Ewing sarcoma—continues to be controversial.

Methods

The medline and embase databases (1975 to June 2011) and the Cochrane Library were searched for pertinent studies. The Web sites of the main guideline organizations and the American Society of Clinical Oncology conference proceedings (2007–2010) were also searched.

Results and Conclusions

Thirty-three papers, including four guidelines, one protocol, and one abstract, were eligible for inclusion.The data suggest that patients with clear margins have a better prognosis, but no prospective studies have indicated how wide margins should be. In limb-salvage surgery for extremity sts, the procedure should be planned to achieve a clear margin. However, to preserve functionality, surgery may result in a very close (<1 cm) or even microscopically positive margin. In this circumstance, the use of preoperative or postoperative radiation should be considered.No studies described the optimal number of tissue sections required to assess adequacy of excision nor the appropriate handling of surgical resection specimens. The Sarcoma Disease Site Group made its recommendations based on expert opinion and consensus.     

鲁北地区子宫内膜癌发病因素病例对照研究

目的：了解子宫内膜癌发病情况及相关因素,为临床进行预防及治疗提供依据。方法：采用病例-对照流行病学分析方法,对鲁北地区6所三级医院2006-05-01-2011-10-01病理确诊的289例子宫内膜癌患者及174例对照进行统一问卷调查;采用单因素和多因素的Logistic回归分析,以OR和95%可信区间为评价指标,分析与子宫内膜癌有关联的危险性因素。结果：鲁北地区子宫内膜癌患者289例,其中子宫内膜样腺癌259例（90%）;非子宫内膜样腺癌（浆液性腺癌,透明细胞癌等）30例（10%）。Ⅰ期患者219例（76%）,Ⅱ期患者29例（10%）,Ⅲ~Ⅳ期患者共41例（14%）。子宫内膜癌的发病年龄为25~78岁,平均发病年龄为55.41岁,58~61岁为发病高峰。已绝经妇女占62%。单因素分析结果表明,高血压（OR=3.67,χ2=33.70,P=0.00）、糖尿病（OR=1.92,χ2=4.13,P=0.04）、肥胖（OR=4.63,χ2=50.62,P=0.00）、饮用茉莉花茶史（OR=2.63,χ2=19.84,P=0.00）、重体力劳动（OR=1.82,χ2=9.28,P=0.00）、月经不规律（OR=12.68,χ2=107.20,P=0.00）、口服中草药调经（OR=15.21,χ2=68.82,P=0.00）、绝经年龄（OR=1.10,χ2=11.56,P=0.00）、未产（OR=19.07,χ2=15.84,P=0.00）和一级亲属恶性肿瘤家族史（OR=2.91,χ2=12.22,P=0.00）等可增加子宫内膜癌发病风险;使用宫内节育器（intrauterine device,IUD）可降低子宫内膜癌发病风险,OR=0.29,χ2=37.21,P=0.00。多因素Logistic回归分析结果表明,高血压（OR=3.69,95%CI：1.89~7.22）、肥胖（OR=3.06,95%CI：1.62~5.75）、月经不规律（OR=4.53,95%CI：2.13~9.60）、口服中草药调经（OR=9.31,95%CI：2.91~29.76）、绝经年龄晚（OR=1.13,95%CI：1.06~1.20）和一级亲属恶性肿瘤家族史（OR=5.20,95%CI：2.13~12.73）是内膜癌发病的危险因素;使用IUD是内膜癌的保护性因素,OR=0.84,95%CI：0.79~0.88。结论：高血压、肥胖和绝经年龄等因素可影响子宫内膜癌的发生,应针对相关危险因素采取相应的预防措施。