C. Le Pechoux

Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials

PURPOSE Since our individual patient data (IPD) meta-analysis (MA) of supportive care and chemotherapy for non-small-cell lung cancer (NSCLC), published in 1995, many trials have been completed. An updated, IPD MA has been carried out to assess newer regimens and determine conclusively the effect of chemotherapy. METHODS Systematic searches for randomized controlled trials (RCTs) were undertaken, followed by central collection, checking, and reanalysis of updated IPD. Results from RCTs were combined to calculate individual and pooled hazard ratios (HRs). RESULTS Data were obtained from 2,714 patients from 16 RCTs. There were 1,293 deaths among 1,399 patients assigned supportive care and chemotherapy and 1,240 among 1,315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR, 0.77; 95% CI, 0.71 to 0.83; P <or= .0001), equivalent to a relative increase in survival of 23% or an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29%. There was no clear evidence that this effect was influenced by the drugs used (P = .63) or whether they were used as single agents or in combination (P = .40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = .77). There was no clear evidence of a difference or trend in the relative effect of chemotherapy across patient subgroups. CONCLUSION This MA of chemotherapy in the supportive care setting demonstrates conclusively that chemotherapy improves overall survival in all patients with advanced NSCLC. Therefore, all patients who are fit enough and wish to receive chemotherapy should do so.

Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM. To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in ∼10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patients performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.

Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data

Summary Background Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy. Methods We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat. Findings The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0·86, 95% CI 0·81–0·92, p<0·0001), with an absolute increase in survival of 4% (95% CI 3–6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0·88, 95% CI 0·81–0·97, p=0·009), representing an absolute improvement in survival of 4% (95% CI 1–8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup. Interpretation The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy. Funding UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Effect of dose rate on local control and complications in definitive irradiation of T1-2 squamous cell carcinomas of mobile tongue and floor of mouth with interstitial iridium-192.

From 1971 to 1988, 134 T1 and 145 T2 biopsy-proven squamous cell carcinomas of mobile tongue and floor of mouth were definitively managed by iridium-192. Implantations were performed using either guide gutters or afterloading plastic catheters. The prescribed dose at the reference isodose (85% of the basal dose rate, Paris system) was 60-70 Gy. Total dose was not adjusted to dose rate or tumor volume. Results of the 279 implants have been analysed to look for a possible influence of dose rate on local control and necrosis. Follow-up patients free of local recurrence is 1-180 months with average of 51 months. The 279 tumors were divided in four groups according to dose and dose rate: greater than or equal to 62.5 Gy and greater than or equal to 0.5 Gy/h (n = 130), greater than or equal to 62.5 Gy and less than 0.5 Gy/h (n = 36), less than 62.5 Gy and greater than or equal to 0.5 Gy/h (n = 81), less than 62.5 Gy and less than 0.5 Gy/h (n = 32). The four groups were comparable according to age, sex, tumor diameter and macroscopic aspect. At 5 years, the estimated local control (Kaplan Meier) was 93, 87, 79 and 52%, respectively (dose adjusted to dose rate: p less than 0.001, dose rate adjusted to dose: p less than 0.01, Log-rank); the necrosis rate was 44, 24, 37 and 5%, respectively (dose adjusted to dose rate: p = 0.08, dose rate adjusted to dose: p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally advanced disease.

Prognostic Factors in Primary Breast Sarcomas: A Series of Patients With Long-Term Follow-Up

PURPOSE To describe the pathologic characteristics and prognostic factors of primary breast sarcomas (PBSs). PATIENTS AND METHODS We reviewed the clinical records and pathologic slides of 83 women with PBS treated in our institution between 1954 and 1991, with a median follow-up of 7.8 years. The majority of patients had undergone surgical treatment. RESULTS The main histologic type was malignant fibrohistiocytoma (n = 57). For the whole population, the 10-year overall survival (OS) and disease-free survival (DFS) rates were 62% and 50%, respectively. For Fédération Nationale des Centres de Lutte Contre le Cancer grade 1, 2, and 3 tumors, the 10-year OS and DFS rates were 82% and 61%, 62% and 51%, and 36% and 25%, respectively (P =.00007 and.004, respectively). For tumors measuring less than 5 cm, 5 to 10 cm, and more than 10 cm, the 10-year OS and DFS rates were 76% and 66%, 68% and 55%, and 28% and 15%, respectively (P =.002 and.009, respectively). In the multivariate analysis, the tumor size and histologic grade were correlated with the 10-year DFS rate (P =.04 and.01, respectively), but only the histologic grade was correlated with OS (P =.01). Angiosarcoma was the only histologic type significantly associated with a poorer outcome in the multivariate analysis. CONCLUSION PBSs have the same clinical history and prognostic factors as sarcomas arising at other sites. Therefore, it is legitimate to use a similar treatment strategy for PBS as for other sarcomas.

Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm—a position paper from the Italian and the French Sarcoma Group

Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/&bgr;-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/β-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.

Does adjuvant radiation therapy increase loco-regional control after optimal resection of soft-tissue sarcoma of the extremities?

Adjuvant radiotherapy (RT) is routinely recommended for most soft-tissue sarcomas (STS) of the extremities. However, its impact on local control is not clearly established after wide complete excision. We performed a retrospective analysis of patients who underwent wide resection in our institution (first or second resection in cases of incomplete surgery) and either did or did not receive adjuvant RT. All histological specimens of patients operated upon between 1975 and 1996 were carefully analysed and only patients with free tumour margins (ftm) were retained for the analysis. The histopathological classification was as follows: minimal resection (mR) (ftm<10 mm) and optimal resection (oR) (ftm >/=10 mm). There were 133 patients with a median age of 44 years (range 16-88 years). The median tumour size was 6 cm (range 1-20 cm) with 28, 44 and 28% of stage I, II and III lesions, respectively. 93 patients (70%) were reoperated upon and residual tumour was found in 55% of the patients (51/93). 69 patients (17 oR and 52 mR) received adjuvant RT and 64 patients did not (54 oR and 10 mR). Other patient characteristics (age, tumour size, stage, deep-seated lesion, histoprognostic grade, adjuvant chemotherapy) were similar in both the RT and no-RT groups. Median follow-up was 10 years (3-25 years). The 5- and 10-year local relapse-free survival rates were 78 and 71%, respectively. 33 patients relapsed locally: 11 in the RT group and 22 patients in the control group (P=0.01). In the univariate analysis, adjuvant RT was correlated with relapse-free survival, while tumour grade and tumour margin status were correlated with overall survival. The multivariate analysis demonstrated a favourable impact of RT and negative influence of malignant fibrous histiocytoma (MFH) on local relapse-free survival; the tumour grade was correlated with overall survival. RT had a positive influence on local control exclusively in patients with mR resection (P=0.005) and in patients with residual tumour cells after re-excision (P=0.001). RT had no influence on 5- and 10-year overall survival. The 5- and 10-year overall survival for the entire population were 77 and 67%, respectively. Optimal resection seems to be the best predictive parameter for a favourable outcome in localised STS. Adjuvant RT is indicated after mR resection and for residual tumour after definitive surgery, but its role after oR resection (primary resection or no residual tumour after re-excision) should be evaluated in a prospective randomised trial.

Retroperitoneal sarcomas: patterns of care in advanced stages, prognostic factors and focus on main histological subtypes: a multicenter analysis of the French Sarcoma Group

BACKGROUND Retroperitoneal sarcomas (RPS) are heterogeneous. Advanced stages include unresectable locoregional (LR) disease, abdominal sarcomatosis and distant metastasis. There is no available report assessing palliative chemotherapy in advanced RPS. This study analyzes management and outcome in a large cohort of patients with advanced RPS, considering main histological subtypes separately. PATIENTS AND METHODS We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 across 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist. RESULTS Five-hundred eighty-six patients were included, 299 patients received palliative chemotherapy, with a median of two lines (range 0-8). Fifty patients underwent palliative surgery. Two hundred fifty-five patients (85%) were assessable for response after first line of chemotherapy. Among them, 69 patients (27%) had progressive disease, 145 (57%) had stable disease, 37 (14.5%) had partial response and 4 (1.5%) complete response. Median time from first line of palliative chemotherapy to progression was 5.9 months [4.9-7.3] and median overall survival (OS), 15.8 months [13-18]. In multivariate analysis, prognosis factors independently associated with poor OS were male gender, performance status (PS) >1 and grade >1. There was no difference according to stage of disease. Palliative surgery did not appear to add any survival benefit. CONCLUSION These results emphasize the scarcity of available options for RPS in the advanced setting and the urgent need to develop new strategies. Patients with good PS should be included in clinical trials and best supportive care should be considered in those with poor PS.BACKGROUND Retroperitoneal sarcomas (RPS) are heterogeneous. Advanced stages include unresectable locoregional (LR) disease, abdominal sarcomatosis and distant metastasis. There is no available report assessing palliative chemotherapy in advanced RPS. This study analyzes management and outcome in a large cohort of patients with advanced RPS, considering main histological subtypes separately. PATIENTS AND METHODS We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 across 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist. RESULTS Five-hundred eighty-six patients were included, 299 patients received palliative chemotherapy, with a median of two lines (range 0-8). Fifty patients underwent palliative surgery. Two hundred fifty-five patients (85%) were assessable for response after first line of chemotherapy. Among them, 69 patients (27%) had progressive disease, 145 (57%) had stable disease, 37 (14.5%) had partial response and 4 (1.5%) complete response. Median time from first line of palliative chemotherapy to progression was 5.9 months [4.9-7.3] and median overall survival (OS), 15.8 months [13-18]. In multivariate analysis, prognosis factors independently associated with poor OS were male gender, performance status (PS) >1 and grade >1. There was no difference according to stage of disease. Palliative surgery did not appear to add any survival benefit. CONCLUSION These results emphasize the scarcity of available options for RPS in the advanced setting and the urgent need to develop new strategies. Patients with good PS should be included in clinical trials and best supportive care should be considered in those with poor PS.

Radiotherapy in the management of epidemic Kaposi's sarcoma of the oral cavity, the eyelid and the genitals

From January 1987 to December 1992, 420 patients with acquired immunodeficiency syndrome (AIDS)-related epidemic Kaposis sarcoma (EKS) were treated with radiotherapy at the oncology department in the Henri Mondor Hospital. Of these, 146 (34.7%) exhibited tumours at 186 sites; 35 were oral, 102 eyelid or conjunctival (ophthalmic), and 49 penile or scrotal (genital) sites. Most patients had received prior chemotherapy. Radiation therapy consisted of 4 MV or 45 kV X-rays, depending on tumor size and location. Doses ranged from 10 to 30 Gy, according to tumor response and toxicity. In oral lesions mucosal reactions were often observed after relatively low doses of radiotherapy. In 27 patients receiving 15 Gy, severe reactions were observed in 6 (22%), moderate reactions in 4 (15%) and mild reactions in 17 (63%). By contrast, irradiation of eyelid or conjunctival lesions and genital lesions, was well-tolerated. Treatment was generally successful in achieving good symptom palliation. Eyelid and conjunctival Kaposis sarcoma seemed to be more radiosensitive when compared with cutaneous sites: a high objective remission rate (96%, 98/102) was observed at doses ranging from 10 to 20 Gy. Penile and scrotal lesions showed a good response to low dose radiation (complete response was scored in 34/49 patients (69.4%)). A meticulous evaluation of tolerance was necessary. Toxicity of oropharyngeal irradiation at relatively low doses is an argument for a restrictive use of this procedure in oral lesions.