Preoperative radiotherapy in breast cancer patients: 32 years of follow-up.

This study evaluates the long-term outcomes of a retrospective cohort of breast cancer (BC) patients who had received curatively intended premastectomy radiation therapy (RT). We analysed locoregional control, disease-free survival (DFS) and overall survival (OS), pathological complete remission (pCR), predictors thereof, and immediate safety. The series consisted of 187 patients with a median age of 49 years [43-60] and T2-T4 or N2 tumours. Between 1970 and 1984, they had received slightly hypofractionated RT to the whole breast, ipsilateral supraclavicular fossa and axilla ± the internal mammary chain (45-55 Gy/18 fractions of 2.5 Gy/34 days) systematically followed by a modified radical mastectomy with an axillary dissection. No other preoperative treatment was given. Among the 166 centrally reviewed tumour biopsy specimens, 22% had a triple-negative (TN) phenotype, 17% were HER2 3 + or amplified and 61% were ER+. The median follow-up was 32 years [23-35]. The 25-year locoregional control rate was 89% [93%-82%] and the 25-year DFS and OS rates were identical, 30% [24%-37%]. A pCR in the tumour and lymph nodes had been achieved in 18 among all patients (10%), but in 26% with TN disease. In the multivariate analysis, the TN status was the only predictive factor of pCR (OR = 5.49, 95% confidence interval [CI] 1.87-16.1, p = 0.002). Also, the pN status (HR = 1.69, [1.28-2.22], p = 0.0002) and TN subtype (HR = 1.80, [1.00-3.26], p = 0.05) exerted a significant prognostic impact on OS. The postoperative complication rate (grade >2) was 19% with 4.3% of localized skin necrosis. Preoperative RT followed by radical surgery is feasible and associated with good long-term locoregional control.

Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC).

Background: Lymphocytic infiltration at diagnosis is prognostic in EOC, however, the impact of NACT on tumour infiltrating lymphocytes (TILs) or PD-L1 expression remains poorly described. Patients and methods: Patients with EOC and sequential samples (pre-NACT, post-NACT or relapse) were retrospectively identified. TILs were evaluated on whole sections; stromal TILs (sTILs) scored as percentage of stromal area with high sTILs defined as ≥50%; intra-epithelial TILs (ieTILs) scored semi-quantitatively (0-3) with high ieTILs ≥2. A smaller number were available for PD-L1 evaluation, cut-off for positivity was ≥5% staining. Results: sTILs were detected in all tumours at diagnosis (range 2-90%, median 20%), with 22% (25/113) showing high sTILs. Among evaluable paired pre/post-NACT samples (N = 83), an overall increase in median sTILs from 20% to 30% was seen following NACT (P = 0.0005); individually the impact of NACT varied with sTILs increasing in 51% (42/83), decreasing in 25%, and stable in 24%. Post-NACT sTILs were predictive of platinum-free interval (PFI), patients with PFI ≥6 months had significantly higher post-NACT sTILs (sTILs 28% versus 18% for PFI <6 months, P = 0.026); pre-NACT sTILS were not predictive. At diagnosis, 23% showed high ieTILs, and following NACT 33% showed increasing ieTILs. Proportion of tumours with PD-L1-positive immune cells was 30% (15/50) pre-NACT and 53% (27/51) post-NACT (P = 0.026). Among paired tumours, 63% of PD-L1-negative tumours became positive after NACT, furthermore cisplatin induced PD-L1 expression in PD-L1-negative EOC cell lines. On multivariate analysis, high sTILs both pre- and post-NACT were independent prognostic factors for progression-free survival (PFS) (HR 0.49, P = 0.02 and HR 0.60, P = 0.05, respectively). No prognostic impact of ieTILs or PD-L1 expression was detected. Conclusions: In EOC, sTILs levels are prognostic at diagnosis and remain prognostic after NACT. TILs and PD-L1 expression increase following NACT. Evaluation of immune parameters in the post-NACT tumour may help select patients for immunotherapy trials.

Adjuvant cisplatin-based chemotherapy in nonsmall-cell lung cancer: new insights into the effect on failure type via a multistate approach.

BACKGROUND: Adjuvant cisplatin-based chemotherapy has become the standard therapy against resected nonsmall-cell lung cancer (NSCLC). Because of variable results on its late effect, we reanalyze the long-term data of the International Adjuvant Lung Cancer Trial (IALT) to describe in details the role of adjuvant chemotherapy. PATIENTS AND METHODS: In the IALT, 1867 patients were randomized between adjuvant cisplatin-based chemotherapy and control, who were followed up for a median of 7.5 years. Of these, 1687 patients were enrolled from 132 centers accepting to report the times to cancer events. We used event history methodology to estimate the effects of adjuvant chemotherapy on the risks of local relapse, distant metastasis, and death. RESULTS: Adjuvant chemotherapy was highly effective against local relapses [HR = 0.73; 95% confidence interval (CI) 0.60-0.90; P = 0.003] and nonbrain metastases (HR = 0.79; 95% CI 0.66-0.94; P = 0.008) but not against brain metastases (HR = 1.1; 95% CI 0.82-1.4; P = 0.61). The effect on noncancer mortality was nonsignificant during the first 5 years (HR = 1.1; 95% CI 0.81-1.5; P = 0.29), whereas the risk of noncancer mortality was subsequently higher with treatment (HR = 3.6; 95% CI 2.2-5.9; P < 0.001). This harmful effect, however, potentially concerned only about 2% of the patients at 8 years. CONCLUSION: Adjuvant cisplatin-based chemotherapy reduced the risk of local relapse and of nonbrain metastasis, thereby improving survival. This treatment exerted no residual effect on mortality during the first 5 years, but a higher risk of noncancer mortality was found thereafter. Detailed long-term follow-up is strongly recommended for all patients in randomized trials evaluating adjuvant treatments in NSCLC.

Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis.

BACKGROUND: Generalized bullous fixed drug eruption (GBFDE) is a rare cutaneous adverse reaction to drugs, and may resemble Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), but is usually considered less severe. OBJECTIVES: To compare the severity and mortality rate in cases of GBFDE and control cases of SJS or TEN of similar extent of skin detachment. METHODS: This was a case-control analysis of 58 patients with GBFDE matched by age and extent of skin detachment to 170 control patients with a validated diagnosis of SJS or SJS/TEN overlap. Data for cases and controls were extracted from the EuroSCAR and RegiSCAR databases resulting from two population-based studies of severe cutaneous adverse reactions conducted in Europe. Preselected outcome criteria were death (primary), and fever, duration of hospitalization and transfer to an intensive care or burn unit (secondary). RESULTS: GBFDE affected mainly older patients (median age 78 years, interquartile range 68-84 years); 13 of 58 cases died (22%). The mortality rate was slightly but not significantly lower for patients with GBFDE than controls [28%, multivariate odds ratio 0·6 (95% confidence interval 0·30-1·4)]. Patients with GBFDE and controls did not differ in other preselected criteria for severity. CONCLUSIONS: Although our study featured limited statistical power, we were not able to confirm that GBFDE had better prognosis than SJS or SJS/TEN of similar disease extent in older patients. Severe cases of GBFDE deserve the attention and active management given to patients with SJS or TEN.

The role of prior corticosteroid use on the clinical course of Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immunologically mediated, severe cutaneous adverse reactions involving cytotoxic T cells, natural killer cells and various mediators. In large studies, up to 15% of SJS/TEN occurred in patients with chronic corticosteroid use. It is unclear if this prior exposure to corticosteroids modified the disease course. OBJECTIVES: To evaluate whether systemic corticosteroid usage prior to the onset of SJS/TEN modified the clinical course and outcome. If a disease-modifying effect is present, information from such an analysis may have implications on the therapeutic use of corticosteroids in SJS/TEN. METHODS: This is a case-control study based on data collected in the EuroSCAR and RegiSCAR studies. Ninety-two cases of SJS/TEN with exposure to corticosteroids prior to the onset of disease, and 321 randomly selected SJS/TEN patients without prior exposure were included. Primary outcomes included progression of disease, disease severity and mortality. A secondary analysis of latency between the beginning of drug use and the onset of disease, based on exposure to a single high-risk drug, was also performed. RESULTS: On multivariate analysis, cases with prior exposure to corticosteroids had a longer progression of disease by 2·2 days [95% confidence interval (CI) 1·1-3·2]. The disease severity and mortality outcome were unaffected. In addition, there is evidence that corticosteroids delayed the onset of SJS/TEN in patients with exposure to high-risk drugs by 7·1 days (CI -0·2 to 14·5). CONCLUSIONS: The prior use of corticosteroids prolonged the period of disease progression without influencing the disease severity or mortality. In addition, when SJS/TEN is preceded by use of a single high-risk drug, the latency between the drug intake and the onset of SJS/TEN may also be increased. These findings suggest that corticosteroids have a mild impact on the course of SJS/TEN, and further studies are required to clarify any potential therapeutic effects.

Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).

BACKGROUND: We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL). PATIENTS AND METHODS: At predetermined intervals, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and brain module were used for self-reported patient data, whereas the EORTC-Radiation Therapy Oncology Group Late Effects Normal Tissue-Subjective, Objective, Management, Analytic scale was used for clinicians' assessment. For each scale, the unfavourable status was analysed with a logistic model including age, grade at baseline, time and PCI dose. RESULTS: Over the 3 years studied, there was no significant difference between the two groups in any of the 17 selected items assessing QoL and neurological and cognitive functions. We observed in both groups a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005). CONCLUSION: Patients should be informed of these potential adverse effects, as well as the benefit of PCI on survival and BM. PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.

ERCC1 influence on the incidence of brain metastases in patients with non-squamous NSCLC treated with adjuvant cisplatin-based chemotherapy.

BACKGROUND: We recently demonstrated that excision repair cross-complementing group 1 protein (ERCC1) is predictive of adjuvant cisplatin-based chemotherapy benefit in resected non-small-cell lung cancer (NSCLC). Non-squamous cell carcinomas (non-SCCs) carry an increased risk of brain metastases (BMs). We hypothesised that there might be an increased incidence of BMs in ERCC1-negative non-SCCs when treated with adjuvant cisplatin-based chemotherapy. PATIENTS AND METHODS: Incidence of BMs and histoclinical parameters were analysed in a population of 761 patients enrolled in the International Adjuvant Lung Cancer Trial. A subgroup analysis was carried out in patients with ERCC1-negative non-SCCs. RESULTS: Of 761 patients, 98 developed BMs alone or in association with other metastatic sites, with a 5-year incidence rate of 18.0% (14.7%-21.8%). In the multivariate analysis, the clinical parameters associated with the occurrence of BMs were the nodal status (P = 0.02) and histological type [give hazard ratio (HR) for non-squamous to quantify introduction assertion, P = 0.002]. Chemotherapy had no effect on BMs [HR = 1.4 (0.90-2.1), P = 0.14]. In patients with non-SCC histology (n = 335), adjuvant chemotherapy was associated with an increased risk of BMs [HR = 2.1 (1.01-4.3), P = 0.04] for ERCC1-negative tumours, whereas there was no evidence of an effect on BMs for ERCC1-positive tumours [HR = 1.1 (0.38-3.0), P = 0.90]. Nevertheless, these two effects are not different (P = 0.30 for interaction) possibly due to a lack of power in this subgroup. CONCLUSIONS: This study suggests that adjuvant cisplatin-based chemotherapy is associated with an increased risk of BMs in patients with resected chemosensitive non-SCCs. If confirmed, these data could provide a rationale for new follow-up and/or prophylactic strategies.

ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis.

Epidermal necrolysis (EN)--either Stevens-Johnson syndrome (SJS) or toxic EN (TEN)--is a severe drug reaction. We constructed and evaluated a specific algorithm, algorithm of drug causality for EN (ALDEN), in order to improve the individual assessment of drug causality in EN. ALDEN causality scores were compared with those from the French pharmacovigilance method in 100 cases and the case-control results of the EuroSCAR study. Scores attributed by ALDEN segregated widely. ALDEN pointed to a "probable" or "very probable" causality in 69/100 cases as compared to 23/100 with the French method (P < 0.001). It scored "very unlikely" causality for 64% of medications vs. none with the French method. Results of ALDEN scores were strongly correlated with those of the EuroSCAR case-control analysis for drugs associated with EN (r = 0.90, P < 0.0001), with probable causality being reported in 218/329 exposures. ALDEN excluded causality in 321 drugs that the case-control analysis had described as "probably not associated" and in 22/233 drugs that had been described as inconclusive exposures. Being more sensitive than a general method, ALDEN, which correlates well with case-control analysis results, can be considered a reference tool in SJS/TEN.

An application of propensity score methods to estimate the treatment effect of corticosteroids in patients with severe cutaneous adverse reactions.

PURPOSE: To investigate whether propensity score (ps) methods could reasonably be applied to estimate the treatment effect on mortality, based on a comparatively small sample of patients with severe cutaneous adverse reactions (SCAR) and who come from different countries where physicians prefer different treatment schemes. METHODS: Ps methods were applied to cope with confounding due to non-randomized treatment assignment for the analysis of the treatment data obtained in the case-control study EuroSCAR. For the study's purpose, the analysis focused on the comparison of the treatments: corticosteroids (STER) and supportive care only (SUPP). RESULTS: 206 French and German patients were treated either with SUPP or STER. Imbalances between treatment groups as well as between the countries were recognized. Concerning the balance between the treatment groups no ps model for the full cohort was satisfying. In addition, the inclusion of a variable for patient's country led to a separation of the patients by country. Thus, we developed ps models for each country separately and estimated the treatment effects (France: odds ratio (OR) 0.52, 95% confidence interval (CI) 0.09-3.10, Germany: OR 0.23, CI 0.06-0.92, Overall: OR 0.33 CI 0.11-1.04). CONCLUSIONS: The application of the ps methods was successful and provided valuable information. We could confirm the findings of the original analysis which was based on standard logistic regression, especially concerning the necessity of a country-specific analysis. The observed country differences in the estimated treatment effects were less pronounced and thus seemed to be more reasonable than those of the past analysis.

Assessing prognosis and optimizing treatment in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT): results of the sCR2 international study.

BACKGROUND: The purpose of this study was to validate a prognostic index [surgical complete response 1 (sCR1)] in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: Data and specimens from 61 patients with normalized tumor markers and postchemotherapy viable nonteratomatous NSGCT treated in 13 institutions were collected. RESULTS: With a median follow-up of 5.4 years, the 5-year progression-free survival (PFS) rate was 65%; the 5-year overall survival (OS) rate was 72%. Favorable PFS was predicted by a complete resection, <10% of viable malignant cells, and a good International Germ Cell Consensus Classification group at presentation. Patients were assigned to one of three risk groups defined in sCR1: no risk factor (good risk), one risk factor (intermediate risk) and two to three risk factors (poor risk group). The 5-year PFS rate was 92%, 78%, and 42%, respectively (P = 0.002) (as compared with 90%, 76%, and 41% in the original sCR1 study). The 5-year OS rate was 90%, 86%, and 52%, respectively (P = 0.009) (as compared with 100%, 83%, and 51% in the original sCR1 study). Postoperative chemotherapy did not appear to improve OS compared with surveillance and treatment only at relapse. CONCLUSION: In patients with postchemotherapy viable NSGCT, a complete resection of residual masses should be rigorously pursued. These data validate the sCR1 prognostic index. Given their excellent outcome, patients in the favorable group may not require postoperative chemotherapy.

Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR).

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a disease characterized by the rapid occurrence of many sterile, nonfollicular pustules usually arising on an oedematous erythema often accompanied by leucocytosis and fever. It is usually attributed to drugs. OBJECTIVES: To evaluate the risk for different drugs of causing AGEP. PATIENTS AND METHODS: A multinational case-control study (EuroSCAR) conducted to evaluate the risk for different drugs of causing severe cutaneous adverse reactions; the study included 97 validated community cases of AGEP and 1009 controls. Results Strongly associated drugs, i.e. drugs with a lower bound of the 95% confidence interval (CI) of the odds ratio (OR) > 5 were pristinamycin (CI 26-infinity), ampicillin/amoxicillin (CI 10-infinity), quinolones (CI 8.5-infinity), (hydroxy)chloroquine (CI 8-infinity), anti-infective sulphonamides (CI 7.1-infinity), terbinafine (CI 7.1-infinity) and diltiazem (CI 5.0-infinity). No significant risk was found for infections and a personal or family history of psoriasis (CI 0.7-2.2). CONCLUSIONS: Medications associated with AGEP differ from those associated with Stevens-Johnson syndrome or toxic epidermal necrolysis. Different timing patterns from drug intake to reaction onset were observed for different drugs. Infections, although possible triggers, played no prominent role in causing AGEP and there was no evidence that AGEP is a variant of pustular psoriasis.

[Nipple areola complex conservation in immediate breast reconstruction: prospective study of 66 cases]. / Conservation aréolo-mamelonnaire en reconstruction mammaire immédiate: étude prospective de 66 cas.

OBJECTIVE OF THE STUDY: Our objective is to define a sub-group of patients in whom skin-sparing mastectomy with immediate reconstruction and preservation of the nipple-areola complex is technically and oncologically feasible without increasing the risk of complications and local recurrence. PATIENTS AND METHODS: Between September 1999 and December 2005, 66 patients presenting an in situ and/or invasive breast carcinoma justifying a mastectomy underwent immediate breast reconstruction preserving the skin and nipple-areolar complex. RESULTS: After a median follow-up of 37 months, definitive conservation of the nipple-areolar complex with good esthetic results was achieved in 71% of the cases. CONCLUSION: This preliminary study provides encouraging results in a selected patient population but requires a longer term follow-up in order to draw definitive conclusions on the oncological safety preserving the nipple-areolar complex.

Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer. Final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial.

LV5FU2 with high-dose leucovorin (LV), weekly infusional 5-fluorouracil (5FU) (AIO schedule) and raltitrexed have been demonstrated to be active agents in first-line treatment of colorectal cancer. We performed a 4-arm randomised trial to compare (1) a low-dose intravenous bolus of LV (20 mg/m2), followed by an intravenous bolus of 5FU (400 mg/m2), followed by a 22-hour continuous infusion of 5FU (600 mg/m2) on day 1 and day 2/2 weeks (ldLV5FU2 arm), (2) a weekly continuous infusion of high-dose 5FU (2.6 g/m2/week) for 6 weeks followed by a rest week (HD-FU arm) and (3) raltitrexed (Tomudex arm; 3 mg/m2/3 weeks) to standard LV5FU2. From 1997 to 2001, 294 patients were included. The 4 arms were well balanced for sex ratio, age, WHO performance status, the primary tumour site and prior adjuvant chemotherapy. Treatment was stopped due to low accrual. Two toxicity-related deaths were observed in the Tomudex arm. The treatments gave rise to different rates of grade 3-4 neutropenia (3, 4, 11 and 14% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively, p = 0.028), leucopenia and vomiting. At least one episode of grade 3-4 toxicity was observed in 27, 25, 38 and 47% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.016). An objective response was observed in 28, 21, 22 and 10% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.04). Progression-free survival (PFS) of the patients in the Tomudex arm was statistically lower compared to that of patients treated with LV5FU2 or ldLV5FU2 (combined group; p = 0.013, log rank test). In conclusion, Tomudex is more toxic and yields shorter PFS than infusional 5FU. Despite the early closure of the study and the lack of power of the comparison, it seems that ldLV5FU2 could be considered as an active, easier and less expensive option for the treatment of metastatic colorectal cancer compared to classic LV5FU2 or weekly HD-FU.

[Modalities of radiotherapy in small cell lung cancer: thoracic radiotherapy and prophylactic cerebral irradiation]. / Modalités de la radiothérapie dans les carcinomes bronchiques à petites cellules: radiothérapie thoracique et irradiation prophylactique cérébrale.

Small cell lung cancers (SCC) represent 20% of all lung cancers. After the initial control of the extension, only one third of the patients with SCC will finally have limited disease. The treatment of limited SCC currently relies on chemo-radiotherapeutic combinations that have improved overall survival and survival without metastases over the last few years. Nevertheless, even in limited forms, survival at 5 years varies from 10 to 15% and rarely exceeds 25% in the best series. The risk of relapse is high: although around 70% of patients with a limited form will have complete response, only 15 to 20% of them will exhibit prolonged survival. Indeed, most patients relapse, and the risk of cerebral dissemination for example is particularly high, reaching 50% at 2 years even in complete responders. After the results of a meta-analysis evaluating prophylactic cranial irradiation (PCI) among SCC complete responders, demonstrating 5% enhancement of survival at 3 years, PCI is part of the standard management of SCC in complete response. Despite the improvement in overall survival with the combined treatments, the mediocre results observed in terms of long-term survival warrant further clinical trials in order to define the optimal polychemotherapeutic and radiotherapeutic modalities, the best means of combining these two therapies and the place for new therapies.

Risk factors for brain relapse in patients with metastatic breast cancer.

BACKGROUND: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer. PATIENTS AND METHODS: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting. RESULTS: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.9-9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7-11, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases. CONCLUSION: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.

Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients.

BACKGROUND: A randomised trial was conducted comparing wide lumpectomy and breast irradiation with modified radical mastectomy. As the follow-up was long (mean duration 22 years), we analysed the variation in the effect of treatment over time. PATIENTS AND METHODS: The trial included 179 patients with a breast cancer measuring