External beam radiotherapy ± chemotherapy in the treatment of anal canal cancer: a single-institute long-term experience on 100 patients.

One-hundred patients treated with curative radiotherapy (RT) ± chemotherapy (CT) for an anal canal carcinoma (T1-4N0-3M0) were retrospectively analyzed. Five- and 10-year local control (LC) rates were 73% and 67%, respectively. Acute and late G3-G4 toxicity rates were 32% and 12%, respectively. Two patients underwent a colostomy for a G4 anal toxicity. This study confirms the outcomes of RT ± CT in the treatment of anal canal cancer. Concomitant CT and LC statistically influenced Overall Survival and Colostomy-Free Survival. CT also statistically reduced the risk of nodal relapse. High rates of acute skin toxicity impose tailored volumes and techniques of irradiation.

Follow-up care amongst long-term childhood cancer survivors: a report from the Swiss Childhood Cancer Survivor Study.

In the Swiss Childhood Cancer Survivor Study, we aimed to assess the proportion of long-term survivors attending follow-up care, to characterise attendees and to describe the health professionals involved. We sent a questionnaire to 1252 patients, of whom 985 (79%) responded, aged in average 27 years (range 20-49). Overall, 183 (19%) reported regular, 405 (41%) irregular and 394 (40%) no follow-up. For 344, severity of late effects had been classified in a previous medical examination. Only 17% and 32% of survivors with moderate and severe late effects respectively had made regular visits a decade later. Female gender, after a shorter time since diagnosis, had radiotherapy, and having suffered a relapse predicted follow-up. In the past year, 8% had seen a general practitioner only, 10% a paediatric or adult oncologist and 16% other health specialists for a cancer related problem. These findings underline the necessity to implement tailored national follow-up programmes.

CPT-11 and concomitant hyperfractionated accelerated radiotherapy induce efficient local control in rectal cancer patients: results from a phase II.

Patients with rectal cancer are at high risk of disease recurrence despite neoadjuvant radiochemotherapy with 5-Fluorouracil (5FU), a regimen that is now widely applied. In order to develop a regimen with increased antitumour activity, we previously established the recommended dose of neoadjuvant CPT-11 (three times weekly 90 mg m(-2)) concomitant to hyperfractionated accelerated radiotherapy (HART) followed by surgery within 1 week. Thirty-three patients (20 men) with a locally advanced adenocarcinoma of the rectum were enrolled in this prospective phase II trial (1 cT2, 29 cT3, 3 cT4 and 21 cN+). Median age was 60 years (range 43-75 years). All patients received all three injections of CPT-11 and all but two patients completed radiotherapy as planned. Surgery with total mesorectal excision (TME) was performed within 1 week (range 2-15 days). The preoperative chemoradiotherapy was overall well tolerated, 24% of the patients experienced grade 3 diarrhoea that was easily manageable. At a median follow-up of 2 years no local recurrence occurred, however, nine patients developed distant metastases. The 2-year disease-free survival was 66% (95% confidence interval 0.48-0.83). Neoadjuvant CPT-11 and HART allow for excellent local control; however, distant relapse remains a concern in this patient population.

Secondary Cancer Risk for Stage I Seminoma Patients - a Comparison of Adjuvant Treatment Versus Surveillance

Background: Post-surgical management of stage I seminoma includes: surveillance with repeated CT-scans and treatment reserved for those who relapse, or adjuvant treatment with either immediate radiation therapy (RT) or carboplatin. The cancer specific survival is close to 100%. Cure without long-term sequelae of treatment is the aim. Our goal is to estimate the risk of radiation-induced secondary cancers (SC) death from for patients undergoing S, adjuvant RT or adjuvant carboplatin (AC).Materials and Methods: We measured organ doses from CT scans (3 phases each one) of a seminoma patient who was part of the active surveillance strategy and from a man undergoing adjuvant RT 20-Gy and a 30-Gy salvage RT treatment to the para-aortic area using helical Intensity Modulated RT (Tomotherapy®) with accurate delineation of organs at risk and a CTV to PTV expansion of 1 cm. Effective doses to organs in mSv were estimated according to the tissue-weighting factors recommendations of the International Commission on Radiological Protection 103 (Ann ICRP 2007). We estimated SC incidence and mortality for a 10,000 people population based on the excess absolute risk model from the Biological Effects of Ionizing Radiation (BEIR) VII (Health Risk of Exposure to Low Levels of Ionizing Radiation, NCR, The National Academies Press Washington, DC, 2006) assuming a seminoma diagnosis at age 30, a total life expectancy of 80 years.Results: The nominal risk for a fatal secondary cancers was calculated 1.5% for 15 abdominal CT scans, 14.8% for adjuvant RT (20 Gy paraaortic field) and 22.2% for salvage RT (30 Gy). The calculation assumed that the risk of relapse on surveillance and adjuvant AC was 15% and 4% respectively and that all patients were salvaged at relapse with RT. n CT abdomen/Pelvis = secondary cancer % RT Dose and % receiving treatment = secondary cancer % Total secondary cancer risk in % Active surveillance 15 = 1.5% 30 Gy in 15% of pts = 3.3% 4.8 Adjuvant carboplatin 7 = 0.7% 30 Gy in 4% of pts = 0.88% 1.58 Adjuvant radiotherapy 7 = 0.7% 20 Gy in 100% of pts = 14.8% 15.5Conclusions: These data suggest that: 1) Adjuvant radiotherapy is harmful and should not anymore be regarded as a standard option for seminoma stage I. 2) AC seems to be an option to reduce radiation induced cancers. Limitations: the study does not consider secondary cancers due to chemotherapy with AC (unknown). The use of BEIR VII for risk modeling with higher doses of RT needs to be validated.

Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.

PURPOSE: Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. RESULTS: KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10(-4)). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). CONCLUSION: In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

Feasibility and efficacy of accelerated weekly concomitant boost postoperative radiation therapy combined with concomitant chemotherapy in patients with locally advanced head and neck cancer.

BACKGROUND: The aim of this study was to assess feasibility and efficacy of weekly concomitant boost accelerated postoperative radiation therapy (PORT) with concomitant chemotherapy (CT) in patients with locally advanced head and neck cancer (LAHNC). METHODS AND MATERIALS: Conformal or intensity-modulated 66-Gy RT was performed in 5.5 weeks in 40 patients. Cisplatin was given at days 1, 22, and 43. Median follow-up was 36 months. RESULTS AND DISCUSSION: Grade 3 mucositis, dysphagia, and erythema was observed in ten (25%), nine (23%), and six (13%) patients, respectively. Grade 3 or more anemia was observed in two (6%) patients, and leukopenia in five (13%) patients. No grade 3 or 4 thrombocytopenia was observed. Grade 3 nephrotoxicity was observed in one patient (3%). No treatment-related mortality was observed. Grade 2 or more xerostomia and edema were observed in ten (25%) and one (3%) patient, respectively. Locoregional relapse occurred in eight patients, and seven patients developed distant metastases. Median time to locoregional relapse was 6 months. Three-year overall, disease-free survival, and locoregional control rates were 63%, 62%, and 81%, respectively. Multivariate analysis revealed that the only prognostic factor was nodal status. CONCLUSION: Reducing overall treatment time using accelerated PORT/CT by weekly concomitant boost (six fractions per week) combined with concomitant cisplatin CT is easily feasible with acceptable morbidity.

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study.

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Educational achievement in Swiss childhood cancer survivors compared with the general population.

BACKGROUND: The objective of this study was to describe educational achievements of childhood cancer survivors in Switzerland compared with the general population. In particular, the authors investigated educational problems during childhood, final educational achievement in adulthood, and its predictors. METHODS: Childhood cancer survivors who were aged <16 years at diagnosis from 1976 to 2003 who had survived for ≥5 years and were currently ages 20 to 40 years received a postal questionnaire during 2007 to 2009. Controls were respondents of the Swiss Health Survey ages 20 to 40 years. Educational achievement included compulsory schooling, vocational training, upper secondary schooling, and university degree. The analysis was weighted to optimize comparability of the populations. The authors analyzed the association between demographic and clinical predictors and educational achievement using multivariable logistic regression. Subgroup analyses focused on survivors aged ≥27 years. RESULTS: One-third of survivors encountered educational problems during schooling (30% repeated 1 year, and 35% received supportive tutoring). In the total sample, more survivors than controls achieved compulsory schooling only (8.7% vs 5.2%) and fewer acquired a university degree (7.3% vs 11%), but more survivors than controls achieved an upper secondary education (36.1 vs 24.1%). In those aged ≥27 years, differences in compulsory schooling and university education largely disappeared. In survivors and controls, sex, nationality, language region, and migration background were strong predictors of achievement. Survivors of central nervous system tumors or those who had a relapse had poorer outcomes (P < .05). CONCLUSIONS: Childhood cancer survivors encountered problems during schooling and completed professional education with some delay. However, with the exception of patients who had central nervous system tumors and those who experienced a relapse, the final educational achievement in survivors of child cancer was comparable to that of the general population.

Primary breast lymphoma: patient profile, outcome and prognostic factors. A multicentre Rare Cancer Network study.

BACKGROUND: To asses the clinical profile, treatment outcome and prognostic factors in primary breast lymphoma (PBL). METHODS: Between 1970 and 2000, 84 consecutive patients with PBL were treated in 20 institutions of the Rare Cancer Network. Forty-six patients had Ann Arbor stage IE, 33 stage IIE, 1 stage IIIE, 2 stage IVE and 2 an unknown stage. Twenty-one underwent a mastectomy, 39 conservative surgery and 23 biopsy; 51 received radiotherapy (RT) with (n = 37) or without (n = 14) chemotherapy. Median RT dose was 40 Gy (range 12-55 Gy). RESULTS: Ten (12%) patients progressed locally and 43 (55%) had a systemic relapse. Central nervous system (CNS) was the site of relapse in 12 (14%) cases. The 5-yr overall survival, lymphoma-specific survival, disease-free survival and local control rates were 53%, 59%, 41% and 87% respectively. In the univariate analyses, favorable prognostic factors were early stage, conservative surgery, RT administration and combined modality treatment. Multivariate analysis showed that early stage and the use of RT were favorable prognostic factors. CONCLUSION: The outcome of PBL is fair. Local control is excellent with RT or combined modality treatment but systemic relapses, including that in the CNS, occurs frequently.

Prostate cancer: F-18-fluorocholine PET-CT utility. [Cancer de la prostate : utilité de la TEP-TDM à la 18F-fluorocholine.]

In oncology, positron emission computed tomography (PET/CT) has become an essential tool for initial staging, response evaluation and follow-up of cancer patients. Most of the frequent tumors (lung, breast, esophagus, and lymphomas) are highly avid for (18)F-fluorodeoxyglucose ((18)FDG), but prostate cancer has not demonstrated significant uptake of FDG. The development of new tracers labeled with (18)F such as choline analogs allowed already to obtain interesting results particularly in patients with biological relapse and inconclusive conventional imaging workup. The impact of (18)F-flurocholine PET/CT on patient management needs to be validated in large studies, but many centers use already this examination in order to guide further management, including radiotherapy planning. (C) 2011 Elsevier Masson SAS. All rights reserved.

Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.

Background: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+ BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.Results: We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95% CI: 1.29-3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.Conclusion: We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

Identification of a Poor-Prognosis BRAF-Mutant-Like Population of Patients With Colon Cancer.

PURPOSE Our purpose was development and assessment of a BRAF-mutant gene expression signature for colon cancer (CC) and the study of its prognostic implications. Materials and METHODS A set of 668 stage II and III CC samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial were used to assess differential gene expression between c.1799T>A (p.V600E) BRAF mutant and non-BRAF, non-KRAS mutant cancers (double wild type) and to construct a gene expression-based classifier for detecting BRAF mutant samples with high sensitivity. The classifier was validated in independent data sets, and survival rates were compared between classifier positive and negative tumors. Results A 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant tumors in PETACC-3 and independent samples. A subpopulation of BRAF wild-type patients (30% of KRAS mutants, 13% of double wild type) showed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. Thus they form a distinct prognostic subgroup within their mutation class. CONCLUSION A characteristic pattern of gene expression is associated with and accurately predicts BRAF mutation status and, in addition, identifies a population of BRAF mutated-like KRAS mutants and double wild-type patients with similarly poor prognosis. This suggests a common biology between these tumors and provides a novel classification tool for cancers, adding prognostic and biologic information that is not captured by the mutation status alone. These results may guide therapeutic strategies for this patient segment and may help in population stratification for clinical trials.

Tumor heterogeneity and cancer stem cell paradigm: updates in concept, controversies and clinical relevance.

Although tumor heterogeneity is widely accepted, the existence of cancer stem cells (CSCs) and their proposed role in tumor maintenance has always been challenged and remains a matter of debate. Recently, a path-breaking chapter was added to this saga when three independent groups reported the in vivo existence of CSCs in brain, skin and intestinal tumors using lineage-tracing and thus strengthens the CSC concept; even though certain fundamental caveats are always associated with lineage-tracing approach. In principle, the CSC hypothesis proposes that similar to normal stem cells, CSCs maintain self renewal and multilineage differentiation property and are found at the central echelon of cellular hierarchy present within tumors. However, these cells differ from their normal counterpart by maintaining their malignant potential, alteration of genomic integrity, epigenetic identity and the expression of specific surface protein profiles. As CSCs are highly resistant to chemotherapeutics, they are thought to be a crucial factor involved in tumor relapse and superficially appear as the ultimate therapeutic target. However, even that is not the end; further complication is attributed by reports of bidirectional regeneration mechanism for CSCs, one from their self-renewal capability and another from the recently proposed concept of dynamic equilibrium between CSCs and non-CSCs via their interconversion. This phenomenon has currently added a new layer of complexity in understanding the biology of tumor heterogeneity. In-spite of its associated controversies, this area has rapidly emerged as the center of attention for researchers and clinicians, because of the conceptual framework it provides towards devising new therapies.

Angiogenic activity of breast cancer patients' monocytes reverted by combined use of systems modeling and experimental approaches.

Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.

Toward a rational design of combination therapy in cancer.

By merging computational systems modeling and experimental approaches, we have uncovered treatments reprogramming pro-angiogenic monocytes present in breast tumor into immunologically potent cells capable of mediating an anti-tumor immune response. The unraveled pathways and ligands which underlie monocyte pro-angiogenic activity have a strong predictive value for breast cancer patient relapse - free survival.