Radiosurgery for classical trigeminal neuralgia: impact of the shot size on clinical outcome.

BACKGROUND: This study compares the outcome of patients suffering from medically refractory classical trigeminal neuralgia (TN) after treatment with radiosurgery using two different shot sizes (5- and 6-mm). METHODS: All patients included in this open, prospective, non-controlled study were treated in a single institution for TN (95 cases in 93 patients) with LINear ACcelerators (LINAC) single-dose radiosurgery using a 5-mm shot (43 cases) or 6-mm shot (52 cases). The target was positioned on the intracisternal part of the trigeminal nerve. RESULTS: The mean Dmax (D0.035) to the brainstem was higher in the 6-mm group: 12.6 vs 21.3 Gy (p < 0.001). Pain relief was significantly better in the 6-mm group: at 12 and 24 months in the 6-mm group the rate of pain-free patients was 90.2 and 87.8%, respectively vs. 73.6 and 73.6% in the 5-mm group (p = 0.045). At 12 and 24 months post-radiosurgical hypoesthesia was more frequent in the 6-mm group: 47.0 and 58% vs.11.3 and 30.8% in the 5-mm group (p = 0.002). To investigate the effect of cone diameter and the dose to the brainstem on outcomes, patients were stratified into three groups: group 1 = 5-mm shot, (all Dmax < 25 Gy, 43 cases), group 2 = 6-mm shot, Dmax < 25 Gy (32 cases), group 3 = 6-mm shot Dmax > 25 Gy (20 cases). At 12 months the rates of hypoesthesia were 11.3, 33.5 and 76.0%, respectively in groups 1, 2 and 3 (p < 0.001) and the rates of recurrence of pain were 26.4, 16.5 and 5%, respectively, (p = 0.11). CONCLUSION: LINAC treatment with a 6-mm shot provided excellent control of pain, but increased the rate of trigeminal nerve dysfunction, especially when the maximum dose to the brainstem was higher than 25 Gy.

Treatment of inoperable elderly head and neck cancer patients.

PURPOSE OF REVIEW: Elderly head and neck cancer (HNC) patients are very rarely enrolled in clinical trials, and even more so in dedicated trials in curative or palliative setting. As a result, no standards of treatment exist for this population and thus, adaptation of standard treatments is commonly used. RECENT FINDINGS: The choice between a monotherapy and a platinum-cetuximab combination is based on the performance status, which is not suitable and/or sufficient to evaluate the patient ability to receive a systemic treatment combined or not with radiotherapy. The evaluation of functional age using geriatric assessment is recommended. However, access to comprehensive geriatric assessment is limited in many centers, and the choice of the type of treatment is often not based on objective and reproducible criteria. As a result, fragile elderly HNC patients may be overtreated with a risk of increased toxicity and fit patients proposed for suboptimal treatment with a risk of failure of tumor control. SUMMARY: It is therefore crucial to develop and evaluate customized treatments by enrolling elderly HNC patients in dedicated therapeutics trials, such as the ELAN (Elderly Head and Neck Cancer) studies or new approaches involving promising immunotherapies. To administer the most suitable therapy, a simple and reproducible geriatric assessment could efficiently guide practitioners.

Detectors assessment for stereotactic radiosurgery with cones.

The purpose of this work is to assess eight detectors performance for output factor (OF), percent depth dose (PDD), and beam profiles in a 6-MV Clinac stereotactic radiosurgery mode for cone irradiation using Monte Carlo simulation as reference. Cones with diameters comprised between 30 and 4 mm have been studied. The evaluated detectors were ionization chambers: pinpoint and pinpoint 3D, diodes: SRS, P and E, Edge, MicroDiamond and EBT3 radiochromic films. The results showed that pinpoints underestimate OF up to -2.3% for cone diameters ≥10 mm and down to -12% for smaller cones. Both nonshielded (SRS and E) and shielded diodes (P and Edge) overestimate the OF respectively up to 3.3% and 5.2% for cone diameters ≥10 mm and in both cases more than 7% for smaller cones. MicroDiamond slightly overestimates the OF, 3.7% for all the cones and EBT3 film is the closest to Monte Carlo with maximum difference of ±1% whatever the cone size is. For the profiles and the PDD, particularly for the small cones, the size of the detector predominates. All diodes and EBT3 agree with the simulation within ±0.2 mm for beam profiles determination. For PDD curve all the active detectors response agree with simulation up to 1% for all the cones. EBT3 is the more accurate detector for beam profiles and OF determinations of stereotactic cones but it is restrictive to use. Due to respectively inappropriate size of the sensitive volume and composition, pinpoints and diodes do not seem appropriate without OF corrective factors below 10 mm diameter cone. MicroDiamond appears to be the best detector for OF determination regardless all cones. For off-axis measurements, the size of the detector predominates and for PDD all detectors give promising results.

Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: A standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC. METHODS: This single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0-1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1-4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1-day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4-5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed. FINDINGS: Between Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72-79). The median number of chemotherapy cycles received was five (IQR 3-6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30-51]) and morbidity events were observed in 24 patients (31% [22-42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3-4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3-4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%). INTERPRETATION: The study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer), Sandoz, GEFLUC, and GEMLUC. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Predictive factors for early and late local toxicities in anal cancer treated by radiotherapy in combination with or without chemotherapy.

BACKGROUND: The treatment of anal cancer is based on concomitant radiotherapy and chemotherapy and is associated with a nonnegligible rate of local severe toxicities that can strongly impair the quality of life. OBJECTIVE: A retrospective analysis was performed to screen the following factors as potential predictive factors for local skin and digestive toxicities, and as potential prognostic factors for cumulative colostomy incidence: sex, age, tumor size, clinical T and N stage, circumferential extension, invasion of anal margin, HIV status, type of chemotherapy, and type of radiotherapy and dose delivered. METHODS: One hundred five patients in our database treated between January 2000 and February 2010 met the eligibility criteria. RESULTS: Median follow-up was 54.1 months (range, 1-133). Early and late severe local toxicities occurred in 33 patients (31.4%) and 18 patients (17.1%). The 5-year cumulative rate of colostomy was 26.6%. Predictive factors for local severe early toxicities were as follows: clinical stage III/IV (p = 0.01), no brachytherapy boost (p = 0.003), and use of chemotherapy (p = 0.01). Only brachytherapy retained its independence in multivariate analysis (OR = 4.8 (1.4-16.3), p = 0.01). Human immunodeficiency virus positivity (p = 0.04) was the only predictive factor for late toxicities in univariate analysis; it was linked independently to the occurrence of ulcer (OR = 0.1 (0.01-0.66), p = 0.01). Tumor size ≥4 cm (p < 0.001) and occurrence of grade 2 to 3 ulcers (p < 0.001) were correlated with greater cumulative colostomy incidence. CONCLUSIONS: In this cohort, nonuse of brachytherapy was an independent predictive factor for local acute toxicity. Human immunodeficiency virus positivity was the only predictive factor for local late toxicities and strongly influenced the onset of ulcer.

Integrin-αvß3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance.

Medulloblastoma is one of the most prevalent solid tumors found in children, occurring in the brain's posterior fossa. The standard treatment protocol involves maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. The identification of pertinent targets for both initial and recurrent medulloblastoma cases is imperative. Both primary and recurrent medulloblastoma are marked by their aggressive infiltration into surrounding brain tissue, robust angiogenesis, and resistance to radiotherapy. While the significant role of integrin-αvß3 in driving these characteristics has been extensively documented in glioblastoma, its impact in the context of medulloblastoma remains largely unexplored. Integrin-αvß3 was found to be expressed in a subset of patients with medulloblastoma. We investigated the role of integrin-αvß3 using medulloblastoma-derived cell lines with ß3-subunit depletion or overexpression both in vitro and in vivo settings. By generating radioresistant medulloblastoma cell lines, we uncovered an increased integrin-αvß3 expression, which correlated with increased susceptibility to pharmacologic integrin-αvß3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/MRI studies on orthotopic models using a radiolabeled integrin-αvß3 ligand (99mTc-RAFT-RGD). This innovative approach presents the potential for a novel predictive imaging technique in the realm of medulloblastoma. Altogether, our findings lay the foundation for employing SPECT/MRI to identify a specific subset of patients with medulloblastoma eligible for integrin-αvß3-directed therapies. This breakthrough offers a pathway toward more targeted and effective interventions in the treatment of medulloblastoma. SIGNIFICANCE: This study demonstrates integrin-αvß3's fundamental role in medulloblastoma tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.

Predictive clinical outcome of the intratumoral CD66b-positive neutrophil-to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer.

BACKGROUND: The role of the interaction between tumor cells and inflammatory cells in nonsmall cell lung carcinoma (NSCLC) is unclear. In this study, the authors assessed the prognostic impact of intratumoral cluster of differentiation 66b (carcinoembryonic antigen-related cell adhesion molecule 8 [CD66b])-positive neutrophils and of the intratumoral CD66b-positive neutrophil-to-cluster of differentiation 8 (cell surface antigen T8 [CD8])-positive lymphocytes (the CD66b-positive neutrophil-to-CD8-positive lymphocyte ratio [iNTR]) in patients with resectable NSCLC. METHODS: Expression levels of CD66b and CD8 were evaluated by immunohistochemistry on tissue microarrays consisting of 632 NSCLC specimens from patients who underwent curative surgery. The relation between clinicopathologic variables and patient outcome was assessed. RESULTS: Intratumoral CD66b-positive neutrophils were elevated in 318 patients (50%). In univariate analysis, an increase in CD66b-positive cells was associated with a high cumulative incidence of relapse (CIR) (median CIR, 51 months for low CD66b-positive cell density; 36 months for high CD66b-positive cell density; P = .002) and trended toward worse overall survival (OS) (median OS, 57 months for low CD66b-positive cell density; 54 months for high CD66b-positive cell density; P = .088). The iNTR was elevated in 190 patients (30%). An increased iNTR was strongly associated with both a high CIR (median CIR: 43 months for an iNTR ≤1; 34 months for an iNTR >1; P < .0001) and poor OS (median OS: 60 months for an iNTR ≤1; 46 months for an iNTR >1; P < .0001). In multivariate analysis, independent prognostic factors for a higher CIR were high iNTR (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.56-0.90; P = .005) and tumor stage >I, (HR, 0.39; 95% CI, 0.30-0.52; P < .0001). Independent prognostic factors for worse OS were a high iNTR (HR, 0.70; 95% CI, 0.54-0.91; P = .007) and tumor stage >I (HR, 0.35; 95% CI, 0.26-0.47; P < .0001). CONCLUSIONS: The current results indicated that the iNTR is a novel, independent prognostic factor for a high rate of disease recurrence and poor OS in patients with resectable NSCLC.

Overexpression of carbonic anhydrase XII in tissues from resectable non-small cell lung cancers is a biomarker of good prognosis.

The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase XII (CAXII) is a transmembrane enzyme that catalyzes the reversible hydration of cell-generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation and enhanced expression is often present in several types of tumors. The aim of our study was to assess the prognostic significance of CAXII tumor tissues expression in patients with NSCLC. Five hundred fifty-five tumors were immunostained for CAXII on tissue microarrays (TMA) and the results were correlated with clinicopathological parameters and outcome of patients. CAXII overexpression was present in 105/555 (19%) cases and was associated with tumors of lower grade (p = 0.015) and histological type (p < 0.001), being significantly higher in squamous cell carcinoma. High CAXII expression correlated with better overall and disease-specific survival of patients with resectable NSCLC in univariate (p < 0.001) and multivariate survival analyses (p < 0.001). In conclusion, this is the first study demonstrating that a high CAXII tumor tissue expression evaluated on TMAs is related to a better outcome in a large series of patients with resectable NSCLC.

A specific approach for elderly patients with head and neck cancer.

Approximately 10% of head and neck (HN) tumors occur in patients aged more than or equal to 80 years. In this population, the main challenge for physicians is to deal with the benefit/risk ratio of treatments and tumor-related symptoms. As elderly patients are generally excluded from clinical trials, there is a lack of evidence-based data with regard to the most appropriate multidisciplinary management. The prevalence of frailty and the pattern of comorbidities in this specific population are still unknown. The management of these tumors in a geriatric context is complex due to the high risk of toxicity of locoregional treatments. Thus, physicians often have to adapt to the treatment schedule to decrease potential adverse effects even with a risk of undertreatment. A retrospective series reported that the treatment delivered to elderly patients presenting with HN tumor complies with an institution's policy in less than 50% of cases, emphasizing the need to assess the outcome of personalized/adapted treatment in geriatric patients. The major issue is to determine which adaptation could be carried out, and then, what could be the respective individual benefit/risk ratio of each adaptation. In this review, we will focus on the locoregional management of elderly patients, and develop the issue of adapted local treatment. We will discuss the feasibility of adapted surgery and radiotherapy and provide current evidence-based data that may allow physicians involved in locoregional treatment of elderly patients with HN cancers to be acquainted with practical guidelines. Then, we will highlight the importance of nutritional support in this population in which the prevalence of malnutrition is high.

Results of vocal rehabilitation using tracheoesophageal voice prosthesis after total laryngectomy and their predictive factors.

The aims of this retrospective study were to evaluate prosthetic voice restoration by tracheoesophageal puncture (TEP) in laryngectomized patients and to identify clinical factors correlated with functional outcomes. Between 2000 and 2008, 103 patients who underwent total laryngectomy or pharyngolaryngectomy (TPL) were included in our study. Functional outcomes were recorded 6 months postoperatively, and results were scored from 0 to 2 for oral diet and speech intelligibility. Lifetime of voice prosthesis and early and late complications were recorded. The impact of several clinical factors on functional outcomes, prosthetic valve lifetime and complications was assessed in univariate analysis. A total of 87 patients (84%) underwent TEP and speech valve placement (79 primary and 8 secondary punctures). Hypopharyngeal tumors (P = 0.005), circular TPL (P = 0.003) and use of a pectoralis major myocutaneous flap (P = 0.0003) were significantly associated with secondary TEP. Successful voice rehabilitation was obtained by 77 of 82 evaluable patients (82%). A high level of comorbidity (ASA score > or = 3; P = 0.003) was correlated to speech rehabilitation failure. The median device lifetimes were 7.6 and 3.7 months for Provox I and II speech valves, respectively. Minor leakage around the valve occurred in 26% of the patients. Late complications occurred in 14 patients (16%) including: severe enlargement of the fistula (n = 3), prosthesis displacement (n = 7) and granulation tissue-formation (n = 4). In conclusion the use of voice prosthesis showed a high success rate of vocal rehabilitation with an acceptable complication rate.

[Rectal cancer: which initial strategy?]. / Cancer du rectum. Quelle stratégie de prise en charge initiale?

Surgery is the main treatment of rectal adenocarcinoma. After careful digital examination, rectoscopy and work-up, treatment decision is taken, in agreement with an informed patient according to the tumor stage. Early T1-2 tumors are treated with surgery first. Advanced T3-4 tumors are treated with pre-operative chemo-radiation often using the "CAP 50" regimen. At the present time, almost 60% of patients are definitively cured of their cancer with 75% being able to avoid permanent stoma. Pelvic relapses are seen in less than 6% of cases. In inoperable patients it is possible to cure a high percentage of early T1-2 tumors using external beam RT associated if possible with chemotherapy and 50 kv Contact X-Ray.

MicroRNAs and lung cancer: new oncogenes and tumor suppressors, new prognostic factors and potential therapeutic targets.

MicroRNAs (miRNAs) are small non-protein-coding RNA that negatively control mRNA expression at a post-transcriptional level. They regulate various cellular functions and bioinformatic data suggest that they collectively control about 30% of human mRNAs. MiRNAs have been recently implicated in several carcinogenic processes, where they can act either as oncogenes or as tumor suppressors. This is the case in lung cancer, i.e. the leading cause of cancer deaths in Western countries, in which about 40-45 miRNAs have been found to be aberrantly expressed, thereby constituting a specific miRNA signature. Some of these miRNAs can play an important role in lung carcinogenesis. Indeed, some transcripts of the let-7 family that are significantly down-regulated in lung tumors have been identified as tumor suppressors through their ability to control several oncogenic pathways, including the RAS pathway. Identification of a growing number of other potential oncogenic or tumor suppressor miRNAs in lung cancers is in constant progress. Recent evidence supports the use of specific miRNA signatures to predict clinical outcome. This review aims to report the current knowledge about the role of miRNAs in lung cancer carcinogenesis, their potential for improving diagnosis and prognosis and their impact on future therapeutic strategies.

Impact of intensity-modulated radiotherapy on health-related quality of life for head and neck cancer patients: matched-pair comparison with conventional radiotherapy.

PURPOSE: To assess the benefit of intensity-modulated radiotherapy (IMRT) compared with conventional RT for the quality of life (QOL) of head and neck cancer survivors. METHODS AND MATERIALS: Cross-sectional QOL measures (European Organization for Research and Treatment of Cancer QOL questionnaire C30 and head and neck cancer module) were used with a French multicenter cohort of patients cured of head and neck cancer (follow-up > or = 1 year) who had received bilateral neck RT (> or = 45 Gy) as a part of their initial treatment. We compared the QOL mean scores regarding RT modality (conventional RT vs. IMRT). The patients of the two groups were matched (one to one) according to the delay between the end of RT and the timing of the QOL evaluation and the T stage. Each QOL item was divided into two relevant levels of severity: "not severe" (responses, "not at all" and "a little") vs. "severe" (responses "quite a bit" and "very much"). The association between the type of RT and the prevalence of severe symptoms was approximated, through multivariate analysis using the prevalence odds ratio. RESULTS: Two comparable groups (67 pairs) were available. Better scores were observed on the head and neck cancer module QOL questionnaire for the IMRT group, especially for dry mouth and sticky saliva (p < 0.0001). Severe symptoms were more frequent with conventional RT concerning saliva modifications and oral discomfort. The adjusted prevalence odds ratios were 3.17 (p = 0.04) for dry mouth, 3.16 (p = 0.02) for sticky saliva, 3.58 (p = 0.02) for pain in the mouth, 3.35 (p = 0.04) for pain in the jaw, 2.60 (p = 0.02) for difficulties opening the mouth, 2.76 (p = 0.02) for difficulties with swallowing, and 2.68 (p = 0.03) for trouble with eating. CONCLUSION: The QOL assessment of head and neck cancer survivors demonstrated the benefit of IMRT, particularly in the areas of salivary dysfunction and oral discomfort.

Long-term results of hypofractionated radiotherapy and hormonal therapy without surgery for breast cancer in elderly patients.

BACKGROUND AND PURPOSE: To evaluate early and late reactions, local control, disease-free survival, cause-specific survival, and overall survival of elderly breast cancer patients treated with definitive once-a-week hypofractionated radiotherapy together with hormonal therapy. PATIENTS AND METHODS: Between 1987 and 1999, 115 patients with a median age of 83 presenting with 124 non-metastatic breast carcinoma were treated with definitive once weekly hypofractionated radiotherapy associated with hormonal therapy. The main reasons for adopting this schedule were patient refusal of surgery, very old age, locally advanced case, and/or comorbid disease. Radiation was delivered as once-a-week, 6.5 Gy for a total breast dose of 32.5 Gy in five fractions, followed with 1-3 fractions of 6.5 Gy to the tumour site. The median follow-up was 41 months. RESULTS: Neoadjuvant hormonal therapy led to 56% reduction of the tumour volume. Late reactions occurred in 46 patients; they were mild to moderate in 87% of these patients. The Kaplan-Meier rate was 52% of patients, with 6% experiencing grade 3 reactions. The 5-year local progression-free rate was 78%. The corresponding cause-specific survival was 71%, and was influenced by T classification, nodal status, oestrogen receptors and the total dose. The first three factors retained an independent prognostic impact on multivariate analysis. The 5-year overall survival was 38%. It was affected by the T classification, lymph node involvement and the performance status (PS). Using a multivariate analysis, only T classification and PS were identified as independent factors regarding overall survival. CONCLUSIONS: Definitive hypofractionated radiotherapy allows a good local control, with acceptable toxicity. This schedule associated with hormonal therapy is a good alternative to surgery in non-operable old patients and in case of patient refusal to surgery and to standard fractionation.

[Cholestatic hepatitis: an uncommon presentation of Churg-Strauss syndrome]. / Hépatite cholestatique: une présentation inhabituelle du syndrome de Churg et Strauss.

Churg-Strauss syndrome is a rare form of severe vasculitis characterized by severe asthma and hypereosinophilia. Liver involvement is rare. We report a case of a woman with serious cholestatic hepatitis and vasculitis, without severe asthma. Marked hypereosinophilia and liver biopsy confirmed diagnosis. Churg-Strauss syndrome must be recognized because digestive involvement is very serious and affect the prognosis of this disease.

Long-term results of adjuvant hypofractionated radiotherapy for breast cancer in elderly patients.

PURPOSE: To evaluate early and late reactions, local control, disease-free survival, cause-specific survival, and overall survival of elderly breast cancer patients treated with adjuvant once-weekly hypofractionated radiotherapy (RT). METHODS AND MATERIALS: Between 1987 and 1999, 150 patients (median age, 78 years) who presented with 151 nonmetastatic breast tumors were treated with surgery and then adjuvant hypofractionated RT. The clinical stage distribution was as follows: T1 in 47.7%, T2 in 43.2%, T3 in 6.1%, and T4 in 3.0%. Axillary lymph nodes were positive in 33.8% of cases. Estrogen receptors were present in 89.9%, and progesterone receptors in 77.3%. Conservative breast surgery was performed in 71.5% and total mastectomy in 28.5%. RT was delivered once weekly in five fractions of 6.5 Gy to a total dose of 32.5 Gy. A boost was delivered to the tumor bed in 33.1%. Adjuvant hormonal therapy was given in 76.2% of patients. The median follow-up was 65 months. RESULTS: The Kaplan-Meier rate of all grades of early skin reactions was 26.5%, and the rate of all late reactions was 45.5%, mainly Grades 1 and 2. Early and late reactions were greater in those who underwent boost RT. The long-term local recurrence rate was 2.3%. The 5-year and 10-year disease-free survival rate was 80% and 71.5%, respectively. The corresponding rates for cause-specific survival were 89.1% and 77.6%. The 5-year and 10-year overall survival rate was 71.6% and 46.5%, respectively. These endpoints were influenced by tumor size, lymph node status, and hormone receptor status to varying degrees; however, tumor size appeared to be a major determinant on multivariate analysis. CONCLUSIONS: This hypofractionated RT scheme resulted in mild early reactions and acceptable late toxicity, in addition to providing excellent long-term local control. It can be proposed to patients who would have difficulties sustaining daily treatment because of old age or disabling associated disease.

Anal canal carcinoma: early-stage tumors < or =10 mm (T1 or Tis): therapeutic options and original pattern of local failure after radiotherapy.

PURPOSE: To investigate the clinical history, management, and pattern of recurrence of very early-stage anal canal cancer in a French retrospective survey. METHODS: The study group consisted of 69 patients with Stage Tis and T1 anal canal carcinoma < or =1 cm treated between 1990 and 2000 (12 were in situ, 57 invasive, 66 Stage N0, and 3 Stage N1). The median patient age was 67 years (range, 27-83 years). Of the 69 patients, 66 received radiotherapy (RT) and 3 with in situ disease were treated by local excision alone without RT. Twenty-six patients underwent local excision before RT (12 with negative and 14 with positive surgical margins). Of the 66 patients who underwent RT, 8 underwent brachytherapy alone (median dose, 55 Gy), 38 underwent external beam RT (median dose, 45 Gy) plus a brachytherapy boost (median boost dose, 20 Gy), and 20 underwent external beam RT alone (median dose, 55 Gy). RESULTS: Of the 69 patients, 68 had initial local control. Of the 66 patients treated by RT, 6 developed local recurrence at a median interval of 50 months (range, 13-78 months). Four patients developed local failure outside the initial tumor bed. Of the 3 patients with Tis treated by excision alone, 1 developed local recurrence. No relation was found among prior excision, dose, and local failure. The 5-year overall survival, colostomy-free survival, and disease-free survival rate was 94%, 85%, and 89%, respectively. The rate of late complications (Grade 1-3) was 28% and was 14% for those who received doses <60 Gy and 37% for those who received doses of > or =60 Gy (p = 0.04). CONCLUSION: Most recurrences occurred after a long disease-free interval after treatment and often outside the initial tumor site. These small anal cancers could be treated by RT using a small volume and moderate dose (40-50 Gy for subclinical lesions and 50-60 Gy for T1).

Total radiation dose and overall treatment time are predictive for tumor sterilization in cervical carcinoma treated with chemoradiation and pulsed-dose-rate brachytherapy.

BACKGROUND AND PURPOSE: Treatment of locally advanced cervical cancer involves multidisciplinary care using external beam radiotherapy, chemotherapy, brachytherapy, and surgery. We aimed to compare both tumor and treatment characteristics between patients with complete pathologic response (CR) and patients with residual disease (RD). PATIENTS AND METHODS: This monocentric retrospective study included 40 consecutive patients, treated with external beam radiotherapy, pulsed-dose-rate brachytherapy, and completion surgery. Treatment planning was performed to obtain a cumulative D90 value for the intermediate-risk clinical target volume (CTV) ≥60 Gy(α/ß=10). Different clinical and dosimetric parameters were analyzed and compared between patients with RD and those with CR. RESULTS: We observed 18 (45%) patients with CR and 22 (55%) patients with RD. In univariate analysis, patients with RD had a significantly longer overall treatment time than those with CR (59.5 vs. 53 days, p = 0.0321). The D90 value for the high-risk CTV (HR-CTV) was higher in the group with CR than in the group with RD (65.9 vs. 64.2 Gy(α/ß=10); p = 0.0439). In multivariate analysis, overall treatment time remained the only predictive factor for CR (p = 0.033), even if the difference for D90 HR-CTV kept a trend toward significance (p = 0.057). CONCLUSIONS: This study showed that tumor sterilization is significantly correlated with overall treatment time and probably with cumulative dose delivered to the HR-CTV. These results emphasize the attention that must be given to treatment organization and dosimetry optimization.

[Preneoplastic anal lesions and anal canal carcinoma]. / Lésions prénéoplasiques et cancer du canal anal.

Anal canal cancer rate is relatively high among HIV-positive patients, particularly in homosexual men, where it is twice that of HIV-negative homosexual men. As for uterine cervix cancer, it is possible that anal canal cancer is linked to human papillomaviruses (HPV): in fact, its oncogenic serotypes are found in 60% of tumours. Most of anal mucosa in HIV-positive patients is infected by HPV. It causes Anal Squamous Intraepithelial Lesions (ASTI): low grade and high grade squamous intraepithelial lesions, which can probably progress to invasive anal cancer. In the anal mucosa, HPV induces clinically flat condylomata. They generally are invisible and revealed only by acetic acid application. Sixty percent of seropositive gay men and 26% of seropositive women have anal ASTI. This rate is higher than in the general population. A decreasing of systemic and local immunity and so probable interactions between HPV and HIV could explain the frequency of anal ASTI among seropositive patients. Introduction of highly active antiretroviral therapy does not really influence the evolution of anal dysplasia. Screening of preneoplastic lesion is possible with anal Pap smear, and when it is positive, patients must undergo high resolution anuscopy. Cost effectiveness analyses indicate that only the highest risk group (HIV-positive gay men) should have anal screening. Only high grade squamous intraepithelial lesions have to he systematically treated, low grade squamous intraepithelial lesions could he simply followed up. The best treatment of anal dysplasia is surgical excision, with careful follow-up, because of high recurrence rate among seropositive patients.