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.

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.

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.

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.

Integrating respiratory-gated PET-based target volume delineation in liver SBRT planning, a pilot study.

BACKGROUND: To assess the feasibility and benefit of integrating four-dimensional (4D) Positron Emission Tomography (PET) - computed tomography (CT) for liver stereotactic body radiation therapy (SBRT) planning. METHODS: 8 patients with 14 metastases were accrued in the study. They all underwent a non-gated PET and a 4D PET centered on the liver. The same CT scan was used for attenuation correction, registration, and considered the planning CT for SBRT planning. Six PET phases were reconstructed for each 4D PET. By applying an individualized threshold to the 4D PET, a Biological Internal Target Volume (BITV) was generated for each lesion. A gated Planning Target Volume (PTVg) was created by adding 3 mm to account for set-up margins. This volume was compared to a manual Planning Target Volume (PTV) delineated with the help of a semi-automatic Biological Target Volume (BTV) obtained from the non-gated exam. A 5 mm radial and a 10 mm craniocaudal margins were applied to account for tumor motion and set-up margins to create the PTV. RESULTS: One undiagnosed liver metastasis was discovered thanks to the 4D PET. The semi-automatic BTV were significantly smaller than the BITV (p = 0.0031). However, after applying adapted margins, 4D PET allowed a statistically significant decrease in the PTVg as compared to the PTV (p = 0.0052). CONCLUSIONS: In comparison to non-gated PET, 4D PET may better define the respiratory movements of liver targets and improve SBRT planning for liver metastases. Furthermore, non respiratory-gated PET exams can both misdiagnose liver metastases and underestimate the real internal target volumes.

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.

Contrasted effects of the multitarget TKi vandetanib on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines.

OBJECTIVES: Overexpression of epidermal growth factor receptor (EGFR) and angiogenic factors is associated with the progression of androgen-independent prostate cancer (AIPC). We examined the effects of vandetanib, an inhibitor of vascular endothelial growth factor (VEGFR), EGFR, and rearranged during transfection (RET) tyrosine-kinase activities, alone or combined with docetaxel, on PC3 docetaxel-sensitive (PC3wt) or docetaxel-resistant (PC3R) AIPC cell growth in vivo and in vitro. METHODS: Mice bearing PC3wt or PC3R tumors were treated for 3 weeks with vandetanib (25 or 50 mg/kg/d p.o., 5 d/wk), docetaxel (10 or 30 mg/kg i.p., 1 d/wk), or their combination (low or high doses). Xenograft tumors were analyzed for expression of Ki-67, EGFR, VEGFR2, and production of VEGFA. RESULTS: On PC3wt, vandetanib at both doses stimulated tumor growth, whereas docetaxel at both doses exerted strong growth-inhibiting effects. The low-dose vandetanib-docetaxel combination resulted in tumor growth similar to that of control, whereas the high-dose combination induced a significant antiproliferative effect. In contrast, on PC3R, the low-dose of vandetanib had no effect on tumor growth, whereas the high-dose of vandetanib significantly inhibited tumor growth. Docetaxel at both doses exerted moderate and transient antitumor effects. The combination of high-dose vandetanib with high-dose docetaxel resulted in antiproliferative effects, which were lower than expected from the sum of individual drug effects. Importantly, tumor analyses revealed overexpression of the EGFR/VEGFR pathways in PC3R relative to PC3wt. CONCLUSION: Present results suggest that vandetanib should not be associated with docetaxel in treatment-naive or docetaxel-resistant prostate cancer (CaP). The use of high-dose vandetanib alone may warrant further investigation in patients with docetaxel-resistant AIPC overexpressing VEGFR/EGFR pathways.

Role of brachytherapy in the boost management of anal carcinoma with node involvement (CORS-03 study).

PURPOSE: To assess retrospectively the clinical outcome in anal cancer patients, with lymph node involvement, treated with split-course radiation therapy and receiving a boost through external beam radiation therapy (EBRT) or brachytherapy (BCT). METHODS AND MATERIALS: From 2000 to 2005, among 229 patients with invasive nonmetastatic anal squamous cell carcinoma, a selected group of 99 patients, with lymph node involvement, was studied. Tumor staging reported was T1 in 4 patients, T2 in 16 patients, T3 in 49 patients, T4 in 16 patients, and T unknown in 14 patients and as N1 in 67 patients and N2/N3 in 32 patients. Patients underwent a first course of EBRT (mean dose, 45.1 Gy) followed by a boost (mean dose, 18 Gy) using EBRT (50 patients) or BCT (49 patients). All characteristics of patients and tumors were well balanced between the BCT and EBRT groups. Prognostic factors of cumulative rate of local recurrence (CRLR), cumulative rate of distant (including nodal) recurrence (CRDR), colostomy-free survival (CFS) rate, and overall survival (OS) rate were analyzed for the overall population and according to the nodal status classification. RESULTS: The median follow-up was 71.5 months. The 5-year CRLR, CRDR, CFS rate, and OS rate were 21%, 19%, 63%, and 74.4%, respectively. In the overall population, the type of node involvement (N1 vs N2/N3) was the unique independent prognostic factor for CRLR. In N1 patients, by use of multivariate analysis, BCT boost was the unique prognostic factor for CRLR (4% for BCT vs 31% for EBRT; hazard ratio, 0.08; P=.042). No studied factors were significantly associated with CRDR, CFS, and OS. No difference with regard to boost technique and any other factor studied was observed in N2/N3 patients for any kind of recurrence. CONCLUSION: In anal cancer, even in the case of initial perirectal node invasion, BCT boost is superior to EBRT boost for CRLR, without an influence on OS, suggesting that N1 status should not be a contraindication to use of a BCT boost technique, as well as emphasizing the important of investigating the benefit of BCT boost in prospective randomized trials.

Correlation in rectal cancer between clinical tumor response after neoadjuvant radiotherapy and sphincter or organ preservation: 10-year results of the Lyon R 96-02 randomized trial.

PURPOSE: To investigate, in rectal cancer, the benefit of a neoadjuvant radiation dose escalation with endocavitary contact radiotherapy (CXRT) in addition to external beam radiotherapy (EBRT). This article provides an update of the Lyon R96-02 Phase III trial. METHODS AND MATERIALS: A total of 88 patients with T2 to T3 carcinoma of the lower rectum were randomly assigned to neoadjuvant EBRT 39 Gy in 13 fractions (43 patients) vs. the same EBRT with CXRT boost, 85 Gy in three fractions (45 patients). Median follow-up was 132 months. RESULTS: The 10-year cumulated rate of permanent colostomy (CRPC) was 63% in the EBRT group vs. 29% in the EBRT+CXRT group (p < 0.001). The 10-year rate of local recurrence was 15% vs. 10% (p = 0.69); 10-year disease-free survival was 54% vs. 53% (p = 0.99); and 10-year overall survival was 56% vs. 55% (p = 0.85). Data of clinical response (CR) were available for 78 patients (36 in the EBRT group and 42 in the EBRT+CXRT group): 12 patients were in complete CR (1 patient vs. 11 patients), 53 patients had a CR ≥ 50% (24 patients vs. 29 patients), and 13 patients had a CR <50% (11 patients vs. 2 patients) (p < 0.001). Of the 65 patients with CR ≥ 50%, 9 had an organ preservation procedure (meaning no rectal resection) taking advantage of major CR. The 10-year CRPC was 17% for patients with complete CR, 42% for patients with CR ≥ 50%, and 77% for patients with CR <50% (p = 0.014). CONCLUSION: In cancer of the lower rectum, CXRT increases the complete CR, turning in a significantly higher rate of long-term permanent sphincter and organ preservation.

Intensity-modulated radiotherapy in head and neck cancer: results of the prospective study GORTEC 2004-03.

BACKGROUND AND PURPOSE: In 2003, the French Authority for Health (HAS) recommended the use of intensity modulated radiotherapy (IMRT) in prospective trial before its routine use. The Oncology and Radiotherapy Group for Head and Neck Cancer (GORTEC) proposed to evaluate prospectively acute and late toxicities, locoregional control and overall survival for patients treated for head and neck cancer (HNC) with IMRT and bilateral neck irradiation. MATERIALS AND METHODS: Between 2002 and 2008, 208 patients with HNC were treated with IMRT in 8 centres. There were 38 nasopharynx, 117 oropharynx, 25 pharyngo-larynx, 24 oral cavity and 4 unknown primary (28.5% stage I-II and 71% Stage III-IV). Ninety-three patients (46%) had postoperative IMRT and 78 patients (37.5%) received concurrent chemotherapy. The doses were 70 Gy to the gross tumour, 66 Gy to the high-risk postoperative sites and 50 Gy to the subclinical disease. Toxicities were graded according to the RTOG-EORTC scales. RESULTS: The median follow-up was 25.3 months (range: 0.4-72 months). There were 29 local-regional failures: 24 were in-field, three were marginal and one was out-field. The two-year loco-regional control and overall survival were 86% and 86.7%, respectively. At 18 months, grade ≥ 2 xerostomia was 16.1%. A mean dose to the spared parotid below 28 Gy led to significantly less grade ≥ 2 xerostomia (8.5% vs 24%) with a relative risk of 1.2 [95% CI: 1.02-1.41, p = 0.03]. Grade ≥ 2 xerostomia increased by approximately 3% per Gy of mean parotid dose up to 28, Gy then 7% per Gy above 33 Gy. CONCLUSIONS: IMRT for HN cancer seems to reduce late toxicities without jeopardising local control and overall survival.

Can we increase the chance of sphincter saving surgery in rectal cancer with neoadjuvant treatments: lessons from a systematic review of recent randomized trials.

PURPOSE: A common hypothesis is that neo-adjuvant treatment in rectal cancer, is able to increase sphincter saving surgery. This review studies data relevant to this question. STUDY SELECTION: A total of 17 randomized trials were analysed. RESULTS: Since 1976, the rate of sphincter saving surgery increased from 20% to 75%. In none of the 17 trials it was possible to demonstrate a significant benefit of the neo-adjuvant regimens on the rate of sphincter saving surgery. There was a reduction in the risk of 5-year local recurrence partly due to these neo-adjuvant treatments. These neo-adjuvant regimens had no significant impact on the overall 5-year survival. CONCLUSIONS: None of the neo-adjuvant treatments tested was able to demonstrate an increase in the rate of sphincter saving surgery. The improvement in conservative surgery is mainly due to technical changes in surgery. Organ preservation after complete clinical response appears as an interesting hypothesis to test.

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.

Anal canal cancer: management of inguinal nodes and benefit of prophylactic inguinal irradiation (CORS-03 Study).

PURPOSE: To evaluate the benefit of prophylactic inguinal irradiation (PII) in anal canal squamous cell carcinoma (ASCC). METHODS AND MATERIALS: This retrospective study analyzed the outcome of 208 patients presenting with ASCC treated between 2000 and 2004 in four cancer centers of the south of France. RESULTS: The population study included 35 T1, 86 T2, 59 T3, 20 T4, and 8 T stage unknown patients. Twenty-seven patients presented with macroscopic inguinal node involvement. Of the 181 patients with uninvolved nodes at presentation, 75 received a PII to a total dose of 45-50 Gy (PII group) and 106 did not receive PII (no PII group). Compared with the no PII group, patients in the PII group were younger (60% vs. 41% of patients age <68 years, p = 0.01) and had larger tumor (T3-4 = 46% vs. 27% p = 0.01). The other characteristics were well balanced between the two groups. Median follow-up was 61 months. Fourteen patients in the no PII group vs. 1 patient in the PII group developed inguinal recurrence. The 5-year cumulative rate of inguinal recurrence (CRIR) was 2% and 16% in PII and no PII group respectively (p = 0.006). In the no PII group, the 5-year CRIR was 12% and 30% for T1-T2 and T3-T4 respectively (p = 0.02). Overall survival, disease-specific survival, and disease-free survival were similar between the two groups. In the PII group, no Grade >2 toxicity of the lower extremity was observed. CONCLUSION: PII with a dose of 45 Gy is safe and highly efficient to prevent inguinal recurrence and should be recommended for all T3-4 tumors. For early-stage tumors, PII should also be discussed, because the 5-year inguinal recurrence risk remains substantial when omitting PII (about 10%).

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.

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.

High-dose split-course radiation therapy for anal cancer: outcome analysis regarding the boost strategy (CORS-03 study).

PURPOSE: To retrospectively assess the clinical outcome in anal cancer patients treated with split-course radiation therapy and boosted through external-beam radiation therapy (EBRT) or brachytherapy (BCT). METHODS AND MATERIALS: From January 2000 to December 2004, a selected group (162 patients) with invasive nonmetastatic anal squamous cell carcinoma was studied. Tumor staging reported was T1 = 31 patients (19%), T2 = 77 patients (48%), T3 = 42 patients (26%), and T4= 12 patients (7%). Lymph node status was N0-1 (86%) and N2-3 (14%). Patients underwent a first course of EBRT: mean dose 45.1 Gy (range, 39.5-50) followed by a boost: mean dose 17.9 Gy (range, 8-25) using EBRT (76 patients, 47%) or BCT (86 patients, 53%). All characteristics of patients and tumors were well balanced between the BCT and EBRT groups. RESULTS: The mean overall treatment time (OTT) was 82 days (range, 45-143) and 67 days (range, 37-128) for the EBRT and BCT groups, respectively (p < 0.001). The median follow-up was 62 months (range, 2-108). The 5-year cumulative rate of local recurrence (CRLR) was 21%. In the univariate analysis, the prognostic factors for CRLR were as follows: T stage (T1-2 = 15% vs. T3-4 = 36%, p = 0.03), boost technique (BCT = 12% vs. EBRT = 33%, p = 0.002) and OTT (OTT <80 days = 14%, OTT ≥80 days = 34%, p = 0.005). In the multivariate analysis, BCT boost was the unique prognostic factor (hazard ratio = 0.62 (0.41-0.92). In the subgroup of patients with OTT <80 days, the 5-year CRLR was significantly increased with the BCT boost (BC = 9% vs. EBRT = 28%, p = 0.03). In the case of OTT ≥80 days, the 5-year CRLR was not affected by the boost technique (BCT = 29% vs. EBRT = 38%, p = 0.21). CONCLUSION: In anal cancer, when OTT is <80 days, BCT boost is superior to EBRT boost for CRLR. These results suggest investigating the benefit of BCT boost in prospective trials.

Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth: a new paradigm for understanding the therapeutic effect of combined treatment.

Bevacizumab (Bvz), a Vascular Endothelial Growth Factor (VEGF)-targeted humanised monoclonal antibody, provides clinical benefit in combination with docetaxel (DXL), a microtubule-stabilising agent, in the treatment of metastatic breast and prostate cancers. Since VEGF and their receptors are expressed by tumour cells, we hypothesised that Bvz, in addition to its impact on neo-vascularisation, could have an impact on tumour cells and enhance the DXL activity. Hence, we studied the effect of DXL and Bvz on metastatic breast (MDA MB-231) and prostate (PC3) cancer cells lines. Bvz alone did not decrease cell proliferation but in combination with DXL, Bvz enhanced the anti-proliferative activity of DXL. Other anti-angiogenic factors Sunitinib, Sorafenib and Gefitinib enhanced the anti-proliferative effect of DXL. qPCR experiments showed that DXL significantly increased the VEGF and VEGF receptor 2 (VEGF-R2) mRNA levels. Activation of VEGF and VEGF-R2 promoters demonstrated that enhanced mRNA levels are partly due to transcriptional activation. ELISA assays showed that DXL induced accumulation of cytoplasmic VEGF but decreased extracellular levels by 39% (MDA) and 48% (PC3). Cell surface localisation of VEGF-R2 was increased by DXL alone, but decreased after combined treatment of DXL plus Bvz. Abnormal expression of VEGF-R2 was also shown on breast and prostate tumour samples reinforcing the results obtained on cellular models. In conclusion, DXL and Bvz in combination decreased extracellular VEGF and VEGF-R2 levels at the plasma membrane thereby blocking an important growth/survival loop. Thus, the combined therapeutic impact of Bvz and DXL observed in clinical trials is associated with enhanced anti-proliferative activity and inhibition of the vascular network.