Selective Electrical Surface Stimulation to Support Functional Recovery in the Early Phase After Unilateral Acute Facial Nerve or Vocal Fold Paralysis.

This article addresses the potential clinical value of surface electrical stimulation in the acute phase of denervation after the onset of facial nerve or recurrent laryngeal nerve paralysis. These two nerve lesions are the most frequent head and neck nerve lesions. In this review, we will work out several similarities concerning the pathophysiology features and the clinical scenario between both nerve lesions, which allow to develop some general rules for surface electrical stimulation applicable for both nerve lesions. The focus is on electrical stimulation in the phase between denervation and reinnervation of the target muscles. The aim of electrostimulation in this phase of denervation is to bridge the time until reinnervation is complete and to maintain facial or laryngeal function. In this phase, electrostimulation has to stimulate directly the denervated muscles, i.e. muscle stimulation and not nerve stimulation. There is preliminary data that early electrostimulation might also improve the functional outcome. Because there are still caveats against the use of electrostimulation, the neurophysiology of denervated facial and laryngeal muscles in comparison to innervated muscles is explained in detail. This is necessary to understand why the negative results published in several studies that used stimulation parameters are not suitable for denervated muscle fibers. Juxtaposed are studies using parameters adapted for the stimulation of denervated facial or laryngeal muscles. These studies used standardized outcome measure and show that an effective and tolerable electrostimulation of facial and laryngeal muscles without side effects in the early phase after onset of the lesions is feasible, does not hinder nerve regeneration and might even be able to improve the functional outcome. This has now to be proven in larger controlled trials. In our view, surface electrical stimulation has an unexploited potential to enrich the early therapy concepts for patients with unilateral facial or vocal fold paralysis.

Selective Surface Electrostimulation of the Denervated Zygomaticus Muscle.

This article describes a first attempt to generate a standardized and safe selective surface electrostimulation (SES) protocol, including detailed instructions on electrode placement and stimulation parameter choice to obtain a selective stimulation of the denervated zygomaticus muscle (ZYG), without unwanted simultaneous activation of other ipsilateral or contralateral facial muscles. METHODS: Single pulse stimulation with biphasic triangular and rectangular waveforms and pulse widths (PW) of 1000, 500, 250, 100, 50, 25, 15, 10, 5, 2, 1 ms, at increasing amplitudes between 0.1 and 20 mA was performed. Stimulations delivered in trains were assessed at a PW of 50 ms only. The stimulation was considered successful exclusively if it drew the ipsilateral corner of the mouth upwards and outwards, without the simultaneous activation of other ipsilateral or contralateral facial muscles. I/t curves, accommodation quotient, rheobase, and chronaxie were regularly assessed over 1-year follow-up. RESULTS: 5 facial paralysis patients were assessed. Selective ZYG response in absence of discomfort and unselective contraction of other facial muscle was reproducibly obtained for all the assessed patients. The most effective results with single pulses were observed with PW ≥ 50 ms. The required amplitude was remarkably lower (≤5 mA vs. up to 15 mA) in freshly diagnosed (≤3 months) than in long-term facial paralysis patients (>5 years). Triangular was more effective than rectangular waveform, mostly because of the lower discomfort threshold of the latter. Delivery of trains of stimulation showed similar results to the single pulse setting, though lower amplitudes were necessary to achieve the selective ZYG response. Initial reinnervation signs could be detected effectively by needle-electromyography (n-EMG). CONCLUSION: It is possible to define stimulation parameters able to elicit an effective selective stimulation of a specific facial muscle, in our case, of the ZYG, without causing discomfort to the patient and without causing unwanted unspecific reactions of other ipsilateral and/or contralateral facial muscles. We observed that the SES success is strongly conditioned by the correct electrode placement, which ideally should exclusively interest the area of the target muscles and its immediate proximity.

Quality of life in rectal cancer patients with or without oxaliplatin in the randomised CAO/ARO/AIO-04 phase 3 trial.

BACKGROUND: The CAO/ARO/AIO trial has shown that oxaliplatin added to preoperative chemoradiotherapy and postoperative chemotherapy significantly improved disease-free survival in locally advanced rectal cancer (LARC). Here, we present a post-hoc analysis of quality of life (QoL) in disease-free patients. PATIENTS AND METHODS: Between 2006 and 2010, 1236 patients with LARC were randomly assigned either to preoperative chemoradiotherapy followed by total mesorectal excision and postoperative chemotherapy (N = 623) or combined with oxaliplatin (N = 613). QoL questionnaires (EORTC QLQ-C30, colorectal module CR38) were completed at baseline, after postoperative chemotherapy and during follow-up. Analysis was performed according intent-to-treat. RESULTS: Available questionnaires (baseline) were 82% (N = 512) in the control and 84% (N = 513) in the investigational group. Response rates were 49% (533 of 1086) at 1 year and 43% (403 of 928) at 3 years. Global health status (GHS) for disease-free patients was stable in both groups (range 0-100). At baseline: standard arm 62.0 (mean, SD 21.6; N = 491) versus oxaliplatin arm 63.2 (mean, SD 22; N = 503); at 3 years: 69.4 (SD 19.3; N = 187) versus 65.4 (SD 22.2; N = 202). After treatment and at 3 years, no significant differences (≥10 points) between groups were found in QoL subscales. Disease-free patients experiencing neurotoxic side-effects (grade 1-4) showed reduced GHS at 3 years versus patients without neurotoxicity (mean 59.2 versus 69.3; P < 0.001), while grade 3-4 rate was low. CONCLUSION: The addition of oxaliplatin was not associated with worse overall QoL. This information is of interest to patients in many ongoing rectal cancer trials. TRIAL REGISTRATION INFORMATION: NCT00349076.

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper.

BACKGROUND: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1.0%. SUMMARY: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

Can MRI quantify the volume changes of denervated facial muscles?

Could manual segmentation of magnetic resonance images be used to quantify the effects of transcutaneous electrostimulation and reinnervation of denervated facial muscle? Five patients with unilateral facial paralysis were scanned during the study while receiving a daily surface electrostimulation of the paralytic cheek region, but also after reinnervation. Their facial muscles were identified in 3D (coronal, sagittal, and axial) and segmented in magnetic resonance imaging (MRI) data for in total 28 time points over the 12 months of study. A non-significant trend of increasing muscle volume were detected after reinnervation. MRI is a valuable technique in the facial paralysis research.

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO-04 randomized phase 3 rectal cancer trial.

Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5-FU-based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO-04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow-up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease-free survival (DFS; HR 1.457; 95% CI 1.163-1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266-2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264-2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment-induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5-FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high-level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies.

Perioperative Systemic Chemotherapy, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: Results of the Prospective Multicenter Phase 2 COMBATAC Trial.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as parts of an interdisciplinary treatment concept including systemic chemotherapy can improve survival of selected patients with peritoneal metastatic colorectal cancer (pmCRC). Nevertheless, the sequence of the therapeutic options is still a matter of debate. Thus, the COMBATAC (COMBined Anticancer Treatment of Advanced Colorectal cancer) trial was conducted to evaluate a combined treatment regimen consisting of preoperative systemic polychemotherapy + cetuximab followed by CRS + HIPEC and postoperative systemic polychemotherapy + cetuximab. PATIENTS AND METHODS: The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase 2 trial. Twenty-six patients with synchronous or metachronous colorectal or appendiceal peritoneal carcinomatosis were included. Enrollment was terminated prematurely by the sponsor because of slow recruitment. Progression-free survival as primary end point and overall survival were estimated by the Kaplan-Meier method. Also evaluated were morbidity according to Common Terminology Criteria for Adverse Events v4.0 and feasibility of the combined treatment concept. RESULTS: Median progression-free survival for the intention-to-treat population (n = 25) was 14.9 months. Median overall survival was not reached during the study duration. Ninety-two adverse events were documented in 16 patients, including 14 serious adverse events in 9 patients. The overall morbidity rate was 64%, and the grade 3/4 morbidity rate was 44%. Of all grade 3/4 morbidity events, 36.4% were related to systemic chemotherapy and 22.7% to surgery, whereas 40.9% were not directly related. There was no treatment-related mortality. CONCLUSION: The results of the COMBATAC trial show that the multimodal treatment concept consisting of perioperative systemic chemotherapy and CRS + HIPEC is safe and feasible. Progression-free survival in selected patients with colorectal or appendiceal peritoneal metastasis might be improved.

Effect of Neoadjuvant Chemotherapy Followed by Surgical Resection on Survival in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Cancer: The AIO-FLOT3 Trial.

IMPORTANCE: Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. OBJECTIVE: To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection. DESIGN, SETTING, AND PARTICIPANTS: The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013. INTERVENTIONS: Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. RESULTS: In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P < .001). The response rate for arm B was 60% (complete, 10%; partial, 50%), which is higher than the 43.3% for arm C. In arm B, 36 of 60 patients (60%) proceeded to surgery. The median overall survival was 31.3 months (95% CI, 18.9-upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI, 7.1-22.9) for the other patients. CONCLUSIONS AND RELEVANCE: Patients with limited metastatic disease who received neoadjuvant chemotherapy and proceeded to surgery showed a favorable survival. The AIO-FLOT3 trial provides a rationale for further randomized clinical trials. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00849615.

Method to test the long-term stability of functional electrical stimulation via multichannel electrodes (e.g., applicable for laryngeal pacing) and to define best points for stimulation: in vivo animal analysis.

The study aim was to identify and analyze intramuscular electrically sensitive points. Electrically sensitive points are herein defined as positions, which allow muscles stimulation with a minimum possible fatigue for a maximum amount of time. A multichannel array electrode was used which could be interesting to retain the function of larynx muscle after paralysis. Eight array electrodes were implanted in the triceps brachii muscle of four rats. While being under anesthesia, the animals were intramuscularly stimulated at 16 different positions. Sihler's staining technique was used to make visible the nerves routes and the intramuscular position of the individual electrode plate. The positions of the motor end plates were determined by means of multichannel-electromyography. The positions that allow longest stimulation periods are located close to the points where the nerves enter the muscle. Stimulation at the position of the motor end plates does not result in stimulation periods above average. Locations initially causing strong muscle contractions are not necessarily identical to the ones allowing long stimulation periods. The animal model identified the stimulation points for minimal possible muscle fatigue stimulation as being located close to the points of entrance of the nerve into the muscle. Stimulation causing an initially strong contraction response is no indication of optimal location of the stimulation electrode in terms of chronic stimulation. The array electrode of this study could be interesting as a stimulation electrode for a larynx pacemaker.

Pre-clinical evaluation of a minimally invasive laryngeal pacemaker system in mini-pig.

Microlaryngoscopic enlargement techniques have been the standard treatment for bilateral vocal fold paralysis (BVFP) for decades. Laryngeal pacing is a promising alternative treatment based on the electrostimulation of the posterior cricoarytenoid (PCA) muscle. This paper reports on the results of a pre-clinical study aiming to evaluate this method. Eight Göttingen mini-pigs were implanted with a laryngeal pacemaker (LP) implant prototype and with two LP electrodes, one in each PCA muscle. The 6-week follow-up included endoscopic stimulation controls in general anaesthesia and radiographic controls of electrode integrity and position stability. Stimulation parameters for optimal glottal opening were evaluated via videolaryngoscopy. Histopathology was performed upon conclusion of the study. 7/8 (87.5 %) animals were successfully implanted with the LP implant prototype and two LP electrodes. In general, stimulation was effectively delivered and correlated with the expected PCA muscle activation. 2/14 (14.3 %) electrodes dislocated and 1/14 (7.1 %) electrode tip broke. The LP system used in this experiment to induce vocal fold abduction by means of selective functional electrical stimulation of the PCA showed promising results. It may be a valid alternative to the current golden standard for BVFP treatment. Clinical studies are needed to confirm the medical relevance of the LP.

Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy.

The aim of this post hoc analysis of the VELOUR study (ClinicalTrials.gov NCT00561470) was to investigate the treatment effect of adding aflibercept to second-line infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who had failed any prior oxaliplatin-containing regimen. Adjuvant rapid relapsers (ARR), who were enrolled directly following relapse during or within 6 months of completion of oxaliplatin-containing adjuvant chemotherapy (N = 124, including 17 patients who also received bevacizumab as part of their adjuvant therapy), were excluded from the original VELOUR intention-to-treat (ITT) population (N = 1226). After exclusion of the ARR, overall survival (OS) in the ITT minus ARR (ITT-ARR) population (N = 1102) was longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm [hazard ratio (HR) 0.78, 95 % confidence interval (CI) 0.68-0.90; median survival difference 1.87 months]. In the subgroup of patients assigned to the prior bevacizumab stratum at randomization, OS was numerically longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm (HR 0.81; 95 % CI 0.63-1.04; median survival difference 2.14 months). Comparison of the post hoc analysis results with the primary analysis from VELOUR suggests that the inclusion of the directly enrolled ARR may have understated the aflibercept treatment benefit for both bevacizumab-pretreated and bevacizumab-naïve patients in the strictly second-line setting although no definitive conclusion may be inferred. The benefit associated with the addition of aflibercept to second-line FOLFIRI in patients with mCRC was observed whatever the timing of first-line disease progression. There were no unexpected safety concerns.

Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial.

BACKGROUND: The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. METHODS: In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609. FINDINGS: Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 99·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 99·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group). INTERPRETATION: Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy. METHODS: In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group. INTERPRETATION: Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Laryngeal pacing in minipigs: in vivo test of a new minimal invasive transcricoidal electrode insertion method for functional electrical stimulation of the PCA.

Functional electrical stimulation (FES) of the posterior cricoarytenoid muscle (PCA) to restore respiratory function of the larynx may become an option for the treatment of bilateral recurrent laryngeal nerve paralysis (RLNP) in the near future. The feasibility of this has been shown in several animal trials and in a human pilot study. The common open surgical inferolateral approach for electrode insertion into the PCA for FES has a risk of damaging the recurrent laryngeal nerve (RLN) and may result in postoperative swelling and scaring of the larynx. Therefore, a minimal invasive electrode insertion technique is needed. A new miniaturized bipolar spiral tip electrode and a new electrical stimulatable insertion needle were tested in a short-term trial for an endoscopically guided and functionally controlled transcricoidal electrode insertion in eight Göttingen minipigs with bilateral normal RLN function. The feasibility of this technique was evaluated and the achieved positions of the electrodes in the PCA were analyzed using intraoperative stimulation threshold data and 3D-CT reconstructions. In seven cases it was possible to place two well-performing electrodes into the PCA. They were positioned one on either side. In one animal no functioning electrode position could be achieved because the PCA was missed. Thresholds of the electrode tips varied between 0.2 and 2.5 mA (mean 0.71 mA). In any case maximal glottal opening could be reached before adductors were co-activated. The majority of electrodes were placed into the central lower part of the PCA with no apparent correlation between threshold and electrode position. Surgical trauma might be further reduced by using endoscopy via a laryngeal mask avoiding the temporary tracheostomy used in this trial. If the implanted electrodes remain stable in long-term tests, we suggest that this method could soon be transferred into human application.

Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.

BACKGROUND: Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. METHODS: This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. INTERPRETATION: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Oxaliplatin: a review of approved uses.

INTRODUCTION: Oxaliplatin, a second-generation platinum analog, has evolved as one of the most important therapeutic agents in colorectal cancer (CRC) treatment. It has had a major impact on the management and outcome of this disease. AREAS COVERED: The pharmacokinetic and pharmacodynamic data of oxaliplatin are reviewed in this paper. It also discusses the current clinical data regarding the use of oxaliplatin in early colon cancer, locally advanced rectal cancer, and in the metastatic setting, with a particular reference to its combination with monoclonal antibodies, and strategies for prevention of cumulative toxicity. EXPERT OPINION: Oxaliplatin has proven beneficial in the treatment of CRC and can currently be regarded as one of the three most important chemotherapeutic drugs used in the treatment of both metastatic disease and adjuvant therapy in stage II/III after resection. With regards to a median overall survival of more than 20 months, and a median progression-free survival for first-line treatment of about 9 - 10 months, the majority of patients will receive all three compounds (oxaliplatin, fluoropyrimidines and irinotecan) during the course of their disease. At the moment there are no drugs in late clinical development which might be able to substitute oxaliplatin in its unique role in CRC.

Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer : is it time for a randomized phase III trial?

BACKGROUND: in the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity. MATERIAL AND METHODS: this review article focuses on phase II-III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings. RESULTS: after preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients' refusal, or investigator's discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease. CONCLUSION: whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial.

[Adjuvant therapy in colon cancer]. / Adjuvante therapie des kolonkarzinoms.

The goal of improving adjuvant treatment can be reached in two ways: firstly, by developing more effective drugs and protocols and, secondly, by selecting suitable patients on the basis of clinical and molecular factors. In UICC (Union internationale contre le cancer) stage II, microsatellite instability (MSI) is a strong prognostic factor. Whether it can also be used as a predictive marker is currently a matter of controversy because the available data are contradictory. The question whether or not the MSI status should be checked before treatment decisions are made in stage II patients can therefore not be clearly answered at present. For adjuvant treatment in stage III, with capecitabine/oxaliplatin (XELOX) there is now a new protocol available that is based on the orally administered prodrug capecitabine. With regard to the question of how much older patients in this stage may also benefit from a combination chemotherapy, new--and contradictory--data have emerged recently: firstly, preliminary results of two new studies have given rise to safety concerns and, secondly, an analysis by the 'ACCENT Collaborative Group' indicated lower efficacy of the 'newer' adjuvant protocols in older people. These findings, however, have now been called into question as a result of a new subgroup analysis from the XELOXA study. The expert group therefore recommended that the decision whether to treat patients older than 70 years with an (oral) fluoropyrimidine alone or in combination with oxaliplatin should be based on clinical parameters such as biological age and comorbidities.

Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer.

PURPOSE: To evaluate the activity and safety of preoperative radiotherapy (RT) and concurrent capecitabine and oxaliplatin (XELOX-RT) plus four cycles of adjuvant XELOX in patients with rectal cancer. PATIENTS AND METHODS: One hundred ten patients with T3/T4 or N+ rectal cancer were entered onto the trial in 11 investigator sites and received preoperative RT (50.4 Gy in 28 fractions). Capecitabine was administered concurrently at 1,650 mg/m2 on days 1 to 14 and 22 to 35, and oxaliplatin was administered at 50 mg/m2 on days 1, 8, 22, and 29. Surgery was scheduled 4 to 6 weeks after completion of XELOX-RT. Four cycles of adjuvant XELOX (capecitabine 1,000 mg/m2 bid on days 1 to 14; oxaliplatin 130 mg/m2 on day 1) were administered. The main end points were activity as assessed by the pathologic complete response (pCR) rate and the feasibility of postoperative XELOX chemotherapy. RESULTS: After XELOX-RT, 103 of 104 eligible patients underwent surgery; pCR was achieved in 17 patients (16%), one patient had ypT0N1 disease, and 53 patients showed tumor regression of more than 50% of the tumor mass. R0 resections were achieved in 95% of patients, and sphincter preservation was accomplished in 77%. Full-dose preoperative XELOX-RT was administered in 96%. Grade 3 or 4 diarrhea occurred in 12% of patients. Postoperative complication occurred in 43% of patients. Sixty percent of patients received all four cycles of adjuvant XELOX, with sensory neuropathy (18%) and diarrhea (12%) being the main grade 3 or 4 toxicities. CONCLUSION: Preoperative XELOX-RT plus four cycles of adjuvant XELOX is an active and feasible treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based treatment with XELOX- based multimodality treatment.

Preclinical evaluation of ZD1839 alone or in combination with oxaliplatin in a panel of human tumor cell lines -- implications for clinical use.

BACKGROUND: Preclinical studies have suggested antitumor activity of an epidermal growth factor (EGF)-receptor targeted therapy with selective tyrosine kinase inhibitors alone or in combination with conventional cytostatic drugs. However, in non-small cell lung cancer (NSCLC), addition of ZD1839 (Iressa) to combination chemotherapy did not improve the therapeutic outcome. Thus, further work is necessary to define factors predicting outcome of combination therapy. MATERIALS AND METHODS: In the present study, the activity of ZD1839 alone or in combination with oxaliplatin (Eloxatin) was evaluated in 12 human cancer cell lines including colon, testicular, anaplastic thyroid and epidermoid carcinoma cells. RESULTS: The EGF-receptor protein was overexpressed in line A431 (epidermoid carcinoma) and near the minimum detection limit in all other cell lines. The single agent activity of ZD1839 was highest in cell line A431. In the other cell lines, it was lower and appeared to be independent of EGF-receptor expression levels. The relative antitumor activity (RAA) was low (RAA = 1). Combined exposure to oxaliplatin and ZD1839 (IC30) resulted in significant synergy in 4 out of 6 colorectal cancer (CRC) cell lines and significant antagonism in 4 out of 6 non-colorectal cancer cell lines. Continuous exposure to ZD1839 (IC30) induced a marked G1-phase arrest and dephosphorylation of EGF-receptor in A431, whereas no significant cell cycle perturbation could be detected in the low-expression cell lines. Other factors than cell cycle perturbation seem to determine the mode of drug interaction between oxaliplatin and ZD1839. CONCLUSION: Based on RAA, the single agent activity of ZD1839 in the investigated cell line panel appeared to be low. Combined exposure to ZD1839 and oxaliplatin exerted synergy in colorectal cancer cell lines, warranting further evaluation in this type of cancer. However, based on the observed antagonism in non-colorectal cancer cell lines, combined treatment with ZD1839 and oxaliplatin is not recommended for other types of cancer. Further research is necessary to identify factors which determine the nature of drug interaction in different tumor types including CRC and lung cancer.