Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.

Switch maintenance chemotherapy versus observation after carboplatin and weekly paclitaxel doublet chemotherapy in elderly patients with advanced non-small cell lung cancer: IFCT-1201 MODEL trial.

PURPOSE: Maintenance chemotherapy is a reasonable choice for patients with metastatic non-small cell lung carcinoma (NSCLC) not progressing after induction therapy with a platinum-based doublet. Nevertheless, there have been no studies dedicated to elderly patients. PATIENTS AND METHODS: We conducted a randomised trial in patients aged 70-89 years, with advanced NSCLC (with neither EGFR mutation nor ALK rearrangement), who had not progressed after four cycles of monthly carboplatin and weekly paclitaxel in order to compare maintenance with either pemetrexed (500 mg/m2 d1, 22) in patients with non-squamous cell carcinoma or gemcitabine (1,150 mg/m2 d1, 8, 22) in squamous cell carcinoma to simple observation. The patients were required to have a performance status (PS) 0-2, mini-mental score >23, and creatinine clearance ≥45 mL/min. The primary end-point was overall survival (OS). RESULTS: 632 patients were enrolled from May 2013 to October 2016. Of the 328 (52.3%) patients randomised after induction therapy, 166 patients were assigned to the observation arm, versus 162 to the switch maintenance arm, 119 of whom received pemetrexed and 43 gemcitabine. The median OS from randomisation was 14.1 months (95% confidence interval [CI]: 12.0-17.0) in the observation arm and 14 months (95% CI: 10.9-16.9) in the maintenance arm (p = 0.72). The median progression-free survival (PFS) from randomisation was 2.7 months (95% CI: 2.6-3.1) in the observation arm versus 5.7 months (95% CI: 4.8-7.1) in the maintenance arm (p < 0.001). CONCLUSION: Switch maintenance therapy significantly prolonged PFS but not OS and, thus, should not be proposed to elderly patients with advanced NSCLC.

Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer. METHODS: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346. FINDINGS: Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group. INTERPRETATION: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. FUNDING: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).

Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study.

PURPOSE: Second-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer (nsNSCLC). METHODS: In this multicentre, open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m2 of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m2) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671. RESULTS: One hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel [5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval [CI]: 0·44-0·86); p = 0·005]. Objective response rates (ORRs) were 22·5% (95% CI: 14·8-30·3) and 5·5% (95% CI: 0·0-11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group). CONCLUSION: Weekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01763671.

Randomized Phase II Trial Evaluating Treatment with EGFR-TKI Associated with Antiestrogen in Women with Nonsquamous Advanced-Stage NSCLC: IFCT-1003 LADIE Trial.

PURPOSE: The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR-tyrosine kinase inhibitor (TKI) with an antiestrogen may overcome resistance to EGFR-TKI. PATIENTS AND METHODS: The IFCT-1003 LADIE trial was a 2 × 2 arms parallel open-label randomized phase II trial. EGFR-TKI-naïve postmenopausal women with advanced lung cancer were treated with gefitinib (G) versus gefitinib + fulvestrant (G+F) in the EGFR-mutated group (EGFR+) or with erlotinib (E) versus erlotinib + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR+ patients. RESULTS: Overall, 204 patients (gefitinib 104 and G+F 100) and 175 patients (erlotinib 87 and E+F 88) were enrolled in the EGFR+ and EGFR-WT cohorts. In the EGFR+ cohort, the primary endpoint was reached, with 58% of the G+F group patients being nonprogressive at 9 months. Adding fulvestrant to gefitinib was not associated with improved PFS (9.9 vs 9.4 months) or overall survival (OS; 22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were nonprogressive at 3 months). Adding fulvestrant to erlotinib was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding estrogen receptor alpha expression. The tolerance was as expected with no treatment-related death. CONCLUSIONS: Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless of EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in an unselected population.

Effects of vertical interarch space and abutment height on stress distributions: a 3D finite element analysis.

This three dimensional Finite Element Analysis study investigated stress distribution and intensity in implants restored with cemented or screwed crown. Two parameters varied: interarch space and abutment height. Highest stresses occurred at the cervical area in all models. Stresses increased mainly with vertical interarch space highness, and secondarily with abutments shortness. From a mechanical point of view, bone and prosthetics components supporting cemented crowns were not as solicited as with screwed crowns.

Does gender and experience influence shade matching quality?

OBJECTIVES: To evaluate the influence of gender and level of experience on shade matching quality. METHODS: A study was simultaneously performed at 15 universities located in 9 countries. A total of 614 color normal participants completed all phases of the experiment. Among them, there were 305 females and 309 males, 319 dental students and 295 dental professionals. A lecture on color matching in dentistry was given to all participants. Initial training was performed using Toothguide Trainer software (TT), while Toothguide Training Box (TTB) was used for both training and testing of participants' shade matching results. The test task was to successively match 15 shade guide tabs with the corresponding shade guide. The shade matching score for each participant was computed as a sum of color differences (SigmaDeltaE(ab)(*) score) between target tabs and selected tabs. Lower scores corresponded to better shade matching results and vice versa. Means and standard deviations were calculated. Mann-Whitney U test was used for statistical analysis of the data (alpha=0.05). RESULTS: The mean shade matching score (S.D.) for all participants was 41 (21). The score for female and male participants was 38 (20) and 44 (21), respectfully (p<0.001). The difference in scores between dental students, 42 (20), and dental professionals, 39 (21), was not statistically significant. CONCLUSION: Within the limitations of this study, females achieved significantly better shade matching results than males, indicating that gender plays an important role in shade matching. The level of experience was not found to be significant factor in shade matching.

Influence of implant length and bicortical anchorage on implant stress distribution.

BACKGROUND: Short implants present superior failure rates for everybody. PURPOSE: The aim of this theoretic study was to assess to what extent implant length and bicortical anchorage affect the way stress is transferred to implant components, the implant proper, and the surrounding bone. MATERIALS AND METHODS: Stress analysis was performed using finite element analysis. A three-dimensional linear elastic model was generated. All implants modeled were of the same diameter (3.75 mm) but varied in length, at 6, 7, 8, 9, 10, 11, and 12 mm (Brånemark System, Nobel Biocare AB, Gothenburg, Sweden). Each implant was modeled with a titanium abutment screw and abutment, a gold cylinder and prosthetic screw, and a ceramic crown. The implants were seated in a supporting bone structure consisting of cortical and cancellous bone. An occlusal load of 100 N was applied at a 30 degrees angle to the buccolingual plane. RESULTS: With the selected model and bone properties, the coronal cortical anchorage was dominating, and the bone stress concentrated to that area. CONCLUSIONS: The maximum bone stress was virtually constant, independent of implant length and bicortical anchorage. The maximum implant stress, however, increased somewhat with implant length and bicortical anchorage.

Corono-radicular reconstruction of pulpless teeth: a mechanical study using finite element analysis.

STATEMENT OF PROBLEM: Following endodontic therapy, teeth need to be protected, particularly in the cervical region, where the majority of fractures occur. The likelihood of a fracture depends on the condition of the crown and the type of reconstruction performed. PURPOSE: This simulation study was designed to compare the effect of different corono-radicular reconstruction methods on stress transmission to dental tissues. MATERIAL AND METHODS: The study software performed stress analysis of complex structures by finite element analysis. Seven 3-dimensional models were created, each representing a tooth embedded in a bony medium. The following parameters affecting corono-radicular restoration were studied: 2 levels of coronal destruction, core materials, post materials when present, and absence of post. The 2 levels of coronal tissue loss were (1) total tissue loss of the coronal dentin and (2) partial tissue loss of the coronal dentin with 2-mm surviving dentin walls. Teeth with 2 different levels of tissue loss (first study parameter) were reconstructed by 4 different techniques: nickel chromium (NiCr) cast post and core, NiCr post and composite core combination, carbon fiber post and composite core combination, and composite restoration without post. A NiCr crown covered each of the models and received a 30 degrees oblique occlusal load at a constant intensity of 100 N. The software computed the stresses (local tensile stress inducing cracks and compressive stress) for each of the models, comparing maximum intensity observed, localization, and concentration. RESULTS: Whatever the type of stress (tensile or compressive), the greatest stress was observed in the cervical region, regardless of the model. Only tensile stresses potentially responsible for fractures were compared. Cervical tensile stresses exceeded 230 Pa in the absence of a ferrule and were less than 140 Pa when a ferrule was present. In the absence of a ferrule, the NiCr composite/post combination generated greater cervical stress (254 Pa) than the cast post and core (235 Pa). Results with a ferrule showed 92 Pa for the NiCr composite/post combination and 90.5 Pa for the cast post and core. In the presence of a ferrule, the tensile stress intensities generated by the composite restoration with no root canal post (139 Pa) were 51% greater than those generated by the NiCr/composite combination and approximately 26% greater than those generated by the composite/carbon combination. CONCLUSION: Within the limitations of this study, it was confirmed that all simulated reconstructed teeth were more subject to stress in the cervical region. The absence of a cervical ferrule was found to be a determining negative factor, giving rise to considerably higher stress levels. When no ferrule was present, the NiCr post/composite combination generated greater cervical stress than cast post and cores. Nevertheless, the peripheral ferrule seemed to cancel the mechanical effect of the reconstruction material on the intensity of the stresses. With a ferrule, the choice of reconstruction material had no impact on the level of cervical stress. The root canal post, the purpose of which is to protect the cervical region, was also shown to be beneficial even with sufficient residual coronal dentin. In the presence of a root canal post, cervical stress levels were lower than when no root canal post was present. Moreover, the higher the elasticity modulus, the lower the stress levels.

Treatment of latent syphilis in HIV-infected patients with 10 d of benzylpenicillin G benethamine: a prospective study in Maputo, Mozambique.

Neurosyphilis has been reported in HIV-infected patients previously treated with penicillin G benzathine, which does not achieve treponemicidal levels in cerebrospinal fluid. Therapy combining benzylpenicillin G and its repository form benzylpenicillin G benethamine could be a potentially effective alternative enhanced regimen for treating latent syphilis in HIV-infected patients because peak serum and cerebrospinal fluid concentrations would be achieved early post-administration by the former molecule and sustained for 24 h due to the prolonged half-life of the latter. In this study, 23 asymptomatic HIV and Treponema pallidum co-infected patients received 10 d of combined therapy (2 M IU intramuscular once daily) and were followed up at 3, 6 and 12 months. None experienced side effects or clinical symptoms. Of the 18 patients who were evaluated 1 y later, 8 (44.4%) exhibited serological treatment failure, defined as a positive serum rapid plasma reagin test. In conclusion, a 10-d regimen combining penicillin G and penicillin G benethamine seems to be of no benefit compared to currently recommended treatment.