Javier de Castro Carpeño

Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer

Background Most patients with locally advanced, unresectable, non–small‐cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti–programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum‐based chemoradiotherapy. Methods We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression‐free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12‐month and 18‐month progression‐free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. Results Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression‐free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12‐month progression‐free survival rate was 55.9% versus 35.3%, and the 18‐month progression‐free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Conclusions Progression‐free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461.)

KRAS Mutations in Primary Colorectal Cancer Tumors and Related Metastases: A Potential Role in Prediction of Lung Metastasis

Background KRAS mutations in colorectal cancer primary tumors predict resistance to anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody therapy in patients with metastatic colorectal cancer, and thus represent a true indicator of EGFR pathway activation status. Methodology/Principal Findings KRAS mutations were retrospectively studied using polymerase chain reactions and subsequent sequencing of codons 12 and 13 (exon 2) in 110 patients with metastatic colorectal tumors. These studies were performed using tissue samples from both the primary tumor and their related metastases (93 liver, 84%; 17 lung, 16%). All patients received adjuvant 5-Fluorouracil-based polychemotherapy after resection of metastases. None received anti-EGFR therapy. Mutations in KRAS were observed in 37 (34%) of primary tumors and in 40 (36%) of related metastases, yielding a 94% level of concordance (kappa index 0.86). Patients with primary tumors possessing KRAS mutations had a shorter disease-free survival period after metastasis resection (12.0 vs 18.0 months; P = 0.035) than those who did not. A higher percentage of KRAS mutations was detected in primary tumors of patiens with lung metastases than in patients with liver metastases (59% vs 32%; p = 0.054). To further evaluate this finding we analyzed 120 additional patients with unresectable metastatic colorectal cancer who previously had their primary tumors evaluated for KRAS mutational status for clinical purposes. Separately, the analysis of these 120 patients showed a tendency towards a higher degree of KRAS mutations in primary tumors of patients with lung metastases, although it did not reach statistical significance. Taken together the group of 230 patients showed that KRAS was mutated significantly more often in the primary tumors of patients with lung metastases (57% vs 35%; P = 0.006). Conclusions/Significance Our results suggest a role for KRAS mutations in the propensity of primary colorectal tumors to metastasize to the lung.

A role for cancer stem cells in drug resistance and metastasis in non-small-cell lung cancer.

The cancer stem cell (CSC) theory is currently a very important field in cancer research. This theory states that tumours are organised in a hierarchical manner with a subpopulation of limited number called CSCs with the ability to self-renew and undergo asymmetrical divisions, giving rise to a differentiated progeny that represents most of the tumour populations. CSCs are metastatic and chemoresistant, two features that very likely contribute to the poor response of locally advanced lung cancer. CSCs have been identified in non-small-cell lung cancer cell lines as well as those from patient primary samples. A correlation has been found in terms of chemoresistance and bad prognosis in patient-derived samples enriched with CSCs, indicating that these cells are an important target for future therapy combinations. Therefore, understanding the biology and exploring cell markers and signalling pathways specific for CSCs of lung cancer may help in achieving progress in the treatment of the disease.

Efficacy of Preoperative radiation therapy for resectable rectal adenocarcinoma when combined with oral tegafur-uracil modulated with leucovorin:Results from a phase II study

PURPOSE The aim of this study was to evaluate the efficacy of preoperative radiation therapy for resectable rectal adenocarcinoma (T3-T4) when delivered in combination with chemotherapy (oral tegafur-uracil modulated with leucovorin). METHODS Thirty-eight patients (23 males; mean age, 62 years.) with histologically proven rectal adenocarcinoma with primary tumor clinical classification T3-T4 (resectable) and N0 or N1-N2, according to TNM staging system, took part in the present clinical trial. After tumor and metastasis resectability confirmation, radiation therapy was administered by delivering a dose of 45 Gy in 25 fractions for 5 weeks. Chemotherapy treatment was initiated on the same day as radiotherapy and consisted of intravenous infusion of 6S-steroisomer of leucovorin 250 mg/m2/day in 2 hours on Day 1, followed by oral 350 or 300 mg/m2/day of tegafur (a 5-fluorouracil prodrug) plus uracil on Days 1 to 14 divided into 2 daily doses, and oral 6S-steroisomer of leucovorin 7.5 mg/12 hours on Days 2 to 14, with a total of 102 courses of neoadjuvant chemotherapy (i.e., mean of 2.7 courses per patient). Six additional courses of tegafur-uracil were given postoperatively to all 38 patients but 1 who refused. RESULTS As a result of preoperative chemoradiation treatment, 4 (10.5 percent) complete responses, 20 (52.6 percent) partial responses, and 14 (36.8 percent) patients with disease stabilization were observed. No patients had preoperative disease progression. Histologically proven downstaging was observed in 23 (60 percent) patients. On initial evaluation, only 39 percent of patients were considered as being good candidates for sphincter-preserving surgery; however, on preoperative chemoradiation completion this figure increased up to 60 percent. For the 23 patients eventually undergoing sphincter-preserving surgery, postoperative sphincter function assessment showed excellent function in 15 (65 percent) patients, good in 5 (22 percent), fair in 2 (9 percent), and poor in 1(4 percent). With a median follow-up of 37 (range, 10–62) months, local failure was found in 3 (8 percent) patients and distant failure in 2 (5 percent). Three-year actuarial disease-free survival and 3-year overall survival rates were 83 and 90 percent, respectively. Local control rate was 92 percent. Toxicity and postoperative complication rates were reasonable. CONCLUSIONS Our neoadjuvant radiation therapy protocol is efficient for the preoperative treatment of resectable rectal adenocarcinoma when combined with chemotherapy (oral tegafur-uracil modulated with leucovorin). However, this protocol needs to be tested in a phase-III clinical trial with a larger sample size.

Efficacy of Preoperative Radiation Therapy for Resectable Rectal Adenocarcinoma When Combined With Oral Tegafur-Uracil Modulated With Leucovorin

AbstractPURPOSE: The aim of this study was to evaluate the efficacy of preoperative radiation therapy for resectable rectal adenocarcinoma (T3-T4) when delivered in combination with chemotherapy (oral tegafur-uracil modulated with leucovorin). METHODS: Thirty-eight patients (23 males; mean age, 62 years.) with histologically proven rectal adenocarcinoma with primary tumor clinical classification T3-T4 (resectable) and N0 or N1-N2, according to TNM staging system, took part in the present clinical trial. After tumor and metastasis resectability confirmation, radiation therapy was administered by delivering a dose of 45 Gy in 25 fractions for 5 weeks. Chemotherapy treatment was initiated on the same day as radiotherapy and consisted of intravenous infusion of 6S-steroisomer of leucovorin 250 mg/m2/day in 2 hours on Day 1, followed by oral 350 or 300 mg/m2/day of tegafur (a 5-fluorouracil prodrug) plus uracil on Days 1 to 14 divided into 2 daily doses, and oral 6S-steroisomer of leucovorin 7.5 mg/12 hours on Days 2 to 14, with a total of 102 courses of neoadjuvant chemotherapy (i.e., mean of 2.7 courses per patient). Six additional courses of tegafur-uracil were given postoperatively to all 38 patients but 1 who refused. RESULTS: As a result of preoperative chemoradiation treatment, 4 (10.5 percent) complete responses, 20 (52.6 percent) partial responses, and 14 (36.8 percent) patients with disease stabilization were observed. No patients had preoperative disease progression. Histologically proven downstaging was observed in 23 (60 percent) patients. On initial evaluation, only 39 percent of patients were considered as being good candidates for sphincter-preserving surgery; however, on preoperative chemoradiation completion this figure increased up to 60 percent. For the 23 patients eventually undergoing sphincter-preserving surgery, postoperative sphincter function assessment showed excellent function in 15 (65 percent) patients, good in 5 (22 percent), fair in 2 (9 percent), and poor in 1(4 percent). With a median follow-up of 37 (range, 10–62) months, local failure was found in 3 (8 percent) patients and distant failure in 2 (5 percent). Three-year actuarial disease-free survival and 3-year overall survival rates were 83 and 90 percent, respectively. Local control rate was 92 percent. Toxicity and postoperative complication rates were reasonable. CONCLUSIONS: Our neoadjuvant radiation therapy protocol is efficient for the preoperative treatment of resectable rectal adenocarcinoma when combined with chemotherapy (oral tegafur-uracil modulated with leucovorin). However, this protocol needs to be tested in a phase-III clinical trial with a larger sample size.

The impact of next-generation sequencing on the DNA methylation–based translational cancer research

Epigenetics is currently in an exponential phase of growth, constituting one of the most promising fields in science, particularly in cancer research. Impaired epigenetic processes can lead to abnormal gene activity or inactivity, causing cellular disorders that are closely associated with tumor initiation and progression. Thus, there is a pivotal role of massive sequencing techniques for epigenetics, which aim to find novel biomarkers, factors of prognosis and prediction, and targets for achieving personalized treatments. We present a brief description of the evolution of next-generation sequencing technologies and its coupling with DNA methylation analysis techniques, highlighting its future in translational medicine and presenting significant findings in several malignancies. We also expose critical topics related to the implementation of these approaches, which is expected to be affordable for most research centers in the near future.

Comparison of treatment costs of grade 3/4 adverse events associated with erlotinib or pemetrexed maintenance therapy for patients with advanced non-small-cell lung cancer (NSCLC) in Germany, France, Italy, and Spain

Objective of this indirect economic comparison was to estimate and compare management costs of grade 3/4 adverse events (AEs) reported for first-line erlotinib or pemetrexed maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC). The economic analysis was performed for Germany, France, Italy and Spain. Types and incidences of reported grade 3/4 AEs observed with erlotinib or pemetrexed maintenance therapy were retrieved from two recently published placebo-controlled trials. Country-specific estimates on standard treatment algorithms and incremental medical resource utilization associated with each of the reported grade 3/4 AEs have been obtained from clinical oncologists practicing in the four countries and co-authoring this article. The resource use items were subsequently assigned country-specific tariffs to estimate total per-patients costs associated with the AE profiles of the two compared maintenance regimens. For the economic analysis a customized economic spreadsheet model was employed. Our comparison shows lower total average per-patient AE management costs for erlotinib than for pemetrexed maintenance therapy in all four studied countries. Total estimated cost savings per patient in favour of erlotinib amount to € 121, € 237, € 106, and € 119 for Germany, France, Italy and Spain, respectively. These AE cost savings for erlotinib when compared to pemetrexed represent a decrease by 80%, 71%, 94%, and 82%, respectively. The study also discovered considerable differences in AE management costs across countries which are primarily due to differences in clinicians estimates of hospitalization referral rates. Erlotinib maintenance therapy in patients with advanced NSCLC causes lower AE management costs than pemetrexed maintenance therapy indicating a potentially superior tolerability profile.

A cross-market cost comparison of erlotinib versus pemetrexed for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer

Erlotinib and pemetrexed were approved by the European Medicines Agency for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) to prolong overall survival after first-line therapy. An adjusted, matched, indirect comparison of erlotinib and pemetrexed suggested that survival benefits were not statistically significantly different between treatments. We conducted a cost-comparison analysis of erlotinib versus pemetrexed in first-line maintenance treatment of locally advanced or metastatic, non-squamous NSCLC in France, Germany, Italy and Spain, performed from the perspective of national health-care decision-makers or purchasers. The analysis was limited to direct costs and comprised drug-acquisition costs, administration costs and costs of treating adverse events (AEs). A one-way sensitivity analysis on administration, acquisition and AE costs was also performed. Total monthly per-patient treatment costs for erlotinib in France, Germany, Italy and Spain were €2140, €2732, €1518 and €2048, respectively, and for pemetrexed €3453, €5534, €2921 and €3164, respectively. AE cost was greater for pemetrexed in all countries, as was administration cost. As an oral treatment, erlotinib is not associated with any administration costs, except in Germany, where the cost is lower than for pemetrexed. The sensitivity analysis showed acquisition costs to be the main driver of total monthly per-patient costs. Erlotinib appears to be a cost-saving treatment alternative to pemetrexed, producing comparable survival benefits, based on an indirect comparison, at a lower cost.

Factores etiológicos del cáncer de pulmón: fumador activo, fumador pasivo, carcinógenos medioambientales y factores genéticos

Cada ano se diagnostican en Espana 18.000 nuevos casos de cancer de pulmon (CP). Aproximadamente el 80-90% de los casos se relacionan con el consumo de tabaco. El humo del tabaco contiene mas de 300 sustancias quimicas, de las que mas de 40 son potenciales carcinogenos. En la ultima decada, tanto en Espana como en Europa, se ha observado una preocupante tendencia al aumento de la prevalencia de mujeres fumadoras. El abandono del habito tabaquico reduce sustancialmente el riesgo de desarrollar un CP, que, no obstante, no iguala al de los individuos que nunca han fumado. Por otra parte, la exposicion ambiental al tabaco tambien ha demostrado ser causa de un aumento del riesgo de desarrollar CP. Este trabajo ofrece una revision actualizada sobre los principales factores etiologicos del CP, el riesgo asociado al consumo de tabaco y a su exposicion ambiental, los factores geneticos asociados y la exposicion medioambiental a sustancias como el arsenico, el asbesto o los hidrocarburos aromaticos policiclicos.Every year, in Spain 18,000 new cases of lung cancer (LC) are diagnosed. Approximately, 80-90% LC in men and women are directly attributable to tobacco abuse. Cigarette smoke contains over 300 chemicals, 40 of which are known to be potent carcinogens. In the last decade, as in Spain, prevalence of smoking in women has generally increased in the European Union. LC risk can be substantially reduced after smoking cessation, yet never reaches baseline. On the other hand, environmental tobacco smoke exposure (passive smoking) in nonsmokers appears to have a significantly increased risk of LC. An updated of etiology factors of LC, risk related to duration as well as intensity of smoking, relationship between environmental tobacco smoke exposure and LC risk, genetic predisposition and a variety of occupational and environmental exposures implicated as potential risk factors for the development of LC will be reviewed here.

Effectiveness of bevacizumab- and pemetrexed-cisplatin treatment for patients with advanced non-squamous non-small cell lung cancer

The new targeted agent bevacizumab in combination with cisplatin and gemcitabine, and a third generation chemotherapy, pemetrexed, combined with cisplatin, are approved as first-line treatment for patients with advanced nonsquamous non-small cell lung cancer (NSCLC). As no head-to-head comparison of these treatments exists, this study aimed to compare the effectiveness of the two treatments using an indirect treatment comparison approach. An indirect comparison on progression-free survival (PFS) was performed for two relevant randomised controlled trials using a well-accepted adjusted indirect comparison method. The results were used in a statistical disease model (Markov model) to extrapolate the long-term effectiveness of the two treatments. A hazard ratio of 0.83 for PFS for bevacizumab plus cisplatin and gemcitabine, was calculated suggesting that this treatment is associated with a 17% lower risk of disease progression and death compared with pemetrexed plus cisplatin treatment. The Markov model predicted that bevacizumab plus cisplatin and gemcitabine resulted in 2.5 months additional PFS and overall survival compared with pemetrexed plus cisplatin. Based on this analysis bevacizumab plus cisplatin and gemcitabine is more effective than pemetrexed plus cisplatin for patients with advanced non-squamous NSCLC and should be considered as one of the preferred targeted treatments of choice for these patients.