Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer

BACKGROUND:

Preoperative chemoradiation improves survival in esophageal and gastroesophageal junction (GEJ) cancer. We evaluated irinotecan and cisplatin as induction chemotherapy followed by concurrent chemoradiation in esophageal cancer.

METHODS:

Patients with uT1N1M0 or uT2‐4NanyM0 resectable squamous cancer or adenocarcinoma of the esophagus or GEJ received irinotecan 65 mg/m² and cisplatin 30 mg/m² for 4 treatments in weeks 1 through 5, followed by 4 treatments in weeks 7 through 11 with 50.4 Gy in daily fractions, followed by surgery. The primary endpoint was pathologic complete response (pCR). Positron emission tomography (PET) scan was performed prior to chemotherapy and as restaging prior to radiotherapy.

RESULTS:

Fifty‐five patients were evaluable, 75% of whom had adenocarcinoma and 65% of whom had uT3N1 disease. Thirty‐eight patients underwent R0 resection (69%). The incidence of pCR was 16% (95% confidence interval, 8%‐29%). Median overall survival was 31.7 months. An exploratory analysis of PET response to induction chemotherapy indicated a correlation with pCR (32% vs 4%), R0 resection (84% vs 57%), progression‐free survival (24.1 vs 7.7 months), and overall survival (40.2 vs 25.5 months).

CONCLUSIONS:

Weekly treatment with irinotecan, cisplatin, and radiation achieved results no better and potentially inferior to other phase 2 chemoradiotherapy trials with a low rate of pCR. The use of PET scan after induction chemotherapy to direct chemotherapy during subsequent radiotherapy merits further study. Cancer 2011. © 2011 American Cancer Society.     

The use of hierarchical models for estimating relative risks of individual genetic variants: an application to a study of melanoma

For major genes known to influence the risk of cancer, an important task is to determine the risks conferred by individual variants, so that one can appropriately counsel carriers of these mutations. This is a challenging task, since new mutations are continually being identified, and there is typically relatively little empirical evidence available about each individual mutation. Hierarchical modeling offers a natural strategy to leverage the collective evidence from these rare variants with sparse data. This can be accomplished when there are available higher-level covariates that characterize the variants in terms of attributes that could distinguish their association with disease. In this article, we explore the use of hierarchical modeling for this purpose using data from a large population-based study of the risks of melanoma conferred by variants in the CDKN2A gene. We employ both a pseudo-likelihood approach and a Bayesian approach using Gibbs sampling. The results indicate that relative risk estimates tend to be primarily influenced by the individual case-control frequencies when several cases and/or controls are observed with the variant under study, but that relative risk estimates for variants with very sparse data are more influenced by the higher-level covariate values, as one would expect. The analysis offers encouragement that we can draw strength from the aggregating power of hierarchical models to provide guidance to medical geneticists when they offer counseling to patients with rare or even hitherto unobserved variants. However, further research is needed to validate the application of asymptotic methods to such sparse data.     

Attenuation of Replication-Competent Adenovirus Serotype 26 Vaccines by Vectorization

Replication-competent adenovirus (rcAd)-based vaccine vectors may theoretically provide immunological advantages over replication-incompetent Ad vectors, but they also raise additional potential clinical and regulatory issues. We produced replication-competent Ad serotype 26 (rcAd26) vectors by adding the E1 region back into a replication-incompetent Ad26 vector backbone with the E3 or E3/E4 regions deleted. We assessed the effect of vectorization on the replicative capacity of the rcAd26 vaccines. Attenuation occurred in a stepwise fashion, with E3 deletion, E4 deletion, and human immunodeficiency virus type 1 (HIV-1) envelope (Env) gene insertion all contributing to reduced replicative capacity compared to that with the wild-type Ad26 vector. The rcAd26 vector with E3 and E4 deleted and containing the Env transgene exhibited 2.7- to 4.4-log-lower replicative capacity than that of the wild-type Ad26 in vitro. This rcAd26 vector is currently being evaluated in a phase 1 clinical trial. Attenuation as a result of vectorization and transgene insertion has implications for the clinical development of replication-competent vaccine vectors.     

Management of HER2-Positive Breast Cancer for a Young Patient with Visceral Crisis—The Adjuvant Role of Lifestyle Changes

The safety profile and effectiveness of existing anti-HER2-targeted therapies have not been evaluated in patients with breast cancer and visceral crisis. We report the case of a 26-year-old woman who was diagnosed with advanced HER2-positive breast cancer and initially treated with curative intent therapy in a neoadjuvant setting, using Trastuzumab and Pertuzumab in combination with Docetaxel; her cancer recurred two years later, with liver metastases and pulmonary lymphangitic carcinomatosis, causing visceral crisis. Furthermore, the patient’s clinical status worsened when she developed respiratory failure, hepatomegaly and a severe hepatocytolysis. Since the patient was free of disease more than six months, we started with Paclitaxel half dose because of the hepatic dysfunction, and we gradually reintroduced Trastuzumab and then Pertuzumab. In the meantime, the patient changed her lifestyle by increasing her consumption of fresh fruits and vegetables and fiber and reducing her intake of processed meat, dairy and sugar. As a result, the patient showed a significant improvement in her respiratory symptoms and liver tests in less than two months. Imaging reevaluation showed partial remission of liver metastases and pulmonary lymphangitic carcinomatosis. She underwent seven months of dual anti-HER2 blockade before relapsing cerebrally. Our results suggest that the sequential combination therapy with Trastuzumab, Pertuzumab and Paclitaxel presented in this study, associated with a healthy lifestyle, may be a good management for recurrent HER2-positive breast cancer with pulmonary visceral crisis and severe liver dysfunction.