Thomas J. George

The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma

Aliment Pharmacol Ther 2011; 34: 205–213

Adequacy of Published Oncology Randomized Controlled Trials to Provide Therapeutic Details Needed for Clinical Application

BACKGROUND Randomized controlled trials (RCTs) improve clinical care through evidence-based results. Guidelines exist for RCT result reporting, but specific details of therapeutic administration promote clinical application and reproduction of the trial design. We assess the reporting methodology in RCTs published in major oncology journals. METHODS Ten essential elements of RCT reporting were identified and included drug name, dose, route, cycle length, maximum number of cycles, premedication, growth factor support, patient monitoring parameters, and dosing adjustments for hematologic and organ-specific toxicity. All therapy-based oncology RCTs published between 2005 and 2008 in the New England Journal of Medicine (NEJM), Journal of Clinical Oncology (JCO), Journal of the National Cancer Institute (JNCI), Blood, and Cancer were analyzed for inclusion of these 10 elements. RESULTS Of 339 identified articles, 262 were included in the final analysis (165 from JCO, 31 from NEJM, 27 from Cancer, 20 from JNCI, and 19 from Blood). Premedication, growth factor support, and dose adjustments for toxicities were each reported less than half of the time. Only 30 articles (11%) met the main objective of complete data reporting (ie, all 10 essential elements) and was highest in JNCI (5/20; 25%), followed by Cancer (5/27; 18%), JCO (18/165; 11%), Blood (1/19; 5%), and NEJM (1/31; 3%). The presence of an online appendix did not substantially improve complete reporting. CONCLUSIONS RCTs published in major oncology journals do not consistently report essential therapeutic details necessary for translation of the trial findings to clinical practice. Potential solutions to improve reporting include modification of submission guidelines, use of online appendices, and providing open access to trial protocols.

Factors associated with parameters of engraftment potential of umbilical cord blood

BACKGROUND: Umbilical cord blood (UCB) is an acceptable source of hematopoietic cells for transplantation with success being associated with the nucleated cell count (NCC), CD34+ cells, and colony‐forming unit–granulocyte‐macrophage (CFU‐GM) content infused. A total of 1033 UCB samples with neonatal and paternal characteristics that might influence hematopoietic content were examined.

Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma.

The aim of the present study was to determine the treatment outcome and prognostic factors for survival in patients with peripheral intrahepatic cholangiocarcinoma (ICC). A retrospective chart review was performed for patients diagnosed with ICC between 2000 and 2009 at a single institution. We identified a total of 105 patients with ICC. Among them, 63.8% were older than 60 years of age, 50.5% were male and 88.6% were Caucasian. By preoperative imaging approximately half of the patients (50.5%) were surgical candidates and underwent resection. The other half of the patients (49.5%) were unresectable. The unresectable group received chemoradiotherapy (53%) and transarterial chemoembolization (7.7%) as palliative treatments while 23.0% of the patients (12/52) received best supportive care alone. The median survival rates were 16.1 months (13.1–19.2) for the entire cohort, 27.6 months (17.7–37.6) for curative resection, 12.9 months (6.5–19.2) for palliative chemoradiotherapy and 4.9 months (0.4–9.6) for best supportive care (P<0.001). Independent predictors on multivariate analysis were advanced stage at diagnosis and treatment received. In those patients who underwent resection, advanced AJCC stage and presence of microvascular invasion were also independent predictors of poor survival. We concluded that surgery offers the most beneficial curative option and outcome, emphasizing the importance of resectability as a major prognostic factor. The present study also revealed that use of chemoradiotherapy in the adjuvant setting failed to improve survival but its palliative use in those patients with unresectable ICC offered a modest survival advantage over best supportive care. The overriding factors influencing outcome were stage and the presence of microvascular invasion on pathology.

Opportunities and Challenges in the Era of Molecularly Targeted Agents and Radiation Therapy

The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8-9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy.

Adjuvant Radiotherapy for Cutaneous Melanoma

The purpose of the current study was to discuss the efficacy of adjuvant radiotherapy (RT) in the treatment of melanoma by reviewing the pertinent literature. The risk of locoregional recurrence after surgery alone for locally advanced melanoma is relatively high. The likelihood of a positive sentinel lymph node biopsy (SLNB) exceeds 20% for melanomas >2 mm thick and approximately ≥20% of those patients with positive SLNB will be found to have residual positive lymph nodes on completion lymph node dissection. Patients with positive regional lymph nodes have an approximately ≥20% risk of regional recurrence after surgery alone, particularly if multiple lymph nodes are involved and/or extracapsular extension is present. Postoperative adjuvant RT results in locoregional control rates of 85% to 90% or higher in high‐risk patients with a modest risk of complications. The impact of adjuvant RT on survival is likely minimal. Cancer 2008.

Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity

Abstract Background. To review treatment toxicity for patients with pancreatic and ampullary cancer treated with proton therapy at our institution. Material and methods. From March 2009 through April 2012, 22 patients were treated with proton therapy and concomitant capecitabine (1000 mg PO twice daily) for resected (n = 5); marginally resectable (n = 5); and unresectable/inoperable (n = 12) biopsy-proven pancreatic and ampullary adenocarcinoma. Two patients with unresectable disease were excluded from the analysis for reasons unrelated to treatment. Proton doses ranged from 50.40 cobalt gray equivalent (CGE) to 59.40 CGE. Results. Median follow-up for all patients was 11 (range 5–36) months. No patient demonstrated any grade 3 toxicity during treatment or during the follow-up period. Grade 2 gastrointestinal toxicities occurred in three patients, consisting of vomiting (n = 3); and diarrhea (n = 2). Median weight loss during treatment was 1.3 kg (1.75% of body weight). Chemotherapy was well-tolerated with a median 99% of the prescribed doses delivered. Percentage weight loss was reduced (p = 0.0390) and grade 2 gastrointestinal toxicity was eliminated (p = 0.0009) in patients treated with plans that avoided anterior and left lateral fields which were associated with reduced small bowel and gastric exposure. Discussion. Proton therapy may allow for significant sparing of the small bowel and stomach and is associated with a low rate of gastrointestinal toxicity. Although long-term follow-up will be needed to assess efficacy, we believe that the favorable toxicity profile associated with proton therapy may allow for radiotherapy dose escalation, chemotherapy intensification, and possibly increased acceptance of preoperative radiotherapy for patients with resectable or marginally resectable disease.

Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes

BACKGROUND Squamous cell cancers of the anal canal (ASCC) are increasing in frequency and lack effective therapies for advanced disease. Although an association with human papillomavirus (HPV) has been established, little is known about the molecular characterization of ASCC. A comprehensive genomic analysis of ASCC was undertaken to identify novel genomic alterations (GAs) that will inform therapeutic choices for patients with advanced disease. PATIENTS AND METHODS Hybrid-capture-based next-generation sequencing of exons from 236 cancer-related genes and intronic regions from 19 genes commonly rearranged in cancer was performed on 70 patients with ASCC. HPV status was assessed by aligning tumor sequencing reads to HPV viral genomes. GAs were identified using an established algorithm and correlated with HPV status. RESULTS Sixty-one samples (87%) were HPV-positive. A mean of 3.5 GAs per sample was identified. Recurrent alterations in phosphoinositol-3-kinase pathway (PI3K/AKT/mTOR) genes including amplifications and homozygous deletions were present in 63% of cases. Clinically relevant GAs in genes involved in DNA repair, chromatin remodeling, or receptor tyrosine kinase signaling were observed in 30% of cases. Loss-of-function mutations in TP53 and CDKN2A were significantly enhanced in HPV-negative cases (P < 0.0001). CONCLUSIONS This is the first comprehensive genomic analysis of ASCC, and the results suggest new therapeutic approaches. Differing genomic profiles between HPV-associated and HPV-negative ASCC warrants further investigation and may require novel therapeutic and preventive strategies.

Hepatitis B Reactivation and Rituximab in the Oncology Practice

Rituximab use in hematology and oncology practice has significantly and positively improved the clinical outcomes in patients with a wide variety of B-cell lymphoproliferative disorders. However, emerging data reveal that there is a risk of viral hepatitis B reactivation in some patients treated with rituximab. Many of these cases result in treatment delays, inferior oncologic outcomes, increased morbidity, and more rarely fulminant hepatic decompensation and death. Indeed, the rituximab package insert and many clinical practice guidelines have been modified to reflect these concerns. The true incidence and mechanism of reactivation are still being elucidated. This article focuses on the current evidence that supports these recently revised clinical recommendations along with a review of the risk factors for reactivation, suggested monitoring, and preventative interventions.

A phase II trial of neoadjuvant capecitabine combined with hyperfractionated accelerated radiation therapy in locally advanced rectal cancer.

Objective:Preoperative treatment of rectal cancer with combined chemotherapy and radiation therapy has become a widely accepted strategy. The current challenge is to improve outcomes whereas minimizing morbidity and maximizing the potential for a sphincter sparing procedure. This study sought to evaluate the safety and efficacy of a combination of 2 novel approaches—accelerated, hyperfractionated radiation therapy and twice daily oral capecitabine. Methods:Consenting patients with locally advanced T3–T4, N0-1, M0 rectal adenocarcinoma, located no further than 15 cm from the anal verge, were treated with twice daily fractions of 1.2 Gy M–F to a total of 50.4 Gy for T3 lesions and 55.2 Gy for T4 lesions. Concomitantly, the patients received capecitabine 825 mg/m2 twice per day 7 days per week. Patients were operated on 4 to 6 weeks after completion of therapy. Results:Sixteen of 17 enrolled patients were eligible and all 16 completed the full course of treatment including definitive surgery. Eleven patients had a sphincter sparing procedure and 5 had an abdominoperineal resection. Tumor and/or nodal downstaging occurred in 81% of patients, 100% of resections were R0, and the sphincter preservation rate was 68%. There were 18% pathologic complete remissions and 68% of specimens were node negative with an additional 12% Nx owing to transanal excision. The therapy was well tolerated and there were no unexpected toxicities with only diarrhea reaching grade 3 in 4 patients. Conclusions:This novel approach to preoperative treatment of rectal adenocarcinoma was well tolerated and effective. Comparison with more established approaches appears justified.