Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial

Jaffer A. Ajani, MD; Kathryn A. Winter, MS; Leonard L. Gunderson, MD; John Pedersen, MD; Al B. Benson III, MD; Charles R. Thomas Jr, MD; Robert J. Mayer, MD; Michael G. Haddock, MD; Tyvin A. Rich, MD; Christopher Willett, MD

JAMA. 2008;299(16):1914-1921.

Context  Chemoradiation as definitive therapy is the preferred primary therapy for patients with anal canal carcinoma; however, the 5-year disease-free survival rate from concurrent fluorouracil/mitomycin and radiation is only approximately 65%.

Objective  To compare the efficacy of cisplatin-based (experimental) therapy vs mitomycin-based (standard) therapy in treatment of anal canal carcinoma.

Design, Setting, and Participants  US Gastrointestinal Intergroup trial RTOG 98-11, a multicenter, phase 3, randomized controlled trial comparing treatment with fluorouracil plus mitomycin and radiotherapy vs treatment with fluorouracil plus cisplatin and radiotherapy in 682 patients with anal canal carcinoma enrolled between October 31, 1998, and June 27, 2005. Stratifications included sex, clinical nodal status, and tumor diameter.

Intervention  Participants were randomly assigned to 1 of 2 intervention groups: (1) the mitomycin-based group (n = 341), who received fluorouracil (1000 mg/m² on days 1-4 and 29-32) plus mitomycin (10 mg/m² on days 1 and 29) and radiotherapy (45-59 Gy) or (2) the cisplatin-based group (n = 341), who received fluorouracil (1000 mg/m² on days 1-4, 29-32, 57-60, and 85-88) plus cisplatin (75 mg/m² on days 1, 29, 57, and 85) and radiotherapy (45-59 Gy; start day = day 57).

Main Outcome Measures  The primary end point was 5-year disease-free survival; secondary end points were overall survival and time to relapse.

Results  A total of 644 patients were assessable. The median follow-up for all patients was 2.51 years. Median age was 55 years, 69% were women, 27% had a tumor diameter greater than 5 cm, and 26% had clinically positive nodes. The 5-year disease-free survival rate was 60% (95% confidence interval [CI], 53%-67%) in the mitomycin-based group and 54% (95% CI, 46%-60%) in the cisplatin-based group (P = .17). The 5-year overall survival rate was 75% (95% CI, 67%-81%) in the mitomycin-based group and 70% (95% CI, 63%-76%) in the cisplatin-based group (P = .10). The 5-year local-regional recurrence and distant metastasis rates were 25% (95% CI, 20%-30%) and 15% (95% CI, 10%-20%), respectively, for mitomycin-based treatment and 33% (95% CI, 27%-40%) and 19% (95% CI, 14%-24%), respectively, for cisplatin-based treatment. The cumulative rate of colostomy was significantly better for mitomycin-based than cisplatin-based treatment (10% vs 19%; P = .02). Severe hematologic toxicity was worse with mitomycin-based treatment (P < .001).

Conclusions  In this population of patients with anal canal carcinoma, cisplatin-based therapy failed to improve disease-free-survival compared with mitomycin-based therapy, but cisplatin-based therapy resulted in a significantly worse colostomy rate. These findings do not support the use of cisplatin in place of mitomycin in combination with fluorouracil and radiotherapy in the treatment of anal canal carcinoma.

Trial Registration  clinicaltrials.gov Identifier: NCT00003596

     

Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis

This study was undertaken to present data from a phase 2 study in which patients with unresectable hepatocellular carcinoma (HCC) with and without portal vein thrombosis underwent radioembolization with Yttrium ((90)Y) microspheres. Patients treated were stratified by Okuda, Child-Pugh, baseline bilirubin, tumor burden, Eastern Cooperative Oncology Group (ECOG), presence of cirrhosis and portal vein thrombosis (PVT) (none, branch, and main). Clinical and biochemical data were obtained at baseline and at 4-week intervals following treatment for up to 6 months. Tumor response was obtained using computed tomography (CT). Patients were followed for survival. One hundred eight patients were treated during the study period. Thirty-seven (34%) patients had PVT, 12 (32%) of which involved the main PV. The cumulative dose for those with and without PVT was 139.7 Gy and 131.9 Gy, respectively. The partial response rate using world Health Organization (WHO) criteria was 42.2%. Using European Association for the Study of the Liver (EASL), the response rate was 70%. Kaplan-Meier survival varied depending on location of PVT and presence of cirrhosis. The adverse event (AE) rates were highest in patients with main PVT and cirrhosis. There were no cases of radiation pneumonitis. Conclusion: The use of minimally embolic (90)Y glass microspheres to treat patients with HCC complicated by branch/lobar PVT may be clinically indicated and appears to have a favorable toxicity profile. Further investigation is warranted in patients with main PVT.     

Late complete heart block in an adult patient undergoing percutaneous ventricular septal defect closure

With advances in transcatheter treatment options, percutaneous device closure of ventricular septal defects has become a safe and practical alternative to surgical repair. While outcomes have been excellent, late complete heart bock has been documented during follow up of pediatric patients. We report a case of late complete heart block complicating percutaneous device closure of a ventricular septal defect in a 37-year-old female requiring permanent pacemaker insertion. The patient underwent transcatheter closure of an atrial and ventricular septal defect in the context of treated pulmonary hypertension and significant intracardiac shunting. Seven months after the procedure, the patient was admitted with presyncope, with electrocardiographic monitoring confirming complete heart block. While previously only reported in the pediatric literature, awareness of the possibility of complete heart block should be considered during the late follow up of adult patients.     

Nonclinical aspects of biopharmaceutical development: discussion of case studies at a PhRMA-FDA workshop

Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA-sponsored workshop, "Nonclinical Aspects of Biopharmaceutical Development," industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion.     

Use of Clinical Decision Support to Increase Influenza Vaccination: Multi-year Evolution of the System

Despite recognition that clinical decision support (CDS) can improve patient care, there has been poor penetration of this technology into healthcare settings. We used CDS to increase inpatient influenza vaccination during implementation of an electronic medical record, in which pharmacy and nursing transactions increasingly became electronic. Over three influenza seasons we evaluated standing orders, provider reminders, and pre-selected physician orders. A pre-intervention cross-sectional survey showed that most patients (95%) met criteria for vaccination. During our intervention, physicians were increasingly likely to accept pre-selected vaccination orders, Year 1 (47%), Year 2 (77%), Year 3 (83%); however vaccine administration by nurses was suboptimal. As electronic medical record functionality improved, patient receipt of vaccine increased dramatically, Year 1 [0/36; 0%], Year 2 [8/66; 12%], Year 3 [286/805; 36%]. Successful use of clinical decision support to increase inpatient influenza vaccination only occurred after initiation of CPOE for all medications and integration of an electronic medication administration record. Also, since most patients met criteria for influenza vaccination, complicated logic to identify high-risk patients was unnecessary.     

DNAzymes and cardiovascular disease

Gene silencing techniques are gaining increasing popularity in the literature, both as a tool for unravelling gene function and to potentially deliver therapeutic benefit, especially in the context of cardiovascular disease. Gene-specific catalytic DNA molecules, or DNAzymes, have shown promise in ameliorating the effects of myocardial ischaemia reperfusion injury and in-stent restenosis in various animal models, demonstrating that these agents may be useful in a clinical setting. A review of the recent advances in the use of DNAzymes in treating cardiovascular disease is therefore essential given the increasing clinical burden of cardiovascular disease worldwide. We have thus sought to firstly provide background into the construct and mechanism of action of DNAzymes, with a discussion of recent improvements in design. Secondly, we have examined the effects of DNAzyme-mediated gene inhibition in in vitro studies of both endothelial and smooth muscle migration and proliferation, as well as in vivo models of acute myocardial infraction and neointima formation. Lastly we compare DNAzymes with other gene silencing tools and discuss issues involved in successfully delivering these drugs in a clinical setting.