Navigating uncharted waters: Developing a standardized approach for evaluating and implementing biosimilar products at a comprehensive cancer center.

PURPOSE: The processes for formulary implementation and electronic health record (EHR) integration of biosimilar products at a comprehensive cancer center are described. Implications for research protocols are also discussed. SUMMARY: The existing literature focuses on practical considerations for formulary addition of biosimilar products, but there is a lack of guidance on how to implement the change, particularly within the EHR. Before building the ordering tools for biosimilars, the clinical and informatics teams should determine the role of biosimilars at the institution, identify drug-specific product characteristics that affect medication build, and characterize implications of future formulary changes or drug shortages. Leveraging an orderable record provides the ability to include logic that maps to multiple products and also allows for future implementation of changes within the medication record rather than requiring "swaps" at the treatment protocol level. The institutional review board should coordinate changes in affected research protocols and consent forms and work with principal investigators to amend protocols when necessary. Pharmacy leaders should develop processes to oversee inventory during the transition period and minimize the risk of errors. CONCLUSION: The development of a standardized approach for evaluating and implementing biosimilar products improves efficiency and collaboration among the various team members responsible for the products' integration into existing workflows, including implications for clinical research. Implementing biosimilars for agents used to treat cancer will pose new challenges and require additional considerations. Partial implementation of biosimilars continues to pose multiple challenges in the provision of patient care.

Correction to: Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis.

Following publication of the original article [1], the authors reported an error in their listed affiliations.

Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis.

BACKGROUND: Immune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX. METHODS: Data were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints. RESULTS: Among 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p < 0.001), median times to diarrhea resolution (3 vs. 9 days; p < 0.001) and to steroid titration (4 vs. 13 days; p < 0.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51 days; p = 0.150) was numerically lower in the IFX group. CONCLUSIONS: Despite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted.

New and emerging therapies for advanced or metastatic soft tissue sarcoma.

Soft tissue sarcomas include a rare variety of tumors, which require a multidisciplinary approach to treatment. Patients with advanced or metastatic disease are typically treated with anthracycline-based therapy, but these chemotherapy regimens are associated with poor response rates and average survival duration of one year. Much attention has been turned toward overexpressed gene pathways, and utilizing targeted therapies to inhibit tumor growth. Many new and approved targeted therapies and chemotherapy agents are currently in clinical and preclinical studies for soft tissue sarcoma. As the results of these studies are reported, we hope to see improved response rates and less toxicity, both in the frontline setting and for patients with advanced disease. This article will review the available data for some of the more promising therapies for advanced or metastatic soft tissue sarcomas.

Dabrafenib therapy for advanced melanoma.

OBJECTIVE: To summarize the clinical development of dabrafenib and to highlight the clinically relevant distinct characteristics of dabrafenib in contrast to vemurafenib. DATA SOURCE: An English-language literature search of MEDLINE/PubMed (1966-June 2013), using the keywords GSK2118436, dabrafenib, vemurafenib, selective BRAF inhibitor, and advanced melanoma, was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles on dabrafenib and vemurafenib were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing studies. DATA SYNTHESIS: BRAF(V600E) mutation confers constitutive BRAK kinase activation in melanoma cells, promoting tumor growth. This discovery led to the development of BRAF kinase inhibitors like vemurafenib and dabrafenib. Dabrafenib has been approved to treat patients with BRAF(V600E)-positive unresectable or metastatic melanoma based on its clinical benefit demonstrated in a randomized phase III study. It has also been shown to be safe and effective in patients with BRAF mutant advanced melanoma involving the brain. Dabrafenib is well tolerated, with the most common adverse effects being hyperkeratosis, headache, pyrexia, and arthralgia. Currently, there is no evidence to suggest that one BRAF inhibitor is superior to the other. With similar efficacy, therapy selection will likely be influenced by differential tolerability and cost. CONCLUSIONS: Dabrafenib joins vemurafenib to confirm the superior clinical outcome of the BRAF inhibitors when compared with dacarbazine in patients with BRAF(V600E)-positive advanced melanoma. Active research is ongoing to expand its utility into the adjuvant setting and to circumvent rapid emergence of drug resistance.

Fatal hepatitis C associated fibrosing cholestatic hepatitis as a complication of cyclophosphamide and corticosteroid treatment of active glomerulonephritis.

Fibrosing cholestatic hepatitis (FCH) is an aggressive and usually fatal form of viral hepatitis in immunocompromised patients. It is characterized by progressive cholestasis leading to hepatic failure, and a characteristic histopathological features including: periportal fibrosis, ballooning degeneration of hepatocytes, cholestasis, with minimal inflammation. FCH has been reported almost exclusively in heavily immunosuppressed organ transplant recipients or patients with AIDS. This case report describes a previously immunocompetent patient with previously stable chronic hepatitis C who developed fibrosing cholestatic hepatitis after receiving cyclophosphamide and corticosteroids for active glomerulonephritis.

Granulomatous bronchiolitis with necrobiotic pulmonary nodules in Crohn's disease.

A 37-year-old man with extensive Crohn's disease of the stomach, small and large intestine for almost a decade developed respiratory symptoms and radiological findings suggestive of pneumonia that failed to resolve with antibiotic treatment. Computed tomography scanning of his lungs showed extensive changes with cavitated parenchymal nodules. Histological evaluation of an open lung biopsy showed granulomatous bronchiolitis and pulmonary necrobiosis. Treatment with steroids and immunosuppression resulted in complete resolution of his clinical symptoms of pneumonia and abnormal computed tomography imaging changes. Granulomatous bronchiolitis and necrobiotic nodules may be a manifestation of Crohn's disease in the absence of microbial agents, including mycobacteria or fungal agents. While a multiplicity of complex pulmonary changes may occur in Crohn's disease, their clinical recognition and precise pathological definition may be particularly important if treatment with a biological agent, such as infliximab, is being considered.

Regression of cirrhosis associated with hepatitis B e (HBe) antigen-negative chronic hepatitis B infection with prolonged lamivudine therapy.

In theory, hepatic fibrosis should be a dynamic process with the potential for remodelling after the injury-provoking stimulus has been removed. Clinically, there has been an accumulation of a small number of cases, including hepatitis B e (HBe) antigen-positive chronic hepatitis B infection, in which cirrhosis regressed after successful treatment. We report a 42-year-old HBe antigen-negative Chinese man with detectable serum hepatitis B virus DNA and histologically established cirrhosis (Ludwig score 4) who, after 4 years of successful lamivudine therapy, was found to have regression of cirrhosis on repeat liver biopsy. The repeat biopsy revealed normal liver architecture with fibrosis confined to the portal tracts and short fibrosis septae extending into the lobule without bridging (Ludwig score 1-2). Although cirrhosis may take many years to develop, our experience suggests that successful treatment may reverse the process within a relatively short time.

Complete histological resolution of collagenous sprue.

A 65-year-old woman developed a watery diarrhea syndrome with collagenous colitis. Later, weight loss and hypoalbuminemia were documented. This prompted small bowel biopsies that showed pathological changes of collagenous sprue. An apparent treatment response to a gluten-free diet and prednisone resulted in reduced diarrhea, weight gain and normalization of serum albumin. Later repeated biopsies from multiple small and large bowel sites over a period of over three years, however, showed reversion to normal small intestinal mucosa but persistent collagenous colitis. These results indicate that collagenous inflammatory disease may be a far more extensive process in the gastrointestinal tract than is currently appreciated. Moreover, collagenous colitis may be a clinical signal that occult small intestinal disease is present. Finally, collagenous sprue may, in some instances, be a completely reversible small intestinal disorder.

Abdominal pain as the initial and sole clinical presenting feature of systemic lupus erythematosus.

Classically, a diagnosis of systemic lupus erythematosus (SLE) is dependent on renal, rheumatological, cutaneous and neurological target organ damage with supporting serological markers. A previously healthy 26-year-old Japanese woman whose only manifestation of otherwise occult SLE was severe abdominal pain is reported. A computed tomographic scan of the abdomen revealed thickened loops of small bowel, endoscopic findings were nonspecific and jejunal biopsy revealed a nonspecific enteritis. Laboratory studies revealed lymphopenia, hypocomplementemia, a positive antinuclear antibody, a weakly positive anti-Smith and a strongly positive anti-double stranded DNA. There was a prompt symptomatic recovery with immunosuppressive therapy. The authors' experiences, and a review of the literature suggest that a diagnosis of SLE should be considered in young Asian women who present with significant but clinically enigmatic gastrointestinal illness.