Anticancer therapy-induced adverse events: practicing damage control

Keywords::

• adverse events
• cancer
• therapy

Due to the aggressive nature of cancer systemic treatments are designed to be administered at the maximal tolerated dose (MTD). This MTD is aimed to produce the desired effect without unacceptable toxicity. Because most drugs are approved in the metastatic setting, safety may remain poorly understood upon regulatory agency approval, due to several factors, including relatively small sample sizes, short duration of therapy, and additional factors such as comorbidities or subsequent combination therapies. Notwithstanding these deficiencies, remarkable improvements in clinical outcome have been achieved, with adverse events that are in most cases, manageable. In this supplement of Expert Opinion on Drug Safety, five articles delve into frequent aspects of toxicity that have an impact on daily practice. Notably, articles in this supplement emphasize the importance of translational research and Phase IV trials in the introduction of new cancer agents, in order to maximize efficacy and ascertain a bona fide toxicity profile. In addition, the patient's role in the administration of orally delivered agents is delineated in the article by Gebbia, which also proposes methods to improve patient adherence and persistence, all of which may affect the benefit obtained from therapies.

The authoritative review by Menna is very well written and covers a long history of cancer chemotherapy that involves the use of anthracyclines and the associated cardiotoxicity that has been recognized. Highlighting the reported incidence of cardiotoxicity in studies that were done up to 20 years ago, it is still significant that a true understanding of the rate of cardiotoxicity associated with anthracycline use is not well established. The current methods to detect cardiotoxicity overviewed in this review involve serial assessments of left ventricular ejection fraction, a strategy that has known substantial limitations in the ability to accurately detect an early cardiac damage [1]. Importantly, this manuscript has a careful description of the presumed mechanisms, either an oxidative stress based cardiac dysfunction or a cumulative role of secondary alcohol metabolites of doxorubicin, that may directly contribute to cardiac damage observed clinically. These purported mechanisms can indicate strategies for mitigation of cardiotoxicity during anthracycline chemotherapy. Furthermore, this review outlines synergistic cardiotoxicity that can be observed when anthracycline administration is coupled with non-anthracycline based therapy such as taxanes and anti-HER-based therapy. The authors appeal to the readers to rethink about the little used strategy of dexrazoxane during anthracycline administration, as it may provide significant protection in selected patients. There are some areas that are not covered extensively which should be mentioned in order to have the complete understanding of cardiotoxicity related to anthracycline use. First, cardiac biomarker-based early detection of cardiotoxicity is not firmly established throughout the world but should be part of contemporary monitoring during anthracycline-based therapy [2]. Second, early initiation of cardioprotective heart failure-based therapy is of paramount importance when there are any signals of cardiotoxicity, such as angiotensin converting enzyme inhibitors or carvedilol [3]. Overall, this is a definitive review in many aspects of cardiotoxicity associated with anthracycline use and is an excellent resource for any interested reader.

A comprehensive updated review of bevacizumab in breast cancer with a focus on its safety has been performed by Drs Kumler and Nielsen in this issue [4]. The article provided a balanced view on the efficacy and safety of bevacizumab therapy in breast cancer in the context of overall benefit and risk of this agent in cancer therapy. Vascular endothelial growth factor (VEGF) mediated angiogenesis plays a critical role in cancer growth, progression and metastasis. Bevacizumab as an antibody against VEGF has been approved for the treatment of multiple solid tumors including glioblastoma multiforme, colorectal, non-small-cell lung, and renal cell cancers. The use of bevacizumab in metastatic breast cancer has been recently undergoing intense discussion in the oncology community, even though the FDA has proposed removing its licensed indication for breast cancer treatment.

It needs to be pointed out that despite the improved progression-free survival and response rates, bevacizumab did not significantly increase overall survival as shown in randomized clinical trials for breast cancer patients. Although most side effects associated with bevacizumab are manageable, it is associated with some serious and potentially fatal side effects including bleeding and GI perforation. Overall, the addition of bevacizumab to chemotherapy has been associated with significantly increased fatal adverse events in cancer patients [5]; there is no evidence so far to support this notion in breast cancer. Anti-angiogenesis remains a viable approach to treating breast cancer; further studies need to identify biomarkers in order to select a group of patients who will respond well to bevacizumab-based treatment without serious side effects. Finally, due to the expensive nature of biologicals and limited healthcare expenditure, the use of bevacizumab in breast cancer should be considered in the context of pharmacoeconomics as well as benefits and safety [6].

In the review by Chow, the approval of vinflunine for transitional cell carcinoma of the urothelial tract is delineated as an example of a novel agent, a fluorinated vinca alkaloid with mitotic-inhibitory and tubulin-interacting activity [7,8]. Authors describe how its activity is currently being investigated in cancers of the breast and lung. Moreover, the JAVLOR® Online Non-Interventional Trial (JONAS-1) is described [9], which documents data on the tolerability and efficacy of vinflunine performed under daily routine conditions in Germany. The trial focuses on tolerability including the use of agents against gastrointestinal toxicities, as well as clinical outcome in patients with transitional cell carcinoma of the urothelial tract. This phase IV study is one of several which hope to understand adverse events and clinical outcome in ‘real-life' conditions, following the success of the trial called Bevacizumab Regimens' Investigation of Treatment Effects (BRiTE) [10].

Petrelli details one of the least discussed toxicities from cetuximab and panitumumab, the hypomagnesemia that develops in 17% of patients. The increased risk was greater with panitumumab (12.55) when compared with cetuximab (3.87), probably due to a greater incidence of diarrhea with the former. The risk was lower in head-and-neck- and lung-cancer patients than in colorectal cancer patients, likely related to simultaneous Mg2⁺ implementation when cisplatin was administered. In addition, the authors expose the potential underlying mechanisms of this event, management strategies and clinical presentation, making this article a necessary read for oncologists using these agents.

The study by Gebbia [11] reports on an increasingly common problem, with orally administered agents which are, to some degree, under the patient's control since they can choose when and how to take them. Although these agents require a prescription, the issue of patient adherence and persistence has become increasingly recognized in the oncology realm, especially in the real-world setting, in which rates of both variables are lower, when compared with clinical trials [12]. While it is commonplace in other fields such as dermatology [13], the implications of missing or avoiding a dose in cancer patients is likely to have greater implications, both clinically as well as financially. Although the incidence of nonadherence has been relatively well studied, the authors bring out an important question that may never be answered: what effect does this have on clinical outcome? This may remain unsolved because patients are more likely to be adherent when they take part of a study, affecting a more rigurous examination of this phenomena. The authors also describe reasons for poor adherence in other conditions, which perhaps must be studied and understood in the oncology setting. Decreasing the frequency of daily administration and better physician–patient communication are modifiable factors that could be implemented in most situations. These and other factors are described, which will hopefully accompany more orally administered therapies in years to come. Taken as a whole, this supplement provides additional insight into the breadth of toxicities resulting from conventional and novel anticancer agents, notably anthracyclines and monoclonal antibodies targeting the EGFR and VEGF. Moreover, the implications of phase IV trials, translational research, and patient adherence are set forth in the context of adverse events, all of which will optimize therapies and maximize clinical outcome.

Declaration of interest

The authors have received no payment for the preparation of this manuscript. ME Lacouture has received consulting fees from OSI Pharmaceuticals, BMS, Genentech and Amgen. D Lenihan and S Wu declare no conflict of interests.