Mechanisms of RINV
The processes underlying RINV are presumed to be similar to those underlying CINV, although there are precious little data specifically addressing mechanisms of nausea and vomiting induced by radiotherapy. This hinders the acceptance of RINV as valid clinical entities, and impedes the development of optimal antiemetic strategies. Hypotheses from decades ago suggested that RINV were caused by a toxin within the abdomen that was released by degraded tumor proteins following irradiation. A limited number of animal studies in RINV have used the ferret, dog, monkey and cat, but the comparably ubiquitous and inexpensive laboratory rat is unfortunately not an ideal candidate as it lacks a reliable vomiting reflex. Animal radiotherapy experiments are also more logistically and technically challenging than those involving chemotherapy, which further explains the paucity of RINV animal models. The central roles of the upper abdomen and serotonin in RINV are supported by work by Scarantino et al., who documented increased urinary levels of the serotonin metabolite 5-HIAA following emetogenic upper and mid hemi-body irradiation, and by the efficacy of 5-HT3RAs in the prevention of RINV. However, the mechanisms underlying RINV induced by irradiation of different sites, such as the brain, pelvis and thorax, are largely unknown, and strategies for their prevention are based primarily on research using upper abdominal models. Prospective studies of carefully selected patient cohorts for each anatomical site should be conducted. They should correlate the incidence of RINV with radiotherapy dosimetric measurements, such as the volume of bowel and liver receiving certain cumulative doses of radiation, as well as changes in biomarkers associated with known emetic pathways and antiemetic medications that could help identify both RINV mechanisms and potential therapeutic strategies.
Clinical research into RINV has been declining since a marked surge in testing of the 5-HT3RAs in the 1990s. NK-1RAs have been investigated more in recent years, but the overall trajectory of RINV research is still downward. Indeed, when the MASCC/ESMO 2005 guidelines were updated in 2009, only one well-designed double-blind randomized controlled trial in RINV had been published during the interim period.[2,10] Clinical trials in RINV are difficult to perform; inclusion criteria are necessarily strict, and many medications commonly used by patients with cancer have their own antiemetic properties and they render patients ineligible. Further complicating matters is the fact that fewer men are now treated with para-aortic radiotherapy for testicular cancer than were even a decade ago, and these men made up a significant proportion of patients accrued to previous trials of RINV. Antiemetic research is also not considered glamorous within the field of radiation oncology, which is known for its cutting-edge technology and technical computer-based research. Cooperative group trials will be necessary to efficiently complete RINV studies in the future in order to maximize accrual from eligible patient populations, and to bring together interested investigators, who are in the minority. Patients undergoing palliative radiotherapy will also need to be accrued to studies more now than in the past, as they are the single largest source of patients that receive radiotherapy alone to the regions most often studied in RINV. As antiemetic guidelines also rely on observational data, simple high-quality prospective cohort studies of well-defined groups of patients could have a significant impact in the future.
Heterogeneity of Study End Points
Nausea and vomiting are complicated symptoms that evoke a range of physical, psychological and emotional responses from patients. Studies in RINV vary greatly in their primary and secondary end points, and subtle differences in data reporting can render ostensibly similar end points from different studies incomparable. Vomiting as an event is generally easy to identify and record for patients and investigators, but some studies code retching as an equivalent event. It is not clear if these two events have the same impact on patients, and they should be recorded separately until qualitative studies comparing them are carried out. Nausea is a far more difficult experience to define and investigate. Patients can refer to nausea as a brief episode lasting mere seconds or a prolonged unrelenting period of symptoms that can last hours or days. Coding systems within most previous trials would have considered these experiences to be equivalent, but in reality are they indeed manifestations of the same underlying biological mechanism, and do they have the same effect on patients and their quality of life? They probably do not, but until qualitative studies more accurately define the nausea experience and we construct better tools to record the many nuances of this symptom, nausea will continue to be viewed as a simple, discrete all-or-none event similar to vomiting. The timing of nausea and vomiting events should also be carefully documented in diaries during future studies. Often patients are followed for only 24–48 h following single-fraction radiotherapy or for just the early stages of a course of more protracted therapy. Alternatively, some studies only ask patients to complete diaries until nausea or vomiting occur; with the primary study end points achieved, no further data collection is pursued. This is a problem as delayed nausea and vomiting that set in after the first 24–48 h following radiotherapy initiation are now recognized as legitimate concerns in the RINV literature, and they can be missed without adequate and prolonged follow-up. Studies also need to report cumulative incidence rates of both nausea and vomiting, as opposed to only daily incidence rates for these events. Ultimately, practitioners need to use study data to adequately educate their patients regarding the risks of nausea and vomiting for an entire course of radiotherapy, and without cumulative incidence rate data from trials it is impossible to do so. Consensus among leaders in the RINV field is required so that guidelines for reporting end points in future trials in RINV can be created.
Duration of Antiemetic Therapy
The optimal duration of antiemetic therapies for the prevention of RINV is largely unknown. Previous trials in RINV have focused on comparing classes or combinations of antiemetic agents, but they have typically not compared different durations of administration for these agents. 5-HT3RAs are the most commonly recommended agents for both prophylactic and rescue therapy, but no trials have compared different durations of administration for these agents. An example of the impact of this gap in knowledge is that the MASCC/ESMO guidelines make no recommendation for the duration of 5-HT3RA therapy for moderately emetogenic treatment, whereas the ASCO and NCCN guidelines recommend that they be given prior to every fraction of therapy.[11,101] This may seem like a minor issue, but when one considers that these same recommendations apply for both single-fraction and multi-week courses of radiotherapy, patients could be impacted quite differently by these two recommendations in terms of cumulative side effects and costs associated with these agents. Previous trials of 5-HT3RAs in both single- and multiple-fraction radiotherapy of varying emetogenic potential have administered these agents for periods that last less than, equal to or longer than the duration of radiotherapy. At this point it is not clear if each fraction of radiotherapy induces its own acute phase of RINV. It could be that the contribution of the serotonergic system to RINV diminishes following the first few fractions of radiotherapy and that prolonged administration of 5-HT3RAs is unnecessary. Although the body of work investigating 5-HT3RAs has diminished in recent years, simple questions such as the optimal duration of administration should be pursued. Such investigations could be better informed by prospective cohort studies that document nausea and vomiting while measuring serum or urinary markers relevant to 5-HT3RA therapy or other antiemetic agents.
Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(6):685-692. © 2011 Expert Reviews Ltd.