Radiotherapy-induced Nausea and Vomiting

Kristopher Dennis; Ernesto Maranzano; Carlo De Angelis; Lori Holden; Shun Wong; Edward Chow

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(6):685-692. 

In This Article

Antiemetic Guidelines

Three major antiemetic guidelines exist in the English language literature that make RINV management recommendations. These guidelines from the Multinational Association for Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) suggest strategies for prophylactic and rescue treatment as a function of the anatomic site being irradiated, as this is the most commonly identified risk factor for RINV. The guidelines are summarized in Table 1, and the processes through which each were constructed are explained and compared below.

MASCC/ESMO

The MASCC/ESMO guideline for antiemetics in radiotherapy[2] was written following the Perugia Antiemetic Consensus Conference in June 2009.[8] It updated the previous guideline that was published in 2005.[9] It is based upon expert opinion and level 1–2 evidence from an updated MEDLINE literature search of English language articles from January 2004 to June 2009 using the search terms 'radiotherapy-induced emesis' and 'radiotherapy-induced nausea'. Review articles and articles involving radiochemotherapy or emesis due to causes aside from radiotherapy were excluded. However, neither the definitions of radiochemotherapy and causes of emesis aside from radiotherapy, nor the formal search results were provided in the publication. The management-related discussion is divided according to pharmacologic intervention themes: prophylaxis with non-5-HT3 receptor antagonists, prophylaxis with 5-HT3 receptor antagonists (5-HT3RAs), prophylaxis with a 5-HT3RA plus dexamethasone, prophylaxis with corticosteroids, prophylaxis with neurokinin-1 receptor antagonists (NK-1RAs), duration of prophylaxis and rescue therapy. The antiemetic recommendations for high-, moderate-, low- and minimal-emetic risk radiotherapy are displayed in Table 1. There are a few noteworthy issues to mention regarding these recommendations. For the addition of dexamethasone to a 5-HT3RA in high-risk radiotherapy, the MASCC confidence/consensus ratings were only low-to-moderate/high (depending on whether the text or tables were followed) and the ESMO evidence/grade of recommendation ratings were III/C. This lower level of confidence for adding the corticosteroid is because the combination of medications has not actually been studied in the setting of total body irradiation, but it is beneficial in CINV and moderately emetogenic radiotherapy settings.[10] Dexamethasone was also recommended as an optional addition to a 5-HT3RA for moderate-risk radiotherapy, largely owing to the National Cancer Institute of Canada Clinical Trials Group SC19 study that demonstrated that adding the corticosteroid benefited a number of secondary and quality-of-life end points, although the primary end points of improved complete control of nausea and vomiting during the 5-day period in which prophylaxis was given were not reached.

ASCO

The ASCO guideline for antiemetics in oncology[11] was written by the ASCO antiemetic update committee to revise their previous guideline published in 1999.[12] It is based upon expert opinion as well as a literature review of the MEDLINE and Cochrane Library databases from 1998 to February 2006 that focused on published randomized controlled trials, and systematic reviews and meta-analyses of published Phase II and III randomized controlled trials. The details of this literature search are provided within the appendices of the publication. This search was designed to update both CINV and RINV guidelines, compared with the most recent RINV portion of the MASCC/ESMO antiemetic update search, which focused on RINV alone. The medical subject headings 'radiotherapy' and 'irradiation' were incorporated into the larger MEDLINE antiemesis search strategy in order to capture data relevant to RINV. During preparation of this guideline, the MASCC guideline from 2005[9] was carefully considered by the update committee, as several members of the original ASCO antiemetic guideline expert panel had contributed to that document during the International Antiemetic Consensus Conference in 2004. This was a meeting that brought together representatives from nine oncology organizations[13] who agreed that during later publication of their individual guidelines that the consensus conference results would be referenced. It was hoped that the extensive collaborations and shared deliberations during the conference would result in fewer discrepancies among the individual organization guidelines. As seen in Table 1, the RINV recommendations of the ASCO guidelines are indeed very similar to those of MASCC/ESMO. However, compared with the MASCC/ESMO publication that was dedicated solely to RINV, there is very little space allocated to RINV within the ASCO document, which is dominated by CINV material.[11] Notwithstanding the brevity of the RINV recommendations, two issues deserve mention. For moderate-risk radiotherapy, a 5-HT3RA is recommended as prophylactic treatment. The recommendation specifies that it should be given prior to every fraction of radiotherapy, but then in the next paragraph the authors state that the efficacy of these agents may decrease after the first week of treatment, "making it difficult to suggest the optimal duration of prophylactic treatment." One could argue that if such a suggestion is so difficult then it should not be made, and that the duration of administration for these agents should not be specified; indeed, the MASCC/ESMO guideline makes no specific recommendation in this regard. In the absence of benefit for prolonged administration in the literature, one must be mindful that these agents, although generally well tolerated, do have a known side-effect profile and can be costly. The second issue is that cranial radiosurgery is classified as both moderate and low risk, whereas nonspecific cranial irradiation is classified as minimal risk. In the previous guideline that classified treatments into only three categories (high, intermediate and low risk), both were classified as low risk, and there is no rationale provided for the distinction between the two in the current guideline. Nonspecific cranial irradiation would almost always involve larger treatment volumes than radiosurgery (palliative whole-brain radiotherapy being the obvious example) and in the curative setting it would use higher cumulative doses than radiosurgery as well. It may be that the higher dose per fraction utilized in radiosurgery and the potential this has for increased edema, increased intracranial pressure and ultimately RINV were considered to be more important risk factors. However, any deliberations on the issue were not reported, and we are unaware of any RINV radiosurgery data that would have been included within the literature search findings that would support the change in the risk level allocation. A final note is that a number of anatomic sites are confusingly found within multiple risk categories, and the recommendations found within the table reserved for RINV do not completely match those explained in the body of the text.

NCCN

The most recent NCCN guideline was written by their antiemetic panel members; of the 21 members listed in the document, none are radiation oncologists.[101] NCCN guidelines do not disclose the methodology or results of their examinations of the relevant literature, although the NCCN website states that the goal is to base each recommendation on high-quality evidence from controlled clinical trials or meta-analyses. NCCN guidelines follow a "policy of citing only data that provide useful guidance to treating clinicians rather than formal systematic reviews". The strength of the evidence is identified using the NCCN Categories of Evidence and Consensus. All recommendations for RINV management for this guideline are rated as 2A (based upon lower-level evidence, with uniform NCCN consensus that the intervention is appropriate). The NCCN guidelines do not stratify patients by irradiated anatomic site to the extent that the MASCC/ESMO and ASCO guidelines do. Beyond a stand-alone total-body irradiation category, all other radiotherapy treatments fall under the category of radiotherapy-upper abdomen/localized sites. Unfortunately 'localized sites' are not defined, and this term could be interpreted as incorporating each of the moderate-, low-, and minimal-emetic risk radiotherapy treatments described in the MASCC/ESMO and ASCO guidelines. If applied in this manner, all patients would receive relatively aggressive prophylactic therapy similar to that for moderate-risk radiotherapy in the other two guidelines. This lack of anatomic specificity is a weakness of this guideline, and could be due in part to having no radiation oncologists as panel members. Whether they were consulted or not is unknown given the reporting style of the guideline. All patients who do not receive prophylactic therapy and develop nausea and vomiting are recommended to receive ondansetron as rescue therapy. Patients that receive prophylaxis but develop breakthrough symptoms are to receive any one of six classes of antiemetics that are listed in the treatment for breakthrough CINV. As with the ASCO document, the space allotted to RINV management in the NCCN guideline is very small, but the recommendations are less specific and leave much for the individual practitioner to discern and decide.

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