REVIEW URRENT C OPINION

Nausea and vomiting induced by gastrointestinal radiation therapy: current status and future directions Kristopher Dennis a,b, Michael Poon c, and Edward Chow d

Purpose of review Radiation therapy-induced nausea and vomiting (RINV) are common and troublesome symptoms among patients receiving radiation therapy for gastrointestinal cancers. Their impact on function, quality of life and, ultimately, cancer control warrant a review of their incidence, underlying mechanisms, treatments and research themes. Recent findings Research in RINV is underrepresented relative to that in chemotherapy-induced nausea and vomiting. The incidence of RINV among patients receiving modern day radiation therapy is questioned and supportive care practice patterns vary among radiation oncologists. Antiemetic guideline recommendations for prophylactic and rescue therapy are based solely on the anatomic region being irradiated and not other patient-related, radiation therapy-related, or organ-specific dosimetric factors that likely modulate the risk of RINV. Dosimetric predictors are likely the most attainable biomarker moving forward, but only early steps have been taken. The small bowel and stomach will be the best first candidates for study among patients with gastrointestinal cancers. Studies of the mechanisms underlying RINV are conspicuously lacking. A new generation of observational studies and therapeutic clinical trials is needed, and more attention must be given to the relative impact of nausea and vomiting on the function and quality of life among specific homogeneous patient populations. Summary Optimal supportive care strategies for RINV following radiation therapy for gastrointestinal cancers are lacking, and will not be known until future research answers the many open questions regarding the mechanisms underlying RINV, the true incidence and impact of these symptoms among patients and the best way to predict and mitigate them. Keywords emesis, gastrointestinal, nausea, radiation therapy, vomiting

INTRODUCTION This narrative review describes the current state of observational and interventional research in radiation therapy-induced nausea and vomiting (RINV). The major English language antiemetic clinical practice guidelines are compared and the knowledge gaps that have led to difficulty in implementing these guidelines are discussed. Current controversies, challenges and successes in RINV clinical management and research are summarized, and suggestions for future studies that could ultimately lead to better patient care are explained.

RADIATION THERAPY-INDUCED NAUSEA AND VOMITING RINV are common and troublesome symptoms among patients receiving radiation therapy. RINV www.supportiveandpalliativecare.com

worsen health-related quality of life and performance status, sometimes necessitate costly supportive care interventions and hospitalizations and, when severe, lead to treatment delay or refusal that can compromise tumor control. Unfortunately, research in RINV is underrepresented compared with that in a

Division of Radiation Oncology, University of Ottawa, bOttawa Hospital Research Institute, Ottawa, cFaculty of Medicine and dDepartment of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada Correspondence to Kristopher Dennis, MD, FRCPC, Radiation Medicine Program, The Ottawa Hospital, 501 Smyth Road, Ottawa, Ontario K1H8L6, Canada. Tel: +1 613 737 7700 x70212; e-mail: [email protected] toh.on.ca Curr Opin Support Palliat Care 2015, 9:182–188 DOI:10.1097/SPC.0000000000000130 Volume 9  Number 2  June 2015

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Nausea and vomiting induced by gastrointestinal radiation therapy Dennis et al.

KEY POINTS  RINV are common among patients receiving radiation therapy for gastrointestinal cancers.  Research in RINV is underrepresented, and important knowledge gaps remain with respect to their incidence during modern localized radiation therapy, their potential dosimetric predictors and their underlying mechanisms.  Future studies addressing these knowledge gaps will allow for more evidence-based, effective and personalized supportive care.

chemotherapy-induced nausea and vomiting (CINV), and expert antiemetic panels from the American Society of Clinical Oncology (ASCO) and the Multinational Association of Supportive Care in Cancer (MASCC) consider patients suffering from RINV a special and understudied population [1,2]. The gastrointestinal system is the most implicated, interesting and studied anatomic region with respect to RINV. Early historical accounts of ‘radiation sickness’ syndromes following nonlethal radiation therapy doses to the gastrointestinal system [3] described a latent period of 2–3 h after exposure, then the sudden onset of an active disturbance period when patients would typically complain of nausea, anorexia, fatigue and, possibly, vomiting for up to 2–3 h [4]. Radiation therapy to the gastrointestinal system was believed to more reliably produce these symptoms than radiation therapy to other anatomic regions, a belief that has been validated in contemporary observational studies. The largest of these were the landmark studies conducted in 1996 and 2005 by the Italian Group for Antiemetic Research in Radiotherapy that followed a combined 1954 patients across dozens of centers during their radiation therapy courses and asked them to record nausea and vomiting events in diaries [5,6]. Of the patients that received radiation therapy to the upper abdomen within those studies, 38 and 21% reported vomiting and 67 and 50% reported nausea. Other similar but smaller observational series that followed patients receiving abdominal or pelvic radiation therapy reported rates of nausea ranging from 63 to 83% [7,8 ], and the majority of patients enrolled in studies evaluating pharmacologic agents in the management of RINV receive radiation therapy that affects the gastrointestinal system [2,9], a reflection of how at risk these patients are of developing symptoms. &

ANTIEMETIC GUIDELINES FOR RADIATION THERAPY-INDUCED NAUSEA AND VOMITING Antiemetic clinical practice guidelines acknowledge the extent to which the anatomic site targeted by radiation therapy modulates the risk of nausea and vomiting. The three most visible guidelines in the English literature are the 2011 ASCO guideline [1], the 2011 MASCC guideline [2] and the 2014 National Comprehensive Cancer Network (NCCN) guideline [10]. The ASCO guideline updates its previous 2006 and 1999 versions, the MASCC guideline updates its 2005 version and the NCCN guideline is updated yearly. All make recommendations for either prophylactic therapy to prevent RINV or rescue therapy to treat RINV if they develop after radiation therapy commencement. Recommendations in these guidelines are stratified solely as a function of the anatomic site being irradiated (Table 1). Perhaps, unsurprisingly, the structure and recommendations of the ASCO and MASCC guidelines differ only slightly; they used similar processes for reviewing the same clinical trial data, and key RINV and radiation oncologist experts were panel members for both the guidelines. Both panels admittedly relied on expert opinion for RINV management recommendations to a greater degree than for CINV, reflecting the comparatively smaller body of related literature. Interestingly, none of the NCCN panel members identified themselves as a radiation oncologist, and the recommendations in that guideline are structured differently. All of the guidelines recommend prophylactic rather than rescue therapy for patients undergoing radiation therapy that will affect the ‘upper abdomen’ (and hence gastrointestinal system) and suggest that a 5-hydroxytryptamine type-3 receptor antagonist (5-HT3RA) with or without dexamethasone be prescribed. The ASCO and NCCN guidelines recommend the 5-HT3RA to be given prior to every fraction, whereas the MASCC guideline states that the optimal duration of prophylaxis with these agents is an open question and does not suggest a specific duration of therapy. This latter approach seems to be the more reasonable, as a systematic review of studies that evaluated 5-HT3RAs for RINV found no proof that extended durations of therapy are superior to shorter durations [9]. 5-HT3RAs can also be costly if given daily with radiation therapy for many weeks, and they are known to cause bothersome side-effects including headache, dizziness and constipation. If dexamethasone is to be added to the 5-HT3RA, all guidelines recommend that it should be given during the first five fractions, as it was during a specific trial that suggested the addition of dexamethasone decreased symptoms

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Gastrointestinal symptoms Table 1. Summary of antiemetic guidelines for radiation therapy-induced nausea and vomiting from American Society of Clinical Oncology, Multinational Association of Supportive Care in Cancer and National Comprehensive Cancer Network Emetic risk level classification

Anatomic site of RT/RT technique

Management recommendation

Total nodal irradiation

Prophylaxis

ASCO High

Total nodal irradiation

5-HT3 receptor antagonist prior to each fraction and for at least 24 h after RT completion AND Dexamethasone during first five fractions

Moderate

Upper abdomen Upper body irradiation Half-body irradiation

Low

Prophylaxis 5-HT3 receptor antagonist prior to each fraction Optional dexamethasone during first five fractions Prophylaxis or rescue

Cranium

5-HT3 receptor antagonist; if given as rescue, continue for each remaining fraction

Craniospinal Head and neck Lower thorax region Pelvis Minimal

Extremities Breast

Rescue Dopamine receptor antagonist OR 5-HT3 receptor antagonist

MASCC High (>90% risk)

Total body irradiation

Prophylaxis 5-HT3 receptor antagonist AND Dexamethasone

Moderate (60–90% risk)

Upper abdomen Upper body irradiation Half body irradiation

Low (30–60% risk)

Cranium (all) Craniospinal irradiation

Prophylaxis 5-HT3 receptor antagonist Optional dexamethasone during first five fractions Prophylaxis or rescue 5-HT3 receptor antagonist

Head and neck Lower thorax region Pelvis Minimal (

Nausea and vomiting induced by gastrointestinal radiation therapy: current status and future directions.

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