A number of alternative therapies are available for patients whose nausea and vomiting is not well controlled. Herbal or natural remedies, such as ginger or peppermint, have been suggested for intractable symptoms of nausea and vomiting [48]. It has been suggested that they possess antiemetic properties stemming from calcium channel blocking activity that results in intestinal smooth muscle relaxation, but data is sparse among chemotherapy patients, and there are currently no studies underway [48].

Behavioral therapy techniques, acupuncture or acupressure, and even massage has shown promise in reducing severity and duration of symptoms [4]. The most frequently studied behavioral interventions include systematic desensitization with progressive muscle relaxation, guided imagery, and hypnosis. These interventions appear to be most effective with anticipatory symptoms [75]. Some studies have shown acupuncture may have a significant effect in reducing acute nausea and vomiting, but it does not appear to have any direct effect on delayed symptoms.

Lifestyle modification, including changes in diet and exercise, can also help alleviate symptoms. The NCCN recommends eating food that is “easy on the stomach” or “full-liquid” foods, eating small frequent meals, and eating food at room temperature [8]. Patients should avoid foods that induce nausea and control the overall amount consumed. A dietary consult may be helpful.

If breakthrough symptoms occur after appropriate prophylaxis, drugs from a different drug class should be given as rescue therapy. Patients with delayed breakthrough symptoms (days 2–5) should be considered for a 3-day regimen of a dopamine antagonist such as olanzapine or metoclopramide [10]. A recent phase III trial comparing oral olanzapine (10 mg/day x 3 days) to metoclopramide (10 mg TID x 3 days) found olanzapine to be significantly better at controlling breakthrough symptoms with highly emetogenic therapy [76]. Phenothiazine or dexamethasone may also be effective in this setting [8]. Aprepitant has been approved as an adjunct to 5HT₃ antagonists and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting, but has not been studied for breakthrough symptoms.

If anticipatory symptoms occur, behavioral therapy with systematic desensitization or other relaxation techniques and anti-anxiolytics, such as benzodiazepines, are most beneficial. Alternating routes, formulations, or schedules may be necessary if emesis is ongoing. For patients with refractory symptoms after prophylaxis failed in earlier cycles, a complete change in antiemetic regimen should be considered [10]. For patients receiving highly emetogenic therapy, olanzapine (days 1–3) can be substituted for the NK-1 antagonist aprepitant [67], and for those with moderately emetogenic regimens, aprepitant, or fosaprepitant, can be added [77]. One could also consider substituting high-dose metoclopramide, or other dopamine antagonists, for palonosetron [39]. Benzodiazepines like lorazepam or alprazolam can be given for anxiety with any cycle.

It is important to remember that antiemetic efficacy may decrease as chemotherapy cycles continue [40]. With refractory symptoms especially, it is also important to rule out nontreatment-related causes of nausea and vomiting. Frequent reassessment of emetic risk, disease status, concurrent illnesses, and medications can help ascertain that the best antiemetic regimen is being utilized [39].

Multiday, high-dose, and combination chemotherapies pose unique challenges. When several different agents are required for combination chemotherapy, antiemetic therapy should be tailored to the chemotherapeutic drug with the highest emetic risk [39]. With multiday regimens, patients are at high risk for both acute and delayed symptoms. Recommending a specific antiemetic regimen is difficult in these patients because acute and delayed symptoms begin to overlap after the first day of therapy. The duration of risk for delayed emesis is also difficult to predict, as it depends on the specific regimen used and the emetogenic potential of the drugs administered.

A combination of a first-generation 5-HT₃ receptor antagonist and dexamethasone +/− aprepitant for acute symptoms is recommended daily for each day of a multiday or high-dose chemotherapy with stem cell transplant [83]. Dexamethasone alone is standard for delayed symptoms, and this can be continued for 2–3 days following therapy completion [8, 33, 39]. If desired, IV palonosetron may be substituted for the oral 5-HT₃ receptor antagonist before a 3-day regimen, instead of using multiple daily doses. Unfortunately, these options are not very effective for delayed nausea and vomiting. Complete response rates for delayed symptoms with various high-dose regimens are 30–70 %, and most studies report ~50 % [78].

In 2011, palonosetron was given for 1, 2, or 3 days with dexamethasone in 73 patients receiving multiday high-dose chemotherapy before stem cell transplant. Although the study produced only a 20 % complete response rate (no emesis, no rescue), vomiting control was significantly improved, with 40–45 % of patients experiencing “no emesis” during the 7-day study period and having no serious adverse events [79]. In 2012, the subsequent addition of aprepitant to a 5-HT₃ receptor antagonist plus dexamethasone significantly improved complete response rates in patients receiving 5 days of cisplatin therapy [80].

In a study of 78 patients receiving multiday therapy, aprepitant was added to granisetron plus dexamethasone and continued for an additional 2 days following therapy. Complete response rates were 58 and 73 % for highly and moderately emetogenic chemotherapy, respectively [81]. Due to this, aprepitant is suggested for multiday regimens associated with a significant risk of delayed symptoms, with repeated dosing recommended over multiple cycles [39]. If well tolerated, aprepitant (80 mg) can be safely continued on days 4 and 5 following chemotherapy [82].

Over the past several decades, first generation 5-HT₃ receptor antagonists and dexamethasone have significantly improved the control of acute chemotherapy-induced nausea and vomiting. Unfortunately, these agents alone did not appear to adequately control delayed symptoms. Recent studies, however, have noted improvement in delayed symptoms with the use of three newer agents: palonosetron (a second-generation 5-HT₃ antagonist), aprepitant (an NK-1 receptor antagonist), and olanzapine (an antipsychotic) [10, 66]. The second-generation 5-HT₃ antagonist palonosetron has a longer half-life, higher binding capacity, and a different mechanism of action than first-generation agents and appears to be the most effective agent in its class. Although palonosetron improves complete response rates of both acute and delayed emesis in patients receiving moderately or highly emetogenic therapy, data suggest that all 5-HT₃ receptor antagonists exhibit poor control of nausea [52, 66, 84]. Clinical trials reporting significantly improved emesis have also reported “no nausea” in only 25 %, 32 %, and 33 % of chemotherapy patients with the use of granisetron, palonosetron, and ondansetron, respectively [47, 52, 85].

The combination of palonosetron, dexamethasone and the NK-1 receptor antagonist aprepitant has shown the most promise in clinical trials for improving acute and delayed emesis in patients receiving single-day chemotherapy over a 120-h period following administration. Many of these same studies have measured nausea as a secondary endpoint and have demonstrated that nausea is not well controlled. Olanzapine appears to be important in controlling nausea and has emerged in recent trials as a safe and effective preventative agent (with a 5-HT₃ receptor antagonist and dexamethasone) for emesis or nausea, as well as a very effective agent for the treatment of breakthrough symptoms. Clinical trials using gabapentin, cannabinoids, and ginger have not been definitive regarding efficacy in chemotherapy-induced nausea and vomiting to date. Additional studies are necessary in these settings, as well as in the control of nausea, with multiday chemotherapy and with bone marrow transplantation.

Complications from chemotherapy-induced nausea and vomiting, particularly in patients who may already be debilitated, malnourished, or have recently undergone surgery or radiation therapy, can necessitate hospitalization and cause a wide range of poor health outcomes [11, 30]. Dehydration and electrolyte imbalance also increase the risk of serious medical complications. Poor control of symptoms in these settings can lead to increased healthcare utilization, patient costs, and level of anxiety [26].