Lee Schwartzberg, MD, FACP

The proper management of chemotherapy-induced toxicities can have a significant impact on quality-of-life and outcomes for patients. Any adverse events (AEs), if it is severe enough, may lead to emergency department visits, hospital admissions, dose reduction and potentially even discontinuation of treatment. It is therefore critical to stay up to date on how to manage chemotherapy-induced AEs. For many AEs associated with chemotherapy, prevention and treatment strategies have been developed, while unmet needs remain for others.

Chemotherapy-induced AEs can be grouped in a number of ways including by the affected organ. These AEs, include gastrointestinal toxicity, hematologic AEs, and peripheral neuropathy.

Gastrointestinal (GI) AEs of chemotherapy include nausea, vomiting and diarrhea. These tend to appear relatively early in the treatment course.

Chemotherapy-related diarrhea (CRD) is a common AEs of chemotherapy that tends to occur relatively early on during treatment and resolve over time. It is most commonly seen with fluoropyrimidines and irinotecan among intravenous cytotoxic chemotherapy but is also common with targeted therapies such as tyrosine kinase inhibitors and other oral oncolytics. The pathophysiology behind CRD includes GI epithelial damage leading to secretory diarrhea, increased intraluminal osmotic concentration leading to osmotic diarrhea or a change in gastrointestinal motility. Depending on the severity of the CRD, patients can have acute kidney injury, electrolyte abnormalities such as hyponatremia and even infection, if there is a disruption of the intestinal mucosa.

A number of strategies work moderately well to manage CRD depending on its severity, including oral hydration and following the BRAT diet (bananas, rice, applesauce and toast). Patients can also be given anti-motility agents such as loperamide and diphenoxylate-atropine. No specific preventive stategy has emerged to date for CRD, but titrating oral drugs at initiation up to full dose may reduce the incidence of CRD.

Chemotherapy-induced nausea and vomiting (CINV) is another common GI side effect that can cause significant distress in cancer patients. Importantly, there are certain factors that make CINV more likely to occur, including the type of chemotherapy and patient characteristics. For example, there is a high risk of CINV (>90%) with IV cisplatin whereas there is a low risk (<10%) with IV rituximab. Patient factors that increase the risk of CINV include prior CINV, sex (with higher incidence in women) and age (where younger patients have higher rates).

There are currently a number of effective prophylactic strategies for CINV. In a large majority of patients, even when treating with chemotherapy that is highly emetogenic, nausea and vomiting can be prevented. Options include 5-HT3 receptor antagonists (such as ondansetron), NK-1 receptor antagonists (such as aprepitant), glucocorticoids (such as dexamethasone), and olanzapine, a second-generation antipsychotic. Of note, there is a need for more trials studying antiemetic treatment for patients receiving oral chemotherapy since most of the prior trials have been in patients receiving IV chemotherapy. While these strategies have largely mitigated the vomiting associated with chemotherapy, there is a small subset of patients who experience chronic nausea after chemotherapy, where a residual unmet need exists.

The goal of managing CINV and CRD is to find the right management strategy so that patients experience minimal discomfort and can continue to receive treatment with minimal adjustments or delays.

The more severe and consequential AEs of chemotherapy involve the hematologic system. This is in part because many chemotherapy agents target rapidly proliferating cells, including cells of the hematopoietic system that are frequently recycling. Therefore, it is common to see patients with decreased white blood cell count, red blood cell count or platelet count as a consequence of chemotherapy treatment.

Chemotherapy-induced anemia can cause fatigue, dyspnea, and cardiac events. If severe and/or symptomatic enough, red blood cell transfusions may be indicated. However, even when transfusions are not required, chronic fatigue can be a significant symptom for patients.Besides transfusions, patients can be given erythropoiesis-stimulating agents (ESAs), but this is restricted to the palliative setting due to their interactions with the chemotherapy treatment itself. 

, which can cause significant bleeding if severe enough, may be caused by drugs such as carboplatin and gemcitabine. It is typically managed by dose delays and reductions, but occasionally can be severe enough to require platelet transfusions or TPO agonists.

While all of the chemotherapy-induced hematologic AEs have the potential to be life-threatening, 

 is arguably the most dangerous due to the potential risk of developing life-threatening infection. Neutropenia is defined by an absolute neutrophil count (ANC) of <1500 cells/μL, and severe neutropenia is defined by an ANC of <500 cells/μL. When patients develop fever associated with neutropenia, infection is assumed, and some patients progress to requiring hospitalization and treatment with broad-spectrum IV antibiotics. In severe cases, sepsis and death can occur. CIN remains the number 1 reason for ER visits, hospitalization, sepsis, mortality, and chemotherapy disruption.

Due to the severity of potential downstream complications, the presence of a fever in a cancer patient should always be an alarm for clinicians to do a thorough workup. But even before symptoms ever develop, understanding which patients are more likely to develop neutropenic fever is critical. The risk of severe neutropenia and febrile neutropenia is largely based on the intensity of the chemotherapy regimen. Examples of high-risk regimens include topotecan for small cell lung cancer, docetaxel, and cyclophosphamide for breast cancer, and brentuximab vedotin + AVD for Hodgkin lymphoma among many others. Patient risk factors can also affect the risk of severe/febrile neutropenia. They include age greater than 65 years, female patients, patients with comorbidities (cardiovascular, renal, etc.), prior radiation, prior chemotherapy, and patients with poor nutritional status.

Keeping these risk factors in mind, patients beginning a new chemotherapy regimen should be evaluated for prophylactic treatment with myeloid growth factors. If the predicted risk of neutropenic fever is greater than 20% with a particular regimen, patients should be given granulocyte colony-stimulating factor (G-CSFs) as primary prophylaxis. If the risk is between 10-20%, the decision is made on an individual basis with patient risk factors in mind. It is important to note that the COVID-19 pandemic has influenced guidance on whether or not to give G-CSFs, with updated guidelines given by NCCN and ASCO. Guidelines now state that G-CSFs should also be given with chemotherapy regimens which have a risk of 10-20%, which includes all of the intermediate-risk regimens. In addition, G-CSFs can also be given as secondary prophylaxis in patients who developed neutropenic fever in prior cycles with demonstrated reduction of risk by about 50%. In some clinical scenarios, patients can be given antimicrobial prophylaxis against bacteria (such as gram-negative bacilli), antifungal prophylaxis and antiviral prophylaxis.

In terms of therapeutic use, it is not recommended to administer G-CSFs in patients with afebrile neutropenia. For patients who have febrile neutropenia, the data are mixed with guidelines from ASCO stating that they can be used for patients who are at high risk for infection-related complications or who have factors that may result in poor clinical outcomes. Lastly, antimicrobials are a significant part of treating febrile neutropenia, but they come with their own individual adverse effects that must be taken into consideration when deciding on regimens.

While the introduction of G-CSFs led to a significant advancement in the management of CIN, this side effect remains the primary cause of reductions in dose or duration of treatment. Therefore, it is critically important that we do further studies to parse out how to best prevent and treat CIN in patients receiving chemotherapy in order to attain the best cancer outcomes.

Chemotherapy-induced peripheral neuropathy

 (CIPN) is another side effect that can cause significant distress, but while other AEs are usually short-term, CIPN can be a chronic and debilitating symptom. Platinum therapies such as cisplatin and oxaliplatin, taxanes and vinca alkaloids are usually the main culprits. CIPN is dose-dependent and can be characterized by a “stocking and glove” distribution that is symmetric and distal. It also primarily results in sensory rather than motor symptoms with thalidomide and paclitaxel being exceptions. These symptoms can recede over time, but when they don’t, patients can be left with significant functional impairment that may include chronic pain and issues with proprioception that can lead to falls.

Unfortunately, there are currently no well-established ways of preventing CIPN. Therefore, it’s recommended that oncologists do a thorough assessment of whether a particular agent that has the potential to cause significant neuropathy should be used, particularly in patients who already have underlying neuropathy. Methods that have shown some potential include exercise, cryotherapy, acupuncture and compression therapy while anticonvulsants, metformin and vitamins have not shown a benefit. In terms of symptomatic relief, physical therapy and duloxetine have shown modest benefit with agents like topical menthol and topical capsaicin still in need of further research.

As physicians, we are always balancing the benefits and risks of a particular treatment, but this is especially true for the treatment of cancer because the stakes can be particularly high. Both the cancer itself and the AEs of chemotherapy can be potentially life-threatening so it’s critical that we communicate with our patients about what is recommended based on their individual needs. There must be a shared decision-making process from start to finish from deciding which chemotherapy to use to changes in dose to pausing treatment. Establishing a rapport is also critical in establishing trust so that patients feel comfortable enough to bring up any AEs and any alternative remedies that they may be using that could potentially interfere with their treatment. At times, we must be fairly directive – if a patient experiences a life-threatening AE, given the risk, a change to the regimen must be discussed. As our patients are going through the hardest times of their lives while in treatment, it is our duty and privilege to listen, educate and care for them during that process.

Managing Chemotherapy Toxicities: Where We Are Today

When it comes to managing chemotherapy AEs, our best approaches are preventative.

Many supportive care advances have transformed our ability to give full doses of chemotherapy, which is critically important for agents to achieve their full efficacy, especially in the curative setting such as for cytotoxic agents in breast and colon cancer. However, significant unmet needs remain in a few areas, including chemotherapy-induced neutropenia, patients with chronic nausea or diarrhea after chemotherapy and chemotherapy-induced peripheral neuropathy. Better management of these residual unmet needs will improve patient quality of life during and after treatment, reduce risk associated with serious complications and ultimately improve chemotherapy outcomes.

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Articles

The proper management of chemotherapy-induced toxicities can have a significant impact on quality-of-life and outcomes for patients. 

Managing Chemotherapy Toxicities for Improved Patient Outcomes

 Case-Based Peer Perspectives virtual event, Lee Schwartzberg, MD, medical oncologist, West Cancer Center and Research Institute, discussed the therapeutic options for a 39-year-old woman with HER2-positive breast cancer who was heavily pretreated.

: What are this patient’s therapeutic options at this point?

SCHWARTZBERG: We have a lot of treatment options to consider, including tucatinib [Tukysa], trastuzumab, or capecitabine. These are category 1 treatments according to the National Comprehensive Cancer Network [NCCN] breast cancer guidelines.

 Based on the DESTINY-Breast01 trial [NCT03248492] results, we also have T-DX [fam-trastuzumab deruxtecan-nxki; Enhertu] and neratinib [Nerlynx] and capecitabine.

What was the rationale for developing tucatinib?

Tucatinib is a HER2 selective kinase inhibitor that is a very specific kinase, compared with neratinib. From a biochemical perspective, tucatinib is highly selective for HER2 relative to EGFR. Neratinib strongly inhibits at the same level as tucatinib for HER2, but it also inhibits EGFR. Lapatinib [Tykerb], a previously developed kinase that we were using for the last 10 years until the emergence of these newer agents, is much less potent. It’s really about 20 times less potent than either of the other 2 [agents].

Please describe for us the HER2CLIMB study.

The HER2CLIMB study [NCT02614794] evaluated tucatinib, capecitabine, and trastuzumab.

 [It included] patients who had undergone prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients were allowed to have been treated with lapatinib, but not in the last 12 months and [with] no other investigational or approved TKIs [tyrosine kinase inhibitors]. They were randomized with tucatinib given twice a day continuously, capecitabine 1000 mg/m2 twice a day on days 1 to 14 every 3 weeks, andtrastuzumab in the standard dose. This was a placebo-controlled study. PFS [progression-free survival] by BICR [blinded independent central review] was the primary end point, with multiple other end points.

The demographics were well balanced between the groups. It was a 2:1 randomization, a fairly large trial for a late line HER2- positive group of 600 patients. Half the patients had brain metastases in this study.

Investigators reported a 2.2-month improvement in median PFS for the whole population [HR, 0.54; P <.00001]. The median overall survival [OS] was almost 22 months versus 17, so [there was] about a 5-month improvement in OS [HR, 0.66; P < .00480]. PFS benefit was noted in all subgroups by subgroup analysis.

There were some additional end points. The response rate was about doubled with the addition of tucatinib compared with the placebo group [41% vs 23%; P = .00008], and for the initial report of brain metastases there was also a 2.2-month improvement in PFS for patients with brain metastases, similar to that seen for the whole group [7.6 months vs 5.4 months; HR, 0.48; P < .00001].

Describe the adverse events (AEs) that investigators observed in the trial.

The most common AEs of greater than 20% in the tucatinib arm were diarrhea, elevated liver function test results, and PPE [palmar-plantar erythrodysesthesia]. Grade 3 diarrhea was reported in 13% of patients compared with 9% in the control arm. There was a modest increase in liver function, particularly grade 3, at around 5% for tucatinib versus 0.5%; the PPE syndrome was a bit higher and really [with] no major difference in grade 3 at 13% versus 9%. In terms of AEs leading to tucatinib or placebo discontinuation, investigators reported 6% in the tucatinib arm and 3% in the placebo arm.

Regarding intracranial CNS [central nervous system] responses, the confirmed overall response rate is 47% in the tucatinib arm compared with 20% in the placebo arm. Also, importantly, the duration of response in those patients who responded was more than doubled—6.8 months compared with 3.0 months.

How would you describe the survival responses?

If you look at all patients with brain metastases, the risk of death was decreased by 42%, so, a hazard ratio of 0.58 for the patients who had brain metastases. The median OS was increased substantially to 18 months compared with 12 months per patients who received placebo.

In patients with active brain metastases, similar OS findings were reported. In that subpopulation, the hazard ratio was 0.59 and the median OS was a little longer—20.7 months versus 11.6 months for patients in the placebo arm. The agent seemed to confer the same amount of benefit in patients with activebrain metastases as in those who had treated brain metastases.

The HER2CLIMB-02 trial [NCT03975647] is a randomized phase 3 trial of tucatinib plus T-DM1 versus [placebo plus] T-DM1. In this trial, we will determine if tucatinib adds [benefit] to T-DM1. Importantly...patients are eligible with or without brain metastases.

What are the highlights of the NALA study (NCT01808573)?

The NALA study randomized patients to neratinib plus capecitabine using prophylaxis with loperamide.

 The lapatinib plus capecitabine [regimen] was the previous standard of care in patients who had had 2 or more lines of HER2-directed therapy. Most of these patients had had 2 lines of therapy. Only a third had had prior trastuzumab, pertuzumab, and T-DM1, which is our standard today.

The centrally confirmed PFS was the coprimary end point. The restricted analysis of 24 months showed a 2.2-month improvement in disease PFS, which was highly statistically significant. There was a hazard ratio of 0.76 for the whole curve.

Time to intervention for CNS metastases was evaluated, but this was not a primary or a secondary end point. The time was reduced from 29% to 23% with neratinib compared with lapatinib [and was] statistically significant.

The response rate was 33% versus 27%. The clinical benefit rate was somewhat higher and statistically significant. The median duration of response was 8.5 months versus 5.6 months, [with a] hazard ratio of 0.5 for the duration of response.

The most common AEs observed were again diarrhea, it was 24% grade 3 versus 13% for lapatinib, and there was no real difference in hand-foot syndrome. In fact, it was worse with lapatinib.

There was more all-grade nausea and vomiting for neratinib, a little bit more than lapatinib, and more decreased appetite. Treatment discontinuation, however, due to treatment-emergent AEs, was 11% versus 15% favoring neratinib.

If you look at the maximum toxicity grade 3, it was 24% versus 13%. Eleven percent of patients had grade 3 diarrhea first onset and the median cumulative duration was 3 to 4 days. Treatment discontinuation was similar for diarrhea between the 2 arms.

What were the findings of the CONTROL study (NCT02400476), which looked at the effect of prophylaxis on neratinib-associated diarrhea?

The CONTROL study looked at prophylaxis with a variety of different regimens including loperamide and other regimens.

 This was a sequential cohort study with 5 treatment arms. The last arm evaluated as-needed loperamide. Everyone agrees that this does not always take care of diarrhea and, in fact, can cause constipation, leading to a vicious cycle. In this case, loperamide was given as needed, but the strategy was to do a neratinib dose escalation and to start at typically half dose, then three-quarter dose, then full dose.

The grade 3 toxicity for diarrhea was much lower at 12%, although the all grade remains high for all of these strategies. There was no grade 4 diarrhea reported in any of the arms, including just using loperamide on a routine basis. But the grade 3 diarrhea was lower in each of the cohorts.

Can you discuss trastuzumab deruxtecan? What’s unique about it?

Trastuzumab deruxtecan is a novel antibody-drug conjugate (ADC). It has 3 components. The backbone is trastuzumab, so like T-DM1 it is composed of the trastuzumab molecule. What’s different here are 2 other aspects of the molecule.

First of all, there is a different linker. It’s a tetrapeptide linker that is cleavable and has different properties than the linkers that are used in some of the other ADCs. Secondly, it has a different type of payload—an exatecan derivative—[and] this makes it very different.

Please discuss the DESTINY-Breast01 study.

 Part 1 was a dose expansion study; in part 2, patients were resistant or refractory to, or intolerant of, T-DM1. So these patients were progressing on T-DM1. Investigators had tested 3 different doses [5.4 mg/kg, 6.4 mg/kg, and 7.4 mg/kg]. The [7.4- mg/kg] dose was dropped at the end of phase 1. Patients in part 2 received the 5.4-mg/kg dose, which is the [standard] dose since the trial. The data cutoff was a year ago, with many patients [42%] continuing. The primary end point was response rate in this phase 2 study.

This was a heavily pretreated population, patients [with] mainly an ECOG 0 and 1 [score] who were hormone receptor positive, and most of them were IHC [immunohistochemistry] [HER2- positive] 3 in this particular population. Thirteen percent of patients did have brain metastases on this study.

All patients had to have prior trastuzumab and T-DM1; two- thirds had pertuzumab and, interestingly, another half had other anti-HER2 therapies.

The confirmed overall response rate by independent review was 61% and most of those were PRs [partial responses], but 6% were CRs [complete responses]. The disease control rate was 97% and the clinical benefit rate was 76%. The median duration of response was almost 15 months with a rapid time to response of 1.6 months.

Median PFS was 16.4 months. The median follow-up here was relatively short, at only 11 months at the time of publication.

 The median PFS in the 24 patients with brain metastases was 18.1 months. And the median survival has not yet been reached, with only a median follow-up of 11 months.

The treatment-emergent AE profile was a little different. Here, nausea was the most common toxicity, in addition to fatigue and alopecia. Remember, there was only grade 1 or 2 alopecia that occurred in half the patients with vomiting and some other GI toxicity. Neutropenia was seen in grade 3 or greater in about 15% or 20% of patients and some anemia grade 3 or 4 was reported in under 10% of patients.

The AE of special interest for deruxtecan is interstitial lung disease [ILD], and this was found in about 14% of patients; [it was] mostly grade 1 and 2, but there were 4 grade 5 or deaths due to ILD. The median time to ILD was almost 6 months and a little over 6 months. Only 13 of the 20 patients with grade 2 [ILD] received corticosteroids and the outcomes for some were not known. Of the fatal cases, 3 received steroids and the death occurred sometime after that. The recommendation was to monitor for symptoms of ILD, hold the drug, and start steroids as soon as ILD is suspected.

Can you provide details about the development program for trastuzumab deruxtecan?

There are 3 upcoming trials in breast cancer. The DESTINY- Breast02 study [NCT03523585] is evaluating patients after treatment with T-DM1. We’ve already seen the phase 2 study, which is Breast01. This is a phase 3 trial evaluating T-DM1 versus investigator’s choice of chemotherapy plus anti-HER2 therapy.

The DESTINY-Breast03 trial [NCT03529110] evaluates patients in the second line who have been treated with first-line trastuzumab and taxane therapy and are then going to be randomized to an upfront head-to-head comparison of trastuzumab-deruxtecan with T-DM1.

DESTINY-Breast04 trial [NCT03734029] looks at patients with HER2 low who are IHC 1+ or 2+ but in situ hybridization [ISH]- negative, at least ISH-negative for 2+; most of the IHC 1+ are not tested. The experimental arm is [fam-] trastuzumab deruxtecan and the comparator arm is physician’s choice without anti-HER2 therapy. Investigators are determining whether or not [fam-] trastuzumab deruxtecan has activity.

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 6.2020. Accessed January 7, 2021. https://bit.ly/2XgEAmt

2. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2- positive metastatic breast cancer.

. 2020;382(7):597-609. doi:10.1056/ NEJMoa1914609

3. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial.

. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775

4. Saura C, Oliveira M, Feng YH, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. 

. 2019;37(suppl 15):1002. doi:10.1200/JCO.2019.37.15_suppl.1002 

5. Barcenas CH, Hurvitz SA, Di Palma JA, et al. Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: phase II CONTROL trial. 

. 2019;37(suppl 15):548. doi:10.1200/JCO.2019.37.15_suppl.548

6. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

During a Targeted Oncology Case-Based Peer Perspectives virtual event, Lee Schwartzberg, MD, medical oncologist, West Cancer Center and Research Institute, discussed the therapeutic options for a 39-year-old woman with HER2-positive breast cancer who was heavily pretreated.

Expert Discusses HER2 Selective Kinase Inhibitors in Heavily Pretreated Breast Cancer

The first-generation 5-HT3 receptor antagonists (RAs; ondansetron, granisetron, dolasetron [Anzemet], and tropisetron [Navoban]) revolutionized the management of CINV in terms of efficacy and safety compared with historical antiemetics (eg, metoclopramide [Reglan]).

These agents exhibit comparable efficacy, preventing 50% to 80% of acute CINV in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) regimens and are considered equivalent in CINV guidelines. Despite their efficacy against acute CINV, these agents are much less effective at preventing delayed CINV.

In contrast, the second-generation 5-HT3 RA, palonosetron (Alexi), demonstrates efficacy in preventing both acute and delayed CINV. Palonosetron plus dexamethasone has demonstrated superiority over the first-generation 5-HT3 RAs plus dexamethasone.

These advantages result from the unique pharmacodynamic properties of palonosetron, including a longer half-life and higher receptor binding affinity compared with the first-generation 5-HT3 RAs. In addition, binding of palonosetron to the 5-HT3 receptor creates positive cooperativity that results in further palonosetron binding and eventual receptor internalization, blocking 5-HT3 signaling and crosstalk with NK-1 receptor signaling.

A novel extended-release subcutaneous formulation of granisetron, APF530, was recently approved by the FDA for CINV.

A unique biopolymer delivery system provides sustained release to improve the therapeutic concentration of granisetron over an extended period (>5 days).

A phase III study compared APF530 with ondansetron, both in combination with fosaprepitant (Emend for injection) and dexamethasone in patients receiving HEC.

Delayed-phase complete response (CR) was significantly more common in patients receiving APF530 compared with patients treated with ondansetron (65% vs 57%;

= .014). The most common treatment-related adverse events were constipation, fatigue, headache, and infusion-site reactions.

Development of neurokinin-1 (NK-1) RAs has greatly improved our ability to control CINV. Aprepitant (Emend) was the first NK-1 RA to be approved for CINV based on demonstrated protection against delayed CINV in patients receiving HEC or MEC.

The addition of aprepitant to ondansetron/dexamethasone significantly increased the proportion of patients who did not experience vomiting, but did not have a significant protective effect against nausea. This aprepitant triplet regimen also showed superior prevention of CINVthat is, no vomiting and a CRin patients receiving MEC in a phase III randomized trial compared with ondansetron/dexamethasone alone.

The water insolubility of aprepitant led to the development of the prodrug, fosaprepitant, which is readily converted to aprepitant following intravenous (IV) administration.

A phase III noninferiority trial of 2247 patients receiving cisplatin-based chemotherapy then compared a single dose of IV fosaprepitant to the standard 3-day regimen of oral aprepitant, both in combination with ondansetron/dexamethasone.

CR was improved in the fosaprepitant arm for the delayed (78.9% vs 68.5%;

<.001) phases in comparison with the aprepitant arm, but CR was not improved in the acute phase (93.2% vs 91.0%;

Preclinical study results revealed synergistic activity for netupitant (Akynnzeo), a novel NK-1 RA, and palonosetron that suggested that this combination could be highly effective against CINV.

NEPA300 (netupitant with palonosetron) was subsequently developed to provide a convenient single-dose antiemetic therapy that combined both drugs.

A randomized phase III trial directly compared a single dose of NEPA to a single dose of oral palonosetron (0.5 mg), both with dexamethasone, in 1455 patients receiving doxorubicin (Adriamycin) and cyclophosphamide (AC)based chemotherapy.

NEPA significantly increased the CR rate compared with palonosetron during the delayed phase (76.9% vs 69.5%;

). NEPA provided more protection than palonosetron alone from both emesis and nausea in the delayed and overall phases. The oral fixed-dose NEPA capsule was approved by the FDA in 2014.

Rolapitant, another novel NK-1 RA, was approved by the FDA in 2015 in combination with other antiemetic therapies for the prophylaxis of delayed CINV associated with initial and repeat courses of MEC or HEC. Two phase III trials evaluated rolapitant against granisetron in patients receiving HEC (HEC-1 and HEC-2), each of which enrolled over 500 patients.

In a pooled analysis of both studies, the addition of rolapitant to granisetron and dexamethasone significantly increased the percentage of patients who experienced a CR in the delayed phase (71% vs 60%;

A third phase III study examined 1369 patients receiving MEC, randomizing them to rolapitant (180 mg orally on day 1) or placebo with granisetron (2 mg orally on days 1-3) and dexamethasone.

Of note, at the time of the study design, AC was considered an MEC and patients receiving this combination were included. Significantly more patients receiving rolapitant achieved a CR in the delayed phase (71% vs 62%;

= .0002) and the overall phase (69% vs 58%;

<.0001) compared with the control group (

Differences in the pharmacokinetic properties of NK-1 RAs influence the dosage and use of these agents (

Aprepitant and its prodrug fosaprepitant have a relatively short half-life of 9 to 13 hours, with aprepitant dosed daily for 3 days and fosaprepitant dosed only on day 1.

In contrast, NEPA and rolapitant have half-lives of approximately 80 and 180 hours, respectively, and both agents can be administered as a single dose prior to each chemotherapy cycle.

Another key difference between NK-1 RAs is their interaction with other drugs. Aprepitant, fosaprepitant, and netupitant induce or inhibit cytochrome P450 3A4 (CYP3A4), while rolapitant does not.

This interferes with the metabolism of CYP3A4 substrates, such as dexamethasone and some chemotherapeutic agents, requiring careful consideration and appropriate dose reductions of concomitant dexamethasone. Aprepitant and fosaprepitant also interact with warfarin and oral contraceptives. Rolapitant, on the other hand, inhibits CYP2D6, breast cancer resistance protein (BCRP), and p-glycoprotein.

Olanzapine is an atypical antipsychotic that blocks multiple neutrotransmitters and interacts with dopaminergic, serotonergic, adrenergic, and histamine receptors. A recent large randomized phase III trial evaluated the addition of olanzapine versus placebo to a standard triplet antiemetic regimen of aprepitant or fosaprepitant, a 5-HT3 receptor antagonist, and dexamethasone.

A total of 380 chemotherapy-na&iuml;ve patients receiving HEC (cisplatin or cyclophosphamide/doxorubicin) were randomized to either olanzapine (10 mg orally) or placebo on days 1 through 4. The addition of olanzapine significantly improved the primary endpoint of no chemotherapy-induced nausea in the acute period (74% vs 45%;

= .002) and the delayed period (42% vs 25%;

= .002). Overall nausea prevention also significantly increased (37% vs 22%;

= .002). Side effects associated with olanzapine include short-term sedation, unwanted increased appetite, and weight gain. In this phase III trial, sedation was significantly increased in those receiving olanzapine, including severe sedation in 5% of patients.

Olanzapine has also been investigated as a rescue therapy for patients with breakthrough CINV. A double-blind randomized phase III trial directly compared olanzapine to metoclopramide in chemotherapy-na&iuml;ve patients receiving HEC (cisplatin or doxorubicin/cyclophosphamide) who experienced breakthrough CINV despite prophylactic fosaprepitant, palonosetron, and dexamethasone.

Olanzapine prevented vomiting in 70% or patients compared with 31% with metoclopramide (

<.01). Nausea was also significantly reduced (68% vs 23%;

Carboplatin, previously considered an MEC agent, was reclassified as a highly emetogenic agent when used at higher doses (AUC

4) by the National Comprehensive Cancer Network.

The American Society of Clinical Oncology

as well as the European Society of Medical Oncology and Multinational Association of Supportive care in Cancer

have also reclassified carboplatin at any dose as HEC. Guidelines now generally recommend a 4-drug regimen for HEC, including olanzapine, a 5-HT3 RA, an NK-1 RA, and dexamethasone.

Although vomiting from chemotherapy has been largely abrogated by appropriate prophylaxis, nauseaparticularly delayed nausea&mdash;remains an unsolved issue. Is nausea triggered by other pathways that can be blocked? One potential class of agent that deserves more study is the cannabinoids, particularly with increased access now available. Will active agents in cannabis, such as tetrahydrocannabino, have a useful role in CINV? Why guidelines are not followed in a substantial minority of patients remains an elusive question and worthy of study. How can we incorporate patient risk factors into CINV prophylaxis choices, particularly in MEC? Future clinical trials will need to assess novel antiemetic therapies further, with the goal of complete control of all aspects of CINV. This will greatly improve quality of life for patients and will provide clinicians with the information they need to select optimal CINV prophylaxis from the start.

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Rojas C, Raje M, Tsukamoto T, Slusher BS. Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis. Eur J Pharmacol. 2014;722:26-37. doi: 10.1016/j.ejphar.2013.08.049.

Rojas C, Stathis M, Thomas AG, et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg. 2008;107(2):469-478. doi: 10.1213/ane.0b013e318172fa74.

Granisetron [prescribing information]. Heron Therapeutics: Redwood City, CA; 2016. sustol.com/public/pdfs/PI.pdf. Accessed: June 26, 2017.

Schnadig ID, Agajanian R, Dakhil C, et al. APF530 (granisetron injection extended-release) in a three-drug regimen for delayed CINV in highly emetogenic chemotherapy. Future Oncol. 2016;12(12):1469-1481. doi: 10.2217/fon-2016-0070.

Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al; Aprepitant Protocol 054 Study Group. Addition of the neurokinin 1 receptor antagonist aprepitant&nbsp;to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003;97(12):3090-3098. doi: 10.1002/cncr.11433.

Hesketh PJ, Grunberg SM, Gralla RJ, et al; Aprepitant Protocol 052 Study Group. The oral neurokinin-1 antagonist aprepitant&nbsp;for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the&nbsp;Aprepitant&nbsp;Protocol 052 Study Group. J Clin Oncol. 2003;21(22):4112-4119. doi: 10.1200/JCO.2003.01.095.

Rapoport BL, Jordan K, Boice JA, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer. 2010;18(4):423-431. doi: 10.1007/s00520-009-0690-9.

Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant&nbsp;for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: Randomized, double-blind study protocolEASE. J Clin Oncol. 2011;29(11):1495-1501. doi: 10.1200/JCO.2010.31.7859.

Lasseter KC, Gambale J, Jin B, et al. Tolerability of fosaprepitant and bioequivalency to aprepitant in healthy subjects. J Clin Pharmacol. 2007;47(7):834-840. doi: 10.1177/0091270007301800.

Weinstein C, Jordan K, Green SA, et al. Single-dose fosaprepitant&nbsp;for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: Results of a randomized, double-blind phase III trial. Ann Oncol. 2016;27(1):172-178. doi: 10.1093/annonc/mdv482.

Stathis M, Pietra C, Rojas C, Slusher BS. Inhibition of substance P-mediated responses in NG108-15 cells by netupitant&nbsp;and palonosetron exhibit synergistic effects. Eur J Pharmacol. 2012;689(1-3):25-30. doi: 10.1016/j.ejphar.2012.05.037.

Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol. 2014;25(7):1328-1333. doi: 10.1093/annonc/mdu101.

Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant&nbsp;for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: Two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol. 2015;16(9):1079-1089. doi: 10.1016/S1470-2045(15)00035-2.

Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant&nbsp;for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: A randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol. 2015;16(9):1071-1078. doi: 10.1016/S1470-2045(15)00034-0.

Aprepitant [prescribing information]; Merck Sharp & Dohme Corp: Whitehouse Station, NJ. 2017. Available at: merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf. Accessed May 30, 2017.

Fosaprepitant dimeglumine [prescribing information]; Merck Sharp & Dohme Corp: Whitehouse Station, NJ. 2016. Available at: merck.com/product/usa/pi_circulars/e/emend_iv/emend_iv_pi.pdf. Accessed May 30, 2017.

Netupitant and palonosetron [prescribing information; Helsinn Therapeutics: Iselin, NJ. 2016. Available at: www.akynzeo.com/assets/pdf/Prescribing_Information.pdf. Accessed May 30, 2017.

Rolapitant [prescribing information]; Tesaro, Inc: Waltham, MA. 2015. Available at: varubirx.com/downloads/VARUBI_(rolapitant)_Full_Prescribing_Information.pdf. Accessed May 30, 2017.

Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and&nbsp;vomiting. N Engl J Med. 2016;375(2):134-142. doi: 10.1056/NEJMoa1515725.

Navari RM, Nagy CK, Gray SE. The use of olanzapine&nbsp;versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and&nbsp;vomiting&nbsp;in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013;21(6):1655-1663. doi: 10.1007/s00520-012-1710-6.

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Hesketh PJ, Kris MG, Basch E, et al; American Society of Clinical Oncology. Antiemetics: American&nbsp;Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017;35(28):3240-3261. doi: 10.1200/JCO.2017.74.4789.

Roila F, Molassiotis A, Herrstedt J, et al; participants of the MASCC/ESMO Consensus Conference Copenhagen 2015. 2016 MASCC&nbsp;and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and&nbsp;vomiting&nbsp;and of nausea and&nbsp;vomiting&nbsp;in advanced cancer patients. Ann Oncol. 2016;27(suppl 5):v119-v133. doi: 10.1093/annonc/mdw270.

The goal of selecting optimal antiemetic therapy continues to be a moving target with the emergence of newer agents and patient-related risk factors, as well as the rapid evolution of guidelines for the management of chemotherapy-induced nausea and vomiting.

Lee Schwartzberg, MD, FACP | Authors

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