A Naeim et al. Evidence-based recommendations for cancer nausea and vomiting. J Clin Oncol 2008;26(23):3903-10.

There are many types of neuroreceptors that are involved in the emetic response, including serotonin (5-hydroxytryptamine-3 [5-HT3]), dopamine, corticosteroid, and neurokinin-1 receptors; therefore, antiemetic agents often target different neuroreceptors and can behave synergistically when used in combination. Without the use of prophylactic antiemetic therapy, some highly emetic types of chemotherapy, such as cisplatin, would almost universally result in nausea and/or vomiting, but with the use of optimal antiemetic therapy, clinicians can reduce the prevalence to approximately 25% of patients on highly emetic therapy. Therefore, appropriate pharmacologic prevention and management are essential.

PJ Hesketh. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358(23):2482-94.

Four groups (the Multinational Association of Supportive Care in Cancer, the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the European Society for Medical Oncology) have recently published updated antiemetic guidelines. There is broad agreement among these groups on most key issues. The treatment recommendations that follow reflect a composite of the consensus recommendations of these groups...

High Emetic Risk
The combination of a 5-HT3 antagonist, dexamethasone, and aprepitant is recommended before the administration of chemotherapy that is associated with a high risk of emesis... Patients receiving chemotherapy with high emetogenic potential should receive a combination of aprepitant on days 2 and 3 and dexamethasone on days 2 to 4...

Moderate Emetic Risk
In patients receiving treatment with an anthracycline and cyclophosphamide, a combination of a 5-HT3 antagonist, dexamethasone, and aprepitant is recommended before chemotherapy. Because this chemotherapeutic regimen has a moderate potential for delayed emesis, aprepitant should also be administered on days 2 and 3...

Low Emetic Risk
A single dose of dexamethasone before chemotherapy is recommended for agents associated with a low risk of emesis. A single dose of a dopaminergic antagonist is another reasonable preventive option. No routine prophylaxis for delayed emesis is indicated...

Minimal Emetic Risk
No routine prophylaxis for acute or delayed emesis is warranted for chemotherapeutic agents that are associated with a minimal risk of emesis.

Breast Cancer Update Issue 2, 2007

FRANKIE A HOLMES, MD: I’ve started to incorporate the TC regimen much more frequently in my practice, especially in situations in which I have concerns about chemotherapy tolerance. However, at this time, I have not given up on the standard AC taxane regimen for my patients with node-positive disease. AC is now recognized as a highly emetogenic regimen, and patients may experience delayed nausea and vomiting. I was once on a panel discussing emesis, and someone said, “Oh, that’s just AC.” AC is associated with a lot of delayed nausea and vomiting. You find considerable hidden toxicity if you step into the shoes of a patient. It can be incapacitating. With TC, you don’t have that level of burden of emesis and nausea.

Breast Cancer Update Issue 2, 2008

STEPHEN E JONES, MD: We examined the database from the US Oncology adjuvant trial evaluating TC versus AC for long-term potential toxicities and identified three fatal events: congestive heart failure in a woman younger than age 50, myelodysplastic syndrome and myelofibrosis. Those three patients received AC chemotherapy, and we saw nothing similar in the TC arm.

These are the concerns with anthracyclines. They adversely affect the heart, a fact that has been underappreciated. We are beginning to understand this effect better, particularly in older patients. Data from MD Anderson and the SEER and Medicare databases demonstrate that the occurrence of congestive heart failure may be in excess of 10 or 20 percent among women older than age 65 when treated with anthracyclines.

That’s scary, and I wonder, did I contribute to this? It would be nice to have a treatment that eliminated doxorubicin, which may be responsible for some of the late congestive heart failures.

The anthracyclines also increase nausea and vomiting. In our original report, significantly less Grade III/IV nausea and vomiting was recorded with TC versus AC, and more antiemetics had to be used for those patients with delayed nausea and vomiting.

NCCN Clinical Practice Guidelines in Oncology: Antiemesis — v.3.2008

The development of the 5-HT3-receptor antagonists (such as ondansetron, granisetron, dolasetron mesylate, palonosetron) represents a significant advance in antiemetic therapy. All of these agents have been shown to be effective in controlling the acute nausea and/or vomiting associated with cancer chemotherapy.

Palonosetron is a 5-HT3 antagonist with an approximately 100-fold higher binding affinity for the 5-HT3 receptor compared to the other serotonin antagonists (ie, ondansetron, granisetron, and dolasetron). It has a half-life of approximately 40 hours, which is significantly longer than other commercially available 5-HT3 antagonists... It is recommended (category 1) for acute and delayed emesis prevention when using moderate emetic risk chemotherapy...

In March 2003, the Food and Drug Administration (FDA) approved aprepitant (oral), which selectively blocks the binding of substance P at the NK-1 receptor in the central nervous system. Thus, aprepitant provides a different and complementary mechanism of action to all other commercially available antiemetics. Aprepitant has been shown to augment the antiemetic activity of the 5-HT3 receptor antagonists and the corticosteroid dexamethasone to inhibit both acute and delayed cisplatin-induced emesis.

Breast Cancer Update Issue 3, 2008

JULIE R GRALOW, MD: Nab paclitaxel does not require premedications, has a faster infusion time and has the ability to deliver somewhat higher doses of the drug. I believe we are seeing a dose-response effect above what we’ve traditionally observed with paclitaxel. Certainly the data with every three-week nab paclitaxel versus paclitaxel are in favor of nab paclitaxel.

We have randomized Phase II data showing that when administered weekly, nab paclitaxel may be as good as, if not better than, docetaxel. It’s a fascinating drug, and I like using it a lot. I like not having to administer steroids and antihistamines and the markedly reduced chance of allergic reactions. I’m excited about trials moving nab paclitaxel into the adjuvant setting.

Breast Cancer Update Issue 2, 2007

DR HOLMES: I administer nab paclitaxel in preference to paclitaxel, period, for patients with metastatic disease. It’s a huge advantage. Patients have a life. They have kids. They have day care. At its best, getting through the clinic is difficult. I have emergencies, so I’m backed up. There are all kinds of built-in delays.

We all think we know what it is to go through therapy from the patient’s standpoint, but it’s hard to remember all the delays, all the problems: “Oh gosh, counts aren’t up today. You have to come back later.” To begin with, these people have a life, and their time is valuable. In addition, not having to take the dexamethasone is a huge benefit. How many people are hyperactive? They can’t sleep that first night. They have to take the steroids and then take lorazepam or something else to relax them. Finally, we all know that patients gain weight on adjuvant chemotherapy.

Apparently, they do not eat more, and their energy intake isn’t increased, but their energy expenditure is decreased. Add this anabolic agent on top of that, and we know that some women are sensitized to this. Then there’s that minority of patients who develop acne from the dexamethasone. Really, less is more, and avoiding premedication is a tremendous advantage.

Breast Cancer Update Issue 2, 2008

JOYCE O’SHAUGHNESSY, MD: One of the main advantages of nab paclitaxel is that you don’t need steroids. Steroids weren’t used in the nab paclitaxel trials, and an increasing body of anecdotal evidence suggests that patients who suffer reactions with paclitaxel or docetaxel can receive nab paclitaxel without having anaphylactoid problems. I don’t know of any reason to administer steroids to them.

Breast Cancer Update Issue 5, 2007

SHARON GIORDANO, MD, MPH: We’ve conducted exploratory work examining cognitive dysfunction secondary to chemotherapy. It’s difficult to get information from databases because most of the treatment-related cognitive changes are subtle, and I don’t believe most physicians would notice them during a routine office visit.

The cognitive changes are important to the patient in terms of memory-only span or recall, attention span, but these are picked up on careful neurocognitive testing.

Clearly, a number of issues exist in the patient’s life at the time of diagnosis and treatment, including an enormous amount of stress, possible cytokines released by the cancer that may cause cognitive changes even before starting chemotherapy, the effects of chemotherapy, the effects of menopause in women and the effects of estrogen blockade. So many different things are going on that it’s hard to tease out how much each contributes to the dysfunction.

It clearly is a real phenomenon for some patients. One of my young patients in her thirties received chemotherapy, then had difficulty remembering people’s names at the day care center she operates.

When I saw her a year later at follow-up, it seemed to be getting better. I believe real changes occur, but only some patients are strongly affected in this way.

Colorectal Cancer Update Issue 3, 2008

STEVEN R ALBERTS, MD: The CONcePT trial was designed to evaluate intermittent versus continuous oxaliplatin, with chemotherapy, and the use of calcium and magnesium to decrease oxaliplatin-induced peripheral neuropathy.

The Data and Safety Monitoring Committee halted the trial based on an early analysis that suggested calcium and magnesium were causing some detrimental effect in terms of the response rate, as well as potentially progression-free survival. An independent review group examined the outcomes and it now appears that patients receiving calcium and magnesium were not harmed by it and, indeed, they seem to have a better response rate and a longer duration of disease control.

However, because the trial was stopped early, there’s still some concern regarding whether we can rely on the data. Meanwhile, the North Central Cancer Treatment Group (NCCTG) was evaluating calcium and magnesium in a symptom-control trial. The analysis from that trial also suggested there wasn’t any potential harm in terms of response rates. In addition, the NCCTG and the CONcePT trials both showed some benefit from calcium and magnesium in controlling treatment-induced peripheral neuropathy.

Colorectal Cancer Update Issue 5, 2007

HERBERT I HURWITZ, MD: One approach to maximize the treatment benefit from oxaliplatin in the metastatic setting is to be preemptive through the use of a calendar schedule. This is the OPTIMOX approach, by which stopping and starting treatment are based as much on the calendar as they are on the patient’s symptoms or disease control.

I find that adjustment based on the patient’s symptoms — as long as the threshold of symptoms is lowered — ends up being a nearly identical approach. I have a bias to try to adjust based on how the patient is faring rather than the calendar, but in practice, the two approaches are most likely similar.

Currently my algorithm is to reduce or stop only the problem agent and to continue the portions of therapy that seem to help, as long as they’re well tolerated. For patients who need a break for personal reasons or for asthenia, I believe stopping even the fluoropyrimidine and bevacizumab for a period of several weeks to two months is a reasonable approach, as long as the disease burden and patient symptoms allow for the holiday.

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