Clinical Impact of Chronic Low-Grade Nausea Is Woefully Underestimated

Maurie Markman, MD

Antineoplastic drug therapy has been delivered by the oral route since the earliest days of the modern chemotherapeutic era. Examples include cyclophosphamide in breast cancer and melphalan in ovarian cancer. More recent experiences include an expanded use of oral hormonal therapy in several malignancies and a number of molecularly targeted therapeutics in routine clinical practice.

From the perspective of a patient with cancer, the advantages of oral therapy are fairly obvious. Patients can receive therapy at home, avoid the need for intravenous access, minimize the disruption of daily living by not having to travel to a physician’s office, hospital, or infusion center, and save the time required for the infusion itself. Further, as many advanced, metastatic, or recurrent cancers are currently viewed as chronic conditions, the periods of time where the impact on these activities is relevant may be measured in years rather than a few months.

However, despite this logical preference, the model of antineoplastic drug delivery during the past several decades has been intermittent (most frequently every 1-4 weeks) intravenous infusions. As a result, the toxicity profiles of treatment regimens have focused on this strategy of drug administration. Significantly, a number of the most clinically active cytotoxic chemotherapeutic agents employed over the past several decades as either single agents (eg, doxorubicin, cisplatin, cyclophosphamide) or in combination drug programs produce substantial acute emesis such that major efforts were required to control or at least minimize the often terrible impact of these treatments on quality of life.

Fortunately, the most intense symptoms of emetogenic regimens, including delayed emesis, gradually improved over a few days to a week following the delivery of therapy and the patient’s status returned to a pre-infusion baseline. Considering this symptomatic scenario, it is not surprising that clinical trial toxicity scales highlighted, and investigators’ efforts focused on, the potential for acute severe (grade >3) nausea, retching, and vomiting.

Impact on Adherence

Conversely, nausea described in clinical trial analyses and subsequent peer-reviewed publications as being “low-grade” (grade 1) would likely be considered as having a limited or minimal impact on a patient’s overall quality of life and might even be classified as being “acceptable.”Now, fast forward to the current era where the paradigm is rapidly shifting to include highly clinically active orally administered antineoplastic drugs, where such therapy is routinely delivered daily or several times a day and where treatment may be continued for many years, either for a known active cancer or in a maintenance setting.

This question has now emerged: Under these circumstances, will low-grade (grade 1) nausea that occurs every day as long as a patient takes a medication be considered “acceptable” such that the patient will continue to take the medication? Add to this scenario the fact that the patient has no cancerrelated symptoms or objective signs of the malignancy and is receiving the oral agent to prolong the time to disease progression and favorably affect overall survival. Again, will the development of grade 1 nausea experienced continuously or even intermittently every day the drug is taken result in an acceptable quality of life for that individual? A provocative and concerning response to this inquiry is provided in a recent report examining the utility of tamoxifen compared with placebo in women with a high risk of developing breast cancer.¹

The question being addressed in this analysis was the reasons for patient nonadherence to the cancer prevention regimen. Overall, nearly 70% of women were adherent for a minimum of 4.5 years of therapy, which not surprisingly was superior in the placebo treatment population (74%) compared with tamoxifen (65.2%).

However, perhaps most interesting was the observation that women reporting “nausea” (versus no nausea), regardless of whether they were treated with active drug (HR, 0.57) or placebo (HR, 0.58), were substantially less likely to be adherent to the planned regimen. Notably, women who reported only “mild nausea” experienced a distressing 61% study treatment adherence rate.¹

Another example of the potential negative impact of low-grade nausea is provided by the quite impressive experience with oral PARP inhibitors administered to women with epithelial ovarian cancer as second-line or later treatment or as maintenance therapy in patients who have achieved a second-line or later clinical response to a platinum-based treatment regimen.^2-4 Several drugs have demonstrated substantial clinical activity (ie, objective response rates, time to disease progression) in these clinical settings.

However, trial reports for all 3 approved drugs have notably revealed a rather high (>60%) incidence of low-grade (grade 1 or 2) nausea with more severe emesis (grade 3 or 4) being uncommon.2-4 And, while the risk of study discontinuation due to this adverse effect of treatment was reportedly quite modest in the individual trials, the question is what the realworld experience will be. That is, what is the risk of therapy discontinuation due to this low-grade adverse effect or the decision by a patient—without discussing with or even informing her physician or family—to take fewer pills/capsules/tablets each day or perhaps modify the dosing schedule simply to be able to tolerate the nausea?

The essential point here is this: To optimize the clinical utility of oral antineoplastic agents, there must be a heightened focus on preventing or effectively controlling what has unfortunately been inappropriately labeled as nothing more than “low-grade” nausea.

References

1. Smith SG, Sestak I, Howell A, Forbes J, Cuzick J. Participantreported symptoms and their effect on long-term adherence in the International Breast Cancer Intervention Study I (IBIS I). J Clin Oncol. 2017;35(23):2666-2673. doi: 10.1200/JCO.2016.71.7439.
2. Pujade-Lauraine E, Ledermann JA, Selle F, et al; SOLO2/ENGOT-Ov21 Investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA 1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2
3. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016; 375(22):2154-2164. doi: 10.1056/NEJMoa1611310.
4. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL 2; Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9.