Background
Field of cancer supportive care is rapidly evolving and number of anti-emetic agents
has been approved and added to treatment arsenal in the past two decades. Not unexpectedly,
in a worldwide online survey (ASCO 2014), antiemetics were voted among the “Top 5
advances in 50 years of modern oncology.”[1] Combination regimen are current standard of care, targeting the polypharmacology
of chemotherapy-induced nasua and vomiting (CINV), especially in highly emetogenic
chemotherapy regimen (HEC). However, polypharmacy has potential for additive side
effects and may not be cost effective. Indeed, one has to focus on strategies, so
to achieve the best with the least.
Olanzapine “Four Drug Arm Trial”
Olanzapine “Four Drug Arm Trial”
Last year, a landmark study was published in New England Journal of Medicine by Navari
et al., where the author in a Phase III, randomized, multicenter, double-blind placebo
controlled trial enrolling a total of 380 patients receiving high emetogenic risk
chemotherapy demonstrated the benefit of adding olanzapine (OLN) over and above the
three drug standard anti-emetic regimen-NK 1 receptor antagonist, a 5-hydroxytryptamine
type 3 antagonist (5-HT3), and dexamethasone (Dex).[2] Patients were stratified on following factors: type of chemotherapy regimen, sex,
and type of 5-HT3 antagonist used. Standard regimen included 5-HT3 antagonist (either
0.25 mg of intravenous palonosteron (PAL), 2 mg oral or 1 mg intravenous granisetron,
or 8 mg of oral or intravenous ondansetron), Dex (12 mg on day 1 followed by 8 mg
from day 2 to 4) and NK 1 receptor antagonists on day 1. Primary end point was no
nausea, defined as zero on the visual analogous scale for nausea during the overall
(0–120 h), early (0–24 h) and late (24–120 h) assessment periods. Secondary end point
was defined as complete response (CR) rate (no emesis and no use of rescue medication)
over the overall, early, and late periods. The two arms were well balanced with majority
being breast cancer (60%).
Trial met the primary end point with “no nausea” control rate between the two arms
were, over the overall period (0–120 h: 37% vs. 22%, P = 0.002), late period (24–120 h: 42% vs. 25%, P = 0.002), and early period (0–24 h: 74% vs. 45%, P = 0.002), respectively. It also showed benefit with respect to secondary end points
with complete response rate over the overall period (0–120 h: 64% vs. 41%, P = 0.001), late period (24–120 h: 67% vs. 52%, P = 0.007), and early period (0–24 h: 86% vs. 65%, P = 0.001), respectively.
Comments and Critical Analysis
Comments and Critical Analysis
Before considering four drug regimen a Holy Grail, especially for the countries of
limited resources, there are few pertinent points we would like to underscore. In
previous randomized trial by Navari et al., OPD “OLN, PAL, DEX” was compared to APD “APR, PAL, DEX” regimen, the CR was 97%
versus 87%, 77% versus 73%, 77% versus 73% for acute, delayed and overall period,
respectively, and did not differ, although the figure favored OLN arm. Nausea control
rate were 87% versus 87%, 69% versus 38%, and 69% versus 38%, respectively.[2],[3] Thus, there was significantly more nausea control rate in OPD arm during delayed
and overall period as compared to APD arm. These findings are tempting, and suggest
that given the superior activity of OLN compared to aprepitant. This leads us to think
intuitively that it would be fairer to compare four drug regimens with OPD and not
APD (as OPD might be more active among the two and probably more cost effective).
Second, CR for nausea in the standard three drug arm (NK1 plus Dex plus 5HT3) compared
to previous trial by same author (with similar population, disease types, and chemotherapies)
in first 24 h, 0–120 h and overall 120 h was 45% versus 87%, 25% versus 38% and 22%
versus 38%, respectively.[2],[3] Although cross trial comparison is not advocated; however, the noticed significant
variability is a valuable concern, need questioning. The possible reason could be
that in the current trial about one-fourth patients received granisetron/ondansetron,
in contrast to PAL only in previous one. PAL is novel second generation 5-HT3 antagonist
and shares different pharmacokinetic and pharmacodynamic properties. It has significantly
higher affinity for the 5-HT3 receptor causing conformational changes and has shown
better control of CINV during overall period.[4] Other reason might be that the adherence to oral treatment like medications was
not good as is a well-known phenomenon with antiemetic and might aggravate with increase
in medications.
Third, the role of NK1 antagonists is well documented with cisplatin, but has been
challenged in patients receiving HEC containing anthracycline and cyclophosphamide
(AC).[5],[6] Studies suggesting the beneficial role of NK1 antagonist with AC regimen has used
sub optimal comparator arm.
Finally, in the era of personalized therapy, we need to screen out the sub group benefitted
most from the addition of OLN. We should be on the lookout for biomarkers that guide
the therapy for a given patient.
Conclusions and Future Directions
Conclusions and Future Directions
With the availability of more and more drugs and combination regimen, there is increasing
challenge to choose between them wisely. Even with four drug regimen, there is huge
gap in the required and actual outcome (“no nausea” control rate during overall period,
37% only [2]) and answer to fulfill the gap might not lie in adding more drugs. Role of OLN based
tripe drug anti emetic should be explored in more details, being cheap, and more effective.
Simultaneously, the role of NK 1 antagonist, especially in breast cancer patients,
need to be challenged in the presence of OLN, given the doubtful role and relative
high cost. It would also be prudent to use similar end points and uniform 5 HT3 antagonists
in different antiemetic trials so as to minimize heterogeneity and encourage comparability.
