3. FLOT Regimen Characteristic from Emetogenic Potential Aspect:
In order to explore the emetogenic potential of the FLOT regimen (secondary objective of the current study), we compared “CR”, “no emesis” and “CP” rates in acute, delayed, and overall phases among FLOT and each of FOLFOX and TAC groups. The frequency and proportion of the patients achieving each endpoint are shown in Table 2.
Table 2
Frequency and Proportion of the Patients, Achieving Each Efficacy Endpoint
Efficacy Endpoint | FOLFOX (N=50) n (%) | FLOT (N=52) n (%) | TAC (N=63) n (%) |
Acute Phase | | | |
No Emesis | 49 (98.0) | 46 (88.5) | 58 (92.1) |
Complete Response | 48 (96.0) | 44 (84.6) | 54 (85.7) |
Complete Protection | 48 (96.0) | 44 (84.6) | 52 (82.5) |
Delayed Phase | | | |
No Emesis | 46 (92.0) | 38 (73.1) | 45 (71.4) |
Complete Response | 42 (84.0) | 33 (63.5) | 35 (55.6) |
Complete Protection | 40 (80.0) | 29 (55.8) | 31 (49.2) |
Overall Phase | | | |
No Emesis | 45 (90.0) | 37 (71.2) | 43 (68.3) |
Complete Response | 41 (82.0) | 32 (61.5) | 33 (52.4) |
Complete Protection | 39 (78.0) | 28 (53.8) | 27 (42.9) |
Comparison among FLOT and each of FOLFOX and TAC groups, concerning endpoint-achieving rates, was performed using logistic regression to adjust for covariates. As shown in Table S1. (Online Resource 1, which presents the odds of achieving each endpoint; adjusted for covariates), the odds ratios indicate the significant difference among FLOT and FOLFOX regimens and non-significant difference among FLOT and TAC in relation to the rates of “CR”, “no emesis” and “CP” in the delayed and overall phases, also “CP” in the acute phase. The difference is significant among FLOT and FOLFOX, also, FLOT and TAC concerning “CR” and “no emesis”, in the acute phase. To explain in detail:
The odds of the FOLFOX recipients achieving “CR” in the overall phase is 3.145 times as high as the odds of FLOT recipients (95%C.I.: 1.232-8.025, p=0.017) while the odds of TAC recipients is only 1.006 times as high as the odds of FLOT recipients (95%C.I.: 0.446-2.271, p=0.989). Since the patients in the FOLFOX group are 3.398 times more likely to achieve “CR” in the delayed phase (95% C.I.: 1.284-8.990, p=0.014), patients in the TAC group are only 1.099 times (95%C.I.: 0.480-2.519, p=0.823) more likely than FLOT group.
The odds of achieving “no emesis” in the overall phase is 365.8% higher if the patients are receiving FOLFOX (OR=4.658, C.I.: 1.455-14.910, p=0.010) as opposed to the ones receiving FLOT. The odds for achieving this endpoint is 89.6% higher if the patient is planned to receive TAC (OR=1.896, C.I.: 0.671-5.361, p=0.228) as opposed to the patients in the FLOT group. While individuals in the FOLFOX group show more than 300% increase in the odds of achieving “no emesis” in the delayed phase (OR=4.237, C.I.: 1.287-13.946, p=0.018), the ones in the TAC group show only a 7.9% decrease (OR=0.921, C.I.: 0.405-2.094, p=0.844) in comparison to patients in FLOT group.
In comparison to FLOT recipients, the odds of achieving “CP” in the overall phase is 3.784 and 2.354 times greater for FOLFOX (C.I.: 1.459-9.816, p=0.006) and TAC (C.I.: 0.782-7.088, p=0.128) patients, respectively. The FOLFOX recipients’ odds of achieving “CP” in the delayed phase is approximately three and a half fold greater (OR=3.428, C.I.: 1.355-8.669, p=0.009) than the FLOT recipients’ odds and TAC recipients’ odds is more than one and a half fold higher (OR=1.672, C.I.: 0.674-4.149, p=0.267) than FLOT recipients’ odds.
While antineoplastic regimen is the only significantly associated factor (multivariable logistic regression) with “no emesis” in the delayed phase, antineoplastic regimen and sex are both the statistically significant associated ones with “no emesis” in acute and overall phases, also “CR” and “CP” in the acute phase. Antineoplastic regimen and CINV expectation are statistically significant predictive factors for “CR” not only in the delayed phase but also in the overall phase.
Antineoplastic regimen, age, and CINV expectation are significantly associated with “CP” in the delayed phase, and antineoplastic regimen, age, and sex are the significant predictive factors for “CP” in the overall phase.
As mentioned earlier, the history of pregnancy-associated emesis was explored only in 55.15% (91/165) of the patients who had pregnancy experience and it was statistically significant in the univariable analysis only for “CR” in delayed and overall phases. Hence, multivariable logistic regression (Backward-Wald’s test) was performed again on these endpoints including all previously recognized significant predictive factors (p-value<0.2 in univariable analysis except sex) and history of pregnancy-associated emesis. The outcome clarifies that the FOLFOX recipients’ odds of achieving “CR” in the delayed phase is more than seven and a half fold greater (OR=7.723, C.I.: 1.474-40.454, p=0.016) than the FLOT recipients’ odds and TAC recipients’ odds is two folds higher (OR=2.035, C.I.: 0.598-6.924, p=0.256) than FLOT recipients’ odds. In comparison to FLOT recipients, the odds of achieving “CR” in the overall phase is 8.829 and 3.225 times greater for FOLFOX (C.I.: 1.702-45.812, p=0.010) and TAC (C.I.: 0.856-12.149, p=0.084) patients, respectively. Significant predictive factors are as follows: “CR”-delayed phase: CINV expectation, “CR”-overall phase: antineoplastic regimen, history of pregnancy-associated emesis, and CINV expectation.
Time-to-antiemetic prophylaxis failure (vomiting, retching, or great/severe nausea occurrence) was analyzed using Cox proportional hazards regression, adjusting for sex, age, CINV expectation, antineoplastic regimen, and stage of cancer. The results reveal that while the rate of failure in the FLOT group is 2.63 times as fast as the rate in the FOLFOX group (HR(FOLFOX/FLOT)=0.380, C.I.: 0.172-0.842, p=0.017), the rate of failure is 1.38 times as fast as the rate in TAC group (HR(TAC/FLOT)=0.724, C.I.: 0.365-1.439, p=0.357), denoting the significant difference among FLOT and FOLFOX regimens and non-significant difference among FLOT and TAC regimens Fig. 2.
This analysis was performed for the second time, in 55.15% (91/165) of the patients with pregnancy experience, to adjust not only for age, CINV expectation, antineoplastic regimen, and stage of cancer but also, for the history of pregnancy-associated emesis (as it was a significant factor in the univariable analysis of “CR”-overall phase). The results indicate that the failure rate in the FLOT group is 3.650 and 1.580 times as fast as the rate of failure in FOLFOX (HR(FOLFOX/FLOT)=0.274, C.I.: 0.084-0.887, p=0.031) and TAC (HR(TAC/FLOT)=0.633, C.I.: 0.305-1.314, p=0.220) groups, respectively.
The significant difference among FLOT and FOLFOX and insignificant difference among FLOT and TAC was repeated when Cox proportional hazards regression was also used for time-to-first emetic episode analysis, adjusting for sex, age, antineoplastic regimen, and stage of cancer. The outcome reveals that in FLOT recipients, emesis occurred more than three and a half fold as fast as emesis occurrence in patients receiving FOLFOX (HR(FOLFOX/FLOT)=0.268, C.I.: 0.096-0.746, p=0.012) and more than one and a half fold as fast as emesis occurrence in TAC recipients (HR(TAC/FLOT)=0.575, C.I.: 0.258-1.283, p=0.177) Fig. 3. In addition, in female patients, emesis occurred faster than the male patients (HR(male/female)=0.338, C.I.: 0.138-0.824, p=0.017). Also, as reported previously [19], most of the patients who showed emesis, started vomiting and/or retching within the first three days.
Kruskal-Wallis test was performed to compare the number of emetic episodes among groups and assisted in achieving the secondary objective of the current study. As shown in Table 3, the difference between the number of emetic episodes is statistically significant in the delayed (p=0.012) and overall (p=0.011) phases and pairwise comparison revealed that FOLFOX is the different regimen. In the acute phase, the number of emetic episodes is not significantly different among groups (p=0.161).
Table 3
Comparison of the Number of Emetic Episodes Among the Regimen Groups in Different Phases
CINV Evaluation Phase | Kruskal-Wallis Test (p-value) | Pairwise Comparison of Antineoplastic Regimens |
Regimens | Sig. | Adj. Sig. (Bonferroni Correction) |
Acute Phase | 0.161 | - | - | - |
Delayed Phase | 0.012 | FOLFOX-FLOT | 0.012 | 0.036 |
FLOT-TAC | 0.960 | 1.000 |
FOLFOX-TAC | 0.007 | 0.022 |
Overall Phase | 0.011 | FOLFOX-FLOT | 0.010 | 0.030 |
FLOT-TAC | 0.997 | 1.000 |
FOLFOX-TAC | 0.007 | 0.021 |