In this study, which included only a homogeneous patients group with NSCLC, in the triplet anti-emetic prophylactic treatment with aprepitant and dexamethasone of cisplatin-based HEC, there was no statistically significant difference between granisetron and palonosetron in terms of CR and TC in preventing acute and delayed emesis.
Palonosetron and granisetron in a triple anti-emetic combination were compared for the first time in a non-inferiority study by Tian et al. in 2011. Patients with lung, breast, colorectal, and gastric cancer who received moderate emetogenic chemotherapy (MEC) or HEC were included in this study. Of this study group, 54% consisted of patients who had not previously received chemotherapy, remainig 44% of patients had received. Patients who received palonosetron prophylactically in the first cycle received granisetron in the second cycle or vice versa. When 0.25 mg palonosetron and 3 mg granisetron were compared in patients who received both MEC and HEC, CR and TC rates were found to be similar in preventing acute and delayed emesis.
Four prospective studies that conducted only on breast cancer patients [8–10], along with our previous article published in 2019 , found no statistical difference between first and second-generation setrons in terms of both acute and delayed emesis control. In these studies, only one type of HEC regimen (anthracycline and cyclophosphamide-based chemo) has used. In the pilot study of Wenzel et al., palonosetron was compared with ondansetron and in three other studies with granisetron.[9–11]. Palonosetron was used at a dose of 0.75 mg in two studies [9–10] and 0.25 mg in the other two studies. [8, 11]
The randomized, single-blind study of Kimura et al. was performed in patients with bone or soft tissue sarcoma who received multiple-day of HEC. Three mg dose of granisetron twice daily for five days was compared with 0.75 mg palonosetron administered only on the first day in triplet anti-emetic prophylaxis. The acute phase CR rates were better in favor of palonosetron, but there was a numerical difference in favor of granisetron in the delayed and all phases. Also, the TC ratio was better in the palonosetron arm in the acute phase, but similar in the delayed phase. As a result of the study, the authors stated that there was no statistically significant difference between multi-day administration of granisetron and single-day palonosetron. They also underlined that triplet anti-emetic combinations provide very low TC (4.2% − 8.3%) in preventing emesis due to multi-day HEC applied in bone and soft tissue sarcoma compared to single-day HEC.
Suzuki et al.'s TRIPLE study, considered a corner stone in this field, was performed in patients receiving cisplatin-based HEC for lung, head and neck, upper gastrointestinal tract, and other different primary localized cancers. They compared 1 mg of granisetron with 0.75 mg of palonosetron. In this study, for the first time, delayed CR (59.1% vs. 67.2%, p = 0.0142) and TC (40.7% vs. 47.6%, p = 0.0369) rates showed statistical significance in favor of palonosetron. Acute CR rates were similar.
In a very recently published meta-analysis , the efficacy of palonosetron and granisetron in both dual and triplet anti-emetic combinations was compared in patients receiving MEC and HEC. According to this meta-analysis which including the five studies comparing triplet antiemetic therapy mentioned above, palonosetron and granisetron were equally effective in preventing acute CINV, whereas response rates of palonosetron in the delayed phase were slightly higher than granisetron. Unlike the two studies including breast cancer patients, three of the five studies in the meta-analysis [7, 12, 13] had some similar characteristics, which allowed for slightly better palonosetron results in the delayed period; In all three studies were including patients who received multiple-day of chemotherapy, and patients who have primary tumors of different localizations, and almost half of the patients had received prior chemotherapy particularly in the one study. Firstly, the definitions of acute and delayed emetic periods are even more ambiguous and intertwined in patients who receive multiple-day chemotherapy compared to those who receive single-day chemotherapy.  Secondly, the gastrointestinal tract is as sensitive to mechanical distension as chemotherapies, and these mechanical stimuli can cause 5-HT3 release and trigger vomiting. Therefore, evaluating patients with gastrointestinal system cancer together with patients with other primary cancers may affect the results of study. Thirdly, because of the anticipatory emesis in patients who have received previously chemotherapy and experienced nausea/vomiting, emetic evaluation may not yield beneficial results in subsequent chemotherapy cycles. In conclusion, the authors suggested that granisetron should be used in triple combination, since there was no significant difference between palonosetron and granisetron in HEC prophylaxis and it was more economical.
This meta-analysis also determined that palonosetron was better than granisetron in all phases of vomiting (but not only in the delayed period) in dual anti-emetic combination without NK-1 receptor inhibitors. A recent study compared the palonosetron and granisetron in dual combination with dexamethasone in patients with breast and lung cancer receiving HEC. In the palonosetron arm, blood serum serotonin levels were higher due to greater and longer duration of irreversible binding to 5-HT3 receptors, and palonosetron was better than granisetron in inhibiting both acute and delayed emesis. The significant reduction in the level of substance P due to the crosstalk of palonosetron with NK-1 receptors which has been demonstrated in preclinical studies, did not show clinical relevance in this study. The substance P level was found only numerically lower in the palonosetron arm than in the granisetron. The idea that palonosetron actually inhibits delayed emesis due to substance P reduction is controversial and suggests that other factors may be responsible for this effect.
Another critical point to keep in mind when comparing anti-emetic efficacy is that the pharmacodynamics as well as the pharmacokinetics of these drugs may differ.  All setrons except granisetron are metabolized in the liver by the CYP2D6 system. Because the CYP2D6 system shows frequent genetic polymorphism, the response to anti-emetic drugs may differ from individual to individual. In addition, although it is known that 5-HT4 receptors play an important role in the release of serotonin in the gastrointestinal tract, such as 5-HT3, its effect on CINV has not been sufficiently clarified yet. These and other unknown factors may explain the different results in studies comparing anti-emetics.
The most important limitations of our study are its non-randomized design and the application of the emesis assessment scale by different physicians in different centers. However, the strength of our study is that it consisted of a homogeneous patient group, and that patients who received chemotherapy for more than one day, had brain metastases, and were using opioid-derived drugs that could affect emetic measurement were excluded from the study.