Prevention of Chemotherapy-Induced Nausea and Vomiting
Prevention of Chemotherapy-Induced Nausea and Vomiting
Two challenges currently exist regarding the emetogenicity classification of chemotherapy agents. The first is that a number of newer chemotherapeutic agents have not been evaluated for inclusion in this classification system (Table 4), and the second is that the current category of 'moderately emetogenic' is very broad, encompassing a risk of emesis ranging between 30% and 90%. Consequently, some patients may be receiving antiemetic agents that are not necessary while others would potentially benefit from agents (such as NK1RAs) and are not receiving them.
Before the 2004 Perugia Antiemetic Consensus Conference, there were five levels of antiemetic classification: <10%, 10%–30%, 30%–60%, 60%–90%, and >90%, with the 30%–60% range considered moderately emetogenic. After the 2004 Perugia conference, this classification was changed to four levels by MASCC and ASCO by combining the prior level 3 (30%–60%) and level 4 (60%–90%) into a single group of 30%–90%. The change was made because clinical differentiation between the groups had become difficult with the introduction of new antiemetic agents. However, this broad range of agents makes it difficult to give one recommendation for antiemetic treatment appropriate for the entire range (Table 5). In addition, this broad MEC classification may be a reason for the inconclusive findings in some clinical trials. Consideration could be given to revisiting and redefining the MEC classification system into five categories or to examining data from individual chemotherapeutic agents to identify those patients most likely to benefit from additional antiemetic prophylaxis with an NK1RA.
While carboplatin is classified as a MEC agent by guideline committees, the incidence rates of adverse events of 'nausea and vomiting' reported in two pivotal ovarian trials both in combination with cyclophosphamide resulting in the approval of carboplatin were 93% and 94% (versus 98% and 96% for cisplatin, P = 0.01 and NS, respectively). Vomiting rates were 84% for carboplatin versus 97% for cisplatin (P < 0.001) in one study and 82% versus 91% (P = 0.007), respectively, in the other study. As these studies were conducted before the approval of the 5-HT3RAs, MCP, diphenhydramine, prochlorperazine, and DEX were used for antiemetic prophylaxis. Therefore, these incidence rates of nausea and vomiting are likely an approximate representation of the emetogenic potential of carboplatin.
Considering that the emetic risk of carboplatin may be underestimated and patients may require more antiemetic prophylaxis than they are receiving, Gralla reported a post hoc subgroup analysis from a study by Rapoport which had evaluated the efficacy of an aprepitant regimen with a range of MEC regimens (Table 6). In patients receiving carboplatin, no emesis rates were 84% for the aprepitant group versus 70% for the 5-HT3RA/DEX control. A similar no emesis rate (83%) was seen for NEPA in a carboplatin subgroup (n = 149) in one of the pivotal trials.
Additional studies have been conducted recently evaluating the benefit of the NK1RA regimen in patients receiving carboplatin-based chemotherapy. In these trials, the incremental benefit of the NK1RA triplet regimen over a 5-HT3RA + DEX ranges from 10% to 15% (Table 6).
It is noteworthy that, even with a prophylactic triplet regimen, the response rates in these studies ranged from 62% to 84%, offering confirmation that the emetogenic potential of carboplatin is at the higher end of MEC.
Results await for the subset data from the rolapitant MEC trial where 400 patients received carboplatin and from the large (n = 1000) study of fosaprepitant in patients receiving a variety of MEC agents, excluding AC, (www.clinicaltrials.gov; https://clinicaltrials.gov/ct2/show/NCT01594749?Term=fosaprepitant&rank=24).
In light of the above, it may be appropriate to consider modification of the guideline recommendations to add an NK1RA to the 5-HT3RA/DEX prophylactic regimen in patients receiving carboplatin.
Revisiting the Emetogenicity Classification of Chemotherapeutic Agents
Two challenges currently exist regarding the emetogenicity classification of chemotherapy agents. The first is that a number of newer chemotherapeutic agents have not been evaluated for inclusion in this classification system (Table 4), and the second is that the current category of 'moderately emetogenic' is very broad, encompassing a risk of emesis ranging between 30% and 90%. Consequently, some patients may be receiving antiemetic agents that are not necessary while others would potentially benefit from agents (such as NK1RAs) and are not receiving them.
Before the 2004 Perugia Antiemetic Consensus Conference, there were five levels of antiemetic classification: <10%, 10%–30%, 30%–60%, 60%–90%, and >90%, with the 30%–60% range considered moderately emetogenic. After the 2004 Perugia conference, this classification was changed to four levels by MASCC and ASCO by combining the prior level 3 (30%–60%) and level 4 (60%–90%) into a single group of 30%–90%. The change was made because clinical differentiation between the groups had become difficult with the introduction of new antiemetic agents. However, this broad range of agents makes it difficult to give one recommendation for antiemetic treatment appropriate for the entire range (Table 5). In addition, this broad MEC classification may be a reason for the inconclusive findings in some clinical trials. Consideration could be given to revisiting and redefining the MEC classification system into five categories or to examining data from individual chemotherapeutic agents to identify those patients most likely to benefit from additional antiemetic prophylaxis with an NK1RA.
Carboplatin
While carboplatin is classified as a MEC agent by guideline committees, the incidence rates of adverse events of 'nausea and vomiting' reported in two pivotal ovarian trials both in combination with cyclophosphamide resulting in the approval of carboplatin were 93% and 94% (versus 98% and 96% for cisplatin, P = 0.01 and NS, respectively). Vomiting rates were 84% for carboplatin versus 97% for cisplatin (P < 0.001) in one study and 82% versus 91% (P = 0.007), respectively, in the other study. As these studies were conducted before the approval of the 5-HT3RAs, MCP, diphenhydramine, prochlorperazine, and DEX were used for antiemetic prophylaxis. Therefore, these incidence rates of nausea and vomiting are likely an approximate representation of the emetogenic potential of carboplatin.
Considering that the emetic risk of carboplatin may be underestimated and patients may require more antiemetic prophylaxis than they are receiving, Gralla reported a post hoc subgroup analysis from a study by Rapoport which had evaluated the efficacy of an aprepitant regimen with a range of MEC regimens (Table 6). In patients receiving carboplatin, no emesis rates were 84% for the aprepitant group versus 70% for the 5-HT3RA/DEX control. A similar no emesis rate (83%) was seen for NEPA in a carboplatin subgroup (n = 149) in one of the pivotal trials.
Additional studies have been conducted recently evaluating the benefit of the NK1RA regimen in patients receiving carboplatin-based chemotherapy. In these trials, the incremental benefit of the NK1RA triplet regimen over a 5-HT3RA + DEX ranges from 10% to 15% (Table 6).
It is noteworthy that, even with a prophylactic triplet regimen, the response rates in these studies ranged from 62% to 84%, offering confirmation that the emetogenic potential of carboplatin is at the higher end of MEC.
Results await for the subset data from the rolapitant MEC trial where 400 patients received carboplatin and from the large (n = 1000) study of fosaprepitant in patients receiving a variety of MEC agents, excluding AC, (www.clinicaltrials.gov; https://clinicaltrials.gov/ct2/show/NCT01594749?Term=fosaprepitant&rank=24).
In light of the above, it may be appropriate to consider modification of the guideline recommendations to add an NK1RA to the 5-HT3RA/DEX prophylactic regimen in patients receiving carboplatin.