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44th Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / May 30-June 3, 2008

As reported by Dr. Richard Gralla, Chief of Hematology and Oncology, Vice President for Cancer Services, Monter Cancer Center, North Shore-Long Island Jewish Health System, Lake Success, New York, three important meta-analyses demonstrated both a response and survival advantage with cisplatin over carboplatin-based, third-generation regimens. At the same time, researchers have been unable to demonstrate significant quality-of-life benefits for carboplatin-based regimens over those containing cisplatin, even in patients with advanced stage IV malignancy. The toxicity profiles between the two platinum compounds are nevertheless different.

Results from one meta-analysis demonstrated that the risk of thrombocytopenia was 12% with carboplatin vs. 6% with cisplatin (P<0.01) (Ardizzoni et al. J Natl Cancer Inst 2007;99(11):847-57. The same meta-analysis also showed that cisplatin was associated with marginally (1%) more neuro- and nephrotoxicity than carboplatin. Conversely, cisplatin was associated with an 18% risk of emesis compared with an 8% risk with carboplatin, a difference which was also statistically significant (P<0.01).

In an effort to assess whether the use of modern anti-emetic regimens could reduce the risk of emesis associated with cisplatin to the same level as that with carboplatin, Dr. Gralla and colleagues undertook a meta-analysis of all published cisplatin-based, randomized phase III trials in which investigators randomized patients to the additional neurokinin 1 (NK1) receptor antagonist aprepitant, a serotonin antagonist and a corticosteroid vs. a serotonin antagonist and a corticosteroid. Key end points evaluated included acute and delayed vomiting control; overall five-day control of vomiting; acute and delayed nausea control; and overall five-day control of nausea. The group also undertook a subset analysis of all patients with non-small-cell lung cancer (NSCLC) to determine if the NK1 receptor antagonist also reduced the risk of emesis with cisplatin to reported levels for carboplatin.

Improving Anti-emetic Control in CINV

All patients were treated with a single dose of ondansetron 32 mg plus dexamethasone 12 mg or 20 mg on the day of cisplatin treatment, followed by dexamethasone 8 mg either once or twice daily on days 2, 3 and 4. Half of the patients were then randomized to receive aprepitant 125 mg on day 1 and 80 mg on days 2 and 3. In one study, patients who received the NK1 receptor antagonist also received ondansetron for delayed emesis on days 2, 3 and 4 in addition to dexamethasone. A total of 1527 patients were included in the analysis. For the purposes of study end points, acute period was defined as the initial 24 hours following initiation of the administration of cisplatin, while delayed period was defined as from 24 hours after administration of cisplatin until 120 hours later.

No significant nausea was the patient-determined score on a 100-mm visual analogue scale of <25 mm. The analysis showed that complete control of vomiting during the acute phase was over twice as likely to be achieved with the triple-drug regimen containing aprepitant compared to the ondansetron/dexamethasone arm (odds ratio [OR] 2.16, P<0.0001). This translated into an 11.3% absolute risk difference between the two regimens for complete control of vomiting during the acute period—“meaning that you only need to treat nine patients for one patient to benefit from the addition of aprepitant,” Dr. Gralla noted.

Complete control of delayed vomiting was even more significant with the addition of aprepitant, at an absolute risk difference of 18.1% in favour of the triple drug regimen (OR 2.55, P<0.0001), meaning that only six patients need to be treated with the NK1 receptor antagonist for one patient to achieve complete control of delayed vomiting. The addition of aprepitant to the standard anti-emetic regimen was also associated with a 22.2% absolute risk difference in control of vomiting across all five days of assessment (OR 2.38, P<0.0001), indicating that only five patients need to be treated with the compound in order for one to benefit from complete control of vomiting across all five days of assessment. “This effectively reduces the risk of emesis with cisplatin to the same risk of that with carboplatin and you only need to treat between five and nine patients before one patient benefits,” Dr. Gralla reaffirmed (Table 1).

Table 1. Control of vomiting from all studies, including all 1527 patients at various analysis periods

The effect of adding the NK1 receptor antagonist to a serotonin antagonist plus dexamethasone was somewhat less pronounced on indices of nausea, he added. Nevertheless, across all three studies involving 1527 patients, the addition of aprepitant to standard anti-emetic control was associated with an absolute risk difference in terms of patients experiencing no significant nausea either during the delayed period or across all five days of assessment by 9.9% and 9.1%, respectively—“still in the range of a 30% benefit for a reduction in nausea,” Dr. Gralla told delegates, “and if we combine all three trials, you come up with a P value of <0.05, so there is a significant benefit for nausea, but the magnitude of benefit is less for nausea than it is for vomiting because it is more difficult to control nausea than vomiting.” NSCLC Patients

Confining the analysis to the trial population consisting of only NSCLC patients (n=587), Dr. Gralla and colleagues found an even greater advantage for acute and delayed emesis control, as well as emesis control across all five days of assessment, when aprepitant was added to ondansetron and dexamethasone. In this subset of patients, the triple drug regimen was associated with an absolute risk difference of 9.5% for complete control of vomiting over the acute period (P=0.0008), a 19.2% absolute risk difference in complete control of delayed vomiting (P<0.0001) and a 19.6% absolute risk difference in complete control of vomiting across all five days of assessment (P<0.0001).

The numbers needed to treat for one NSCLC patient to benefit were 11, six and six for complete control of vomiting during the acute period; complete control of vomiting during the delay period; and complete control of vomiting across all five days of assessment. Control of nausea with additional aprepitant was less significant in the NSCLC subset, being associated with an absolute risk difference of 4.5% for no significant nausea during the acute period; a 5.2% absolute risk difference in no significant nausea during the delayed period; and a 3.8% absolute risk difference in no significant nausea across all five days of assessment, again suggesting that nausea is more difficult to control than vomiting regardless of the malignancy being treated with a cisplatin-based regimen.

Summary

According to Dr. Gralla, “The risk of all emesis is underestimated, but delayed emesis in particular.” Even for moderately emetogenic regimens such as adriamycin/cyclophosphamide, “the effect of treatment on emesis is almost the same as cisplatin, strangely enough,” Dr. Gralla observed, “so we have evidence here as well to say the use of the NK1 receptor antagonist is highly indicated.” Dr. Gralla also noted that the serotonin antagonists are valuable in helping control emesis during the acute period, but in his opinion, probably have little effect on the control of delayed emesis. In contrast, dexamethasone is effective in delayed emesis and it should be used for delayed emesis control as well, he added. “The bottom line is, if you want to use the most effective agent, you need good supportive care and in this case, the supportive care is simply taking an NK1 antagonist right from the outset,” Dr. Gralla concluded. “I believe the NK1 antagonists are highly effective in reducing vomiting and moderately effective in reducing nausea, and if you use this agent in addition to cisplatin, you can use the more effective agent without risk of emesis rather than use carboplatin.”