Different treatment durations of loperamide in preventing pyrotinib-induced diarrhea: A randomized, parallel-group sub-study of the phase II PHAEDRA trial
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Curated by eLife
eLife assessment
This study presents a useful finding for the prevention of diarrhea with loperamide in patients with early HER2-positive breast cancer treated with nab-paclitaxel in combination with pyrotinib. The evidence supporting the claims of the authors is somewhat incomplete. The enrollment of patients as a control group who have not received prophylactic treatment for diarrhea would have strengthened the study, and the addition of double-blinding for the assessment of treatment may be necessary. The work will be of interest to scientists working in the field of clinical breast cancer treatment.
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Abstract
Pyrotinib, a pan-HER tyrosine kinase inhibitor, demonstrates efficacy in the treatment of HER2-positive breast cancer. However, the frequent occurrence of treatment-emergent diarrhea necessitating discontinuation, impacts patient outcomes.In this multicenter, open-label, phase II PHAEDRA study enrolling early stage HER2-positive patients for postoperative treatment with nab-paclitaxel and pyrotinib, 120 patients were included for a sub-study and randomly divided into two groups to receive 21 days and 42 days of loperamide for primary prophylaxis of diarrhea, followed by as-needed usage. The primary outcome was the incidence of grade ≥3 diarrhea.Fifty-eight patients in the 21-day group and 59 patients in the 42-day group received at least one dose of pyrotinib. With a median follow-up of 12.1 months, all patients experienced diarrhea of any grade, with grade ≥3 events in 39.7% of the 21-day group and 42.4% of the 42-day group (relative risk: 0.94; 95% confidence interval: 0.61-1.45). The most common treatment-emergent adverse events, other than diarrhea, were hypoesthesia, vomiting, nausea, and rash, mostly grade 1-2, except for one case of grade ≥3 decreased neutrophil count in each group.No significant differences were observed between 21-day and 42-day loperamide durations in preventing grade ≥3 diarrhea. Considering the economic cost and patient compliance, 21-day loperamide prophylaxis might represent a more pragmatic and appropriate approach for clinical application.ClinicalTrials.gov, NCT04659499
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eLife assessment
This study presents a useful finding for the prevention of diarrhea with loperamide in patients with early HER2-positive breast cancer treated with nab-paclitaxel in combination with pyrotinib. The evidence supporting the claims of the authors is somewhat incomplete. The enrollment of patients as a control group who have not received prophylactic treatment for diarrhea would have strengthened the study, and the addition of double-blinding for the assessment of treatment may be necessary. The work will be of interest to scientists working in the field of clinical breast cancer treatment.
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Reviewer #1 (Public Review):
Summary:
This manuscript described a clinical trial to understand the different treatment durations of loperamide in preventing pyrotinib-induced diarrhea. The authors concluded that no significant differences were observed between 21-day and 42-day loperamide durations in preventing grade {greater than or equal to} grade 3 diarrhea. The authors suggested that considering the economic cost and patient compliance, 21-day loperamide prophylaxis might represent a more pragmatic and appropriate approach for clinical application.
Strengths:
It is essential to understand if loperamide for primary prevention of diarrhea helps or not for postoperative treatment with nab-paclitaxel and pyrotinib in HER2-positive patients. This clinical trial would answer this question eventually.
Weaknesses:
(1) There are no patients …
Reviewer #1 (Public Review):
Summary:
This manuscript described a clinical trial to understand the different treatment durations of loperamide in preventing pyrotinib-induced diarrhea. The authors concluded that no significant differences were observed between 21-day and 42-day loperamide durations in preventing grade {greater than or equal to} grade 3 diarrhea. The authors suggested that considering the economic cost and patient compliance, 21-day loperamide prophylaxis might represent a more pragmatic and appropriate approach for clinical application.
Strengths:
It is essential to understand if loperamide for primary prevention of diarrhea helps or not for postoperative treatment with nab-paclitaxel and pyrotinib in HER2-positive patients. This clinical trial would answer this question eventually.
Weaknesses:
(1) There are no patients who have not received prophylactic treatment for diarrhea to serve as a control group. This limited the finding that if the loperamide for primary prevention of diarrhea benefits or not for postoperative treatment with nab-paclitaxel and pyrotinib in HER2-positive patients. This would not help much for the guidance of clinical use of the loperamide for primary prevention of diarrhea.
(2) The clinical trial needs double-blinding for evaluation of treatment. In this manuscript, the blinding was not employed.
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Reviewer #2 (Public Review):
Summary:
Pyrotinib, a pan-HER tyrosine kinase inhibitor, has shown significant survival benefits in patients with HER2-positive breast cancer. However, diarrhea is a frequent and important adverse event during pyrotinib treatment. Severe diarrhea may require interruption of pyrotinib treatment, thus affecting its anti-tumor effect and becoming a clinical safety issue. This study evaluated the incidence of diarrhea in patients with early-stage HER2-positive breast cancer treated with nab-paclitaxel and pyrotinib using 42- and 21-day loperamide primary prevention strategies. No significant differences were observed between the 21- and 42-day loperamide durations in the prevention of grade 3 and above diarrhea. Considering the economic cost and patient compliance, 21-day loperamide prophylaxis might represent a …
Reviewer #2 (Public Review):
Summary:
Pyrotinib, a pan-HER tyrosine kinase inhibitor, has shown significant survival benefits in patients with HER2-positive breast cancer. However, diarrhea is a frequent and important adverse event during pyrotinib treatment. Severe diarrhea may require interruption of pyrotinib treatment, thus affecting its anti-tumor effect and becoming a clinical safety issue. This study evaluated the incidence of diarrhea in patients with early-stage HER2-positive breast cancer treated with nab-paclitaxel and pyrotinib using 42- and 21-day loperamide primary prevention strategies. No significant differences were observed between the 21- and 42-day loperamide durations in the prevention of grade 3 and above diarrhea. Considering the economic cost and patient compliance, 21-day loperamide prophylaxis might represent a more pragmatic and appropriate approach for clinical application.
Strengths:
This study has a reasonable design, a clear hypothesis and methodology, and clear results, making the conclusion reliable. Most importantly, the findings have practical implications for the clinical management of pyrotinib-induced diarrhea.
Weaknesses:
Although the paper does have strengths in the practical implications for the clinical management of pyrotinib-induced diarrhea, there are still many data presentations that are not clear:
(1) The baseline characteristics mention that at the cut-off date on September 27, 2023, two patients withdrew from the 21-day group due to intolerable diarrhea and received other anti-tumor therapies for liposarcoma on the face. In the 42-day group, one patient was lost to follow-up and two withdrew from the study due to intolerable diarrhea and bone metastases. So, in the study, how many cases are in each group? The numbers of cases indicated in Figures 1 and 2 are inconsistent.
(2 ) Why does Figure 3a only compare 3 months of data, while Figure 3b compares 12 months of data?
(3) It is mentioned in lines 222-229 that a combination treatment of nab-paclitaxel plus pyrotinib is 1-3 months, whereas those of pyrotinib alone is 3-12 months. So, what is the exact duration of the combination treatment and pyrotinib alone treatment?
(4) This study found that no significant differences were observed between 21-day and 42-day loperamide durations in preventing grade 3 and above diarrhea. However, nab-paclitaxel can also cause diarrhea, and the conclusions would be more reliable if a control group that was not given loperamide were added. It is suggested that the authors add relevant data to further confirm the conclusion.
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