Thrombopoietin receptor agonists for prevention and treatment of chemotherapy-induced thrombocytopenia in patients with solid tumours

Background

Chemotherapy-induced thrombocytopenia (CIT) is a platelet count less than 100×109/L with or without bleeding in cancer patients receiving chemotherapy. CIT carries the risk of sub-optimal overall survival and bleeding.

Thrombopoietin receptor agonists (TPO-RAs) may be used to:

(1) prevent CIT in patients with normal platelet count before chemotherapy, (2) prevent recurrence of CIT, and (3) treat CIT in patients with low platelet count during chemotherapy.

Review questions

With this review we aimed to find out whether TPO-RAs (i.e. eltrombopag and romiplostim) can prevent or treat CIT in patients with solid tumours.

Study characteristics

We searched Cochrane Central Register of Controlled Trials, MEDLINE, online registries of ongoing trials, and conference proceedings. The evidence is current to September 2017. We found six trials eligible for inclusion, of which two are still ongoing, and one awaiting classification study. We included 268 adult and elder participants (no children were included).

Two studies compared eltrombopag with placebo for patients with normal platelet counts before chemotherapy (to prevent CIT). One study compared romiplostim with placebo for patients with low platelet counts during chemotherapy (to prevent recurrence of CIT). All of the studies were funded by the drug manufacturers.

Key results

To prevent CIT, the review shows that when patients (206 participants) with normal platelet count before chemotherapy are given eltrombopag (multiple-dose oral administration with chemotherapy), compared to placebo:

- the use of TPO-RAs may make little or no difference to the all-cause mortality (low quality of evidence);

- there is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (very low quality of evidence);

- there is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (very low quality of evidence);

- no studies were found that looked at overall survival, the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life.

To prevent recurrence of CIT, the review shows that when patients (62 participants) with low platelet counts during a chemotherapy cycle are given romiplostim (single-dose subcutaneous administration with chemotherapy), compared to placebo:

- there is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (very low quality of evidence);

- there is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (very low quality of evidence);

- no studies were found that looked at overall survival, the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life.

We found one ongoing study (expected recruitment 74 participants), planning to give romiplostim (subcutaneous administration with chemotherapy) to participants. As yet, there are no reported outcomes.

To treat CIT, one ongoing study (expected recruitment 83 participants) planned to give eltrombopag (seven days orally) to participants when their platelet counts are less than 75×109/L during chemotherapy. Its completion date (March 2017) has passed and no results have been reported.

One study awaiting classification included patients with normal platelet counts before chemotherapy (to prevent CIT), patients with low platelet counts during chemotherapy (to prevent recurrence of CIT), and others (uncertain whether CIT had happened). There was no evidence for a difference in the number and severity of bleeding episodes. This study did not address overall survival or quality of life.

Quality of the evidence

There is low and very low quality evidence for the use of TPO-RAs to prevent CIT or prevent recurrence of CIT in patients with solid tumours.

Conclusion

No certain conclusions can be drawn due to the lack of strong evidence in the review. The available weak evidence did not support the use of TPO-RAs for preventing CIT or preventing recurrence of CIT in patients with solid tumours. No completed studies looked at the use of TPO-RAs for treating CIT in patients with solid tumours.

Authors' conclusions: 

No certain conclusions can be drawn due to the lack of strong evidence in the review. The available weak evidence did not support the use of TPO-RAs for preventing CIT or preventing recurrence of CIT in patients with solid tumours. There was no evidence to support the use of TPO-RAs for treating CIT in patients with solid tumours.

Read the full abstract...
Background: 

Chemotherapy-induced thrombocytopenia (CIT) is defined as a peripheral platelet count less than 100×109/L, with or without bleeding in cancer patients receiving myelosuppressive chemotherapy. CIT is a significant medical problem during chemotherapy, and it carries the risk of sub-optimal overall survival and bleeding. Alternative interventions to platelet transfusion are limited. Different stages of preclinical and clinical studies have examined the thrombopoietin receptor agonists (TPO-RAs) for CIT in patients with solid tumours.

Objectives: 

To assess the effects of TPO-RAs to prevent and treat CIT in patients with solid tumours:

(1) to prevent CIT in patients without thrombocytopenia before chemotherapy, (2) to prevent recurrence of CIT, and (3) to treat CIT in patients with thrombocytopenia during chemotherapy.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, to 28 September 2017), MEDLINE (from 1950 to 28 September 2017), as well as online registers of ongoing trials (Clinical Trials, Chinese Clinical Trial Register, Australian New Zealand Clinical Trial Registry, WHO ICTRP Search Portal, International Standard Randomised Controlled Trial Number registry, GlaxoSmithKline Clinical Study Register, and Amgen Clinical Trials) and conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, European Society of Medical Oncology, and Conference Proceedings Citation Index-Science, from 2002 up to September 2017) for studies.

Selection criteria: 

Randomised controlled trials (RCTs) comparing TPO-RAs alone, or in combination with other drugs, to placebo, no treatment, other drugs, or another TPO-RAs for CIT in patients with solid tumours.

Data collection and analysis: 

Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard methodological methods expected by Cochrane.

Main results: 

We identified six trials eligible for inclusion, of which two are ongoing, and one awaiting classification study. The three included trials were conducted at many different sites in Europe, America, and Asia. All of the three studies recruited adult and elder participants (no children were included) with solid tumours, and compared TPO-RAs with placebo. No studies compared TPO-RAs alone, or in combination with other drugs, to no treatment, or other drugs, or another TPO-RAs.

We judged the overall risk of bias as high as we found a high risk for detection bias. We assessed the risk of bias arising from inadequate blinding of outcome assessors as high for number and severity of bleeding episodes (one of the primary outcomes).

To prevent CIT: We included two trials (206 participants) comparing TPO-RAs (eltrombopag, multiple-dose oral administration with chemotherapy) with placebo. The use of TPO-RAs may make little or no difference to the all-cause mortality at 33 weeks of follow-up (RR 1.35, 95% CI 0.53 to 3.45; one trial, 26 participants; low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 0.62, 95% CI 0.22 to 1.78; two trials, 206 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (RR 0.36, 95% CI 0.06 to 2.06; two trials, 206 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life.

To prevent recurrence of CIT: We included one trial (62 participants) comparing TPO-RAs (romiplostim, single-dose subcutaneous administration with chemotherapy) with placebo. There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 2.80, 95% CI 0.17 to 47.53; one trial, 62 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (no severe/life-threatening bleeding episodes; one trial, 62 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life. We found one ongoing study (expected recruitment 74 participants), it is planned to give TPO-RAs (romiplostim, subcutaneous administration with chemotherapy) to participants, but to date this trial has not reported any outcomes.

To treat CIT: We found one ongoing study (expected recruitment 83 participants), which is planned to give TPO-RAs (eltrombopag, seven days orally) to participants when their platelet counts are less than 75×109/L during chemotherapy. This trial was originally planned to complete in March 2017, however, the completion date has passed and no results are reported.

The one awaiting classification study included patients without thrombocytopenia before chemotherapy (to prevent CIT), patients with thrombocytopenia during chemotherapy (to prevent recurrence of CIT), and other patients during chemotherapy (uncertain whether CIT had happened). There was no evidence for a difference in the number of patients with at least one bleeding episode of any severity (RR 0.27, 95% CI 0.07 to 1.02; one trial, 75 participants). There was no evidence for a difference in the number of patients with at least one severe/life-threatening bleeding episode (RR 0.44, 95% CI 0.03 to 6.77; one trial, 75 participants). This study did not address overall survival or quality of life.

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