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Feasibility of using a pragmatic trials model to compare two primary febrile neutropenia prophylaxis regimens (ciprofloxacin versus G-CSF) in patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer (REaCT-TC)

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Abstract

Purpose

Optimal primary febrile neutropenia (FN) prophylaxis (i.e. ciprofloxacin or granulocyte-colony stimulating factors [G-CSF]) for patients receiving docetaxel-cyclophosphamide (TC) chemotherapy is unknown. We assessed the feasibility of using a novel pragmatic comparative effectiveness trial to compare these standard-of-care options.

Methods

Early-stage breast cancer patients receiving TC chemotherapy were randomised to either ciprofloxacin or G-CSF. Trial methodology consists of broad eligibility criteria, simply-defined endpoints, integrated consent model incorporating oral consent, and web-based randomisation in the clinic. Primary feasibility endpoints included patient and physician engagement (if > 50% of patients approached agree to participate and if > 50% of physicians approached patients for the study). Secondary clinical endpoints included the following: first occurrence rates of FN, treatment-related hospitalisation, or chemotherapy dose reduction/delay/discontinuation, as well as patient satisfaction with the oral consent process.

Results

Of 204 patients approached, 91.2% (186/204) agreed to randomisation. Sixteen of twenty (80%) participating medical oncologists randomised patients. Median patient age was 57.7 (range 31.8–84.1). The 186 patients received 557 cycles of chemotherapy. Overall incidences of first events by patient (n = 186) were as follows: FN (18/186, 21.43%), treatment-related hospitalisation (11/186, 13.10%), chemotherapy reduction (19/186, 22.62%), chemotherapy discontinuation (16/186, 19.05%), and chemotherapy delays (5/186, 5.95%). A total of 37.77% (69/186) of patients and 12.39% (69/557) of chemotherapy cycles had at least one of these first events. Patients were highly satisfied with the oral consent process.

Conclusion

This study met its feasibility endpoints. This model offers a means of comparing standard-of-care treatments in a practical and cost-efficient manner.

Trial registration

Trial registration: ClinicalTrials.gov: NCT02173262

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Acknowledgements

We are grateful for patients and their families for their assistance with this study, as well as physicians for approaching patients. Highest accrual by physician was as follows: Clemons (95), Hilton (27), Joy (11), Tonkin (10), Price-Hiller (8), Zhu (6), and Verma (5).

Funding

Funding for this study was from the Department of Medicine’s Patient Quality and Safety Committee PQ&I Project Grant and matched funding from the Division of Medical Oncology.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Medical Oncology, The Ottawa Hospital Cancer Centre, The University of Ottawa, Ottawa, Canada

    Mark Clemons, John Hilton, Shailendra Verma, Anne Kehoe & Mohammed FK Ibrahim

  2. Cancer Research Program, The Ottawa Hospital Research Institute, Ottawa, Canada

    Mark Clemons, Sasha Mazzarello, John Hilton, Marta Sienkiewicz, Carol Stober & Lisa Vandermeer

  3. Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada

    Mark Clemons, Brian Hutton, Ranjeeta Mallick & Dean Fergusson

  4. Division of Medical Oncology, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada

    Anil Joy, Julie Price-Hiller & Xiaofu Zhu

Authors
  1. Mark Clemons
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  2. Sasha Mazzarello
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  4. Anil Joy
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  7. Shailendra Verma
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Corresponding author

Correspondence to Mark Clemons.

Ethics declarations

Conflict of interest

BH consults for Cornerstore Research. All other authors have nothing to disclose.

Research involving human participants

The study was approved by the local Research Ethics Board at each participating centre (The Ottawa Health Science Network Research Ethics Board and Health Research Ethics Board of Alberta).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Appendices

Appendix 1. Consent script

Multi-centre study to determine the feasibility of using an integrated consent model to compare two standard-of-care regimens for primary prophylaxis of taxotere/cyclophosphamide-induced febrile neutropenia

REaCT-TC OTT 14-03

“Our discussion today is a new approach to informing and consenting patients to participate in this study. The traditional approach is to provide a paper copy of the detailed information sheet and consent form for you to sign. Using this integrated model for consenting we will have a discussion and you may give a verbal consent to participate or not to participate. I will document our discussion and your decision in your progress notes that are part of your health records.

As we’ve talked about, you will be receiving four cycles of taxotere and cyclophosphamide chemotherapy for your breast cancer. Because this chemotherapy can cause low white cell counts, it increases your risk of infections. We therefore give patients medications to reduce the chance of this happening. I can treat you with either a drug called G-CSF or a drug called ciprofloxacin. GCSF and Ciprofloxacin have considerably different costs that ultimately impact our health care system. They’re both approved by Health Canada and I commonly use either one of them in patients to reduce the chance of infections with chemotherapy. G-CSF is given as a daily injection at home during the 4 cycles and ciprofloxacin is a tablet that you take twice a day at home starting 5 days after chemotherapy for 14 days of each of the 4 cyclesThey can both have side effects that are potentially mild and are significantly less than those that the chemotherapy causes. There are no common side effects of taking G-CSF however a less common side effect could be brief pain at the injection site and sometimes muscle aches. The most common side effect of Ciprofloxacin is diarrhea which can be easily treated with anti-diarrhea medication. Because we really don’t know if one is better than the other, some of the Oncologists at The Ottawa Hospital Cancer Centre (TOHCC) are doing this study by randomly (like a flip of a coin, so that we can obtain an unbiased answer) giving participants one or the other drug and then comparing results over a period of 1 year. We are also looking at how feasible it is for study doctors to enter participants on this study using this integrated consent model. If you choose to participate there won’t be any special procedures or visits and you will receive a copy of this document for your reference.

If you do participate and decide to stop your participation in the study you may do so and we can discuss together how to proceed, likely this would mean switching to the other drug that was not assigned to you.

At the end of the study, there will be a satisfaction survey for you to complete.

Your participation in this study is voluntary. If you choose not to participate, your decision will not affect the care you receive at this institution at this time, or in the future. You will not have any penalty or loss of benefits to which you are otherwise entitled to.

All research-related records will be kept for 10 years after termination of the study. No identifiable information will leave this institution. The study sponsor Dr. Clemons located at TOHCC, The Ottawa Hospital Science Network Research Ethics Board (OHSN-REB) and the Ottawa Hospital Research Institute may review your relevant study records for audit purposes.

If you have any questions about this study please refer to your list of contact numbers to reach me. The OHSN-REB has reviewed this protocol. The Board considers the ethical aspects of all research studies involving human participants at the Ottawa Hospital Cancer Centre. If you have any questions about your rights as a study participant, you may contact the Chairperson at XXX.

A description of this clinical trial will be available on http://www.ClinicalTrials.gov . This website will not include information that can identify you. At most, the website will include a summary of the results. You can search this website at any time.

Do you have any questions?”

Appendix 2. Patient satisfaction survey

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Clemons, M., Mazzarello, S., Hilton, J. et al. Feasibility of using a pragmatic trials model to compare two primary febrile neutropenia prophylaxis regimens (ciprofloxacin versus G-CSF) in patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer (REaCT-TC). Support Care Cancer 27, 1345–1354 (2019). https://doi.org/10.1007/s00520-018-4408-6

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