Addressing Myelotoxicity as a Consequence of Treatment for Extensive-Stage Small Cell Lung Cancer
In this companion article, Dr Paul Bunn discuss the implications from the pooled results of trilaciclib on chemotherapy induced myelosuppression (CIM) and reviews management strategies for patients that might develop neutropenia while on chemotherapy for the treatment of extensive-stage small cell lung cancer (ES-SCLC).
In this Precision Medicine Perspectives series Addressing Myelotoxicity as a Consequence of Treatment for Extensive-Stage Small Cell Lung Cancer, experts comment on the data from a pooled analyses of trilaciclib on chemotherapy induced myelosuppression. Patients who experience myelosuppression may often develop neutropenia or thrombocytopenia while on chemotherapy for the treatment of ES-SCLC. Dr Bunn shares his insights and provides advice on ways to manage neutropenia. Chemotherapy induced myelosuppression can also affect a patient’s quality of life. Dr Paul Bunn discusses the impact of trilaciclib on a patient’s quality of life and how that might factor into his treatment decision-making.
Targeted Oncology™: How is chemotherapy induced myelosuppression currently managed?
Dr Bunn: For extensive stage small cell lung cancer (ES-SCLC), management has changed over the last few years. Etoposide and carboplatin chemotherapy have been a standard. More recently, trials [are] adding either durvalumab or atezolizumab to the etoposide-carboplatin backbone [and] they have shown improved progression free survival and overall survival outcomes, so [that] is now [the] standard. This now means that all patients [that] receive platinum doublet chemotherapy and [might] experience the associated side effects with platinum-doublet chemotherapy. The most common side effect, besides nausea and vomiting, is myelosuppression. Chemotherapy induced myelosuppression in patients being treated for extensive-stage small cell may manifest as neutropenia or febrile neutropenia, anemia, which sometimes requires blood transfusions, or thrombocytopenia, which might require platelet transfusions.
Targeted Oncology™: Please provide a brief overview of the three trials that were evaluated in the pooled results of trilaciclib on chemotherapy induced myelosuppression in patients with extensive stage small cell lung cancer.
Dr Bunn: Trilaciclib has been studied in 3 trials [in patients with extensive stage small cell lung cancer] to determine whether trilaciclib could alleviate any of the side effects [associated with chemotherapy], particularly the myelosuppression. So the question is, would the neutrophil counts be lower? Would patients require less support from G-CSF [transfusions]? Would patients require less red blood cell transfusions if they get trilaciclib with the chemotherapy? Would they require fewer platelet transfusions if they received trilaciclib in addition to the etoposide-carboplatin chemotherapy? The pooled analysis from these trials showed that patients who received trilaciclib required less G-CSF support, required less red blood cell transfusions, and required less platelet transfusions. In addition, there was fewer dose reductions due to myelosuppression. The pooled analyses showed a favorable outcome for trilaciclib in reducing [chemotherapy induced] myelosuppression.
Targeted Oncology™: Please comment on the anti-tumor efficacy endpoints that were assessed in the pool results of trilaciclib and chemotherapy induced myelosuppression.
Dr Bunn: If you are going to reduce the side effects of chemotherapy, then you also want to know how the [efficacy] outcomes will be affected. Clinical efficacy outcomes include progression free survival (PFS), overall survival (OS), and objective response rate (ORR). While it's important to reduce toxicity, it's [also] important that efficacy is not compromised when reducing toxicity. In these pooled analyses, there was no reduction seen in the overall response rate, in progression free survival, and in overall survival when trilaciclib was added to chemotherapy. Safety was affected in a favorable way, but efficacy was not affected in any way from the addition of trilaciclib to etoposide-carboplatin chemotherapy.
Targeted Oncology™: Could you go over some of the key efficacy results from the pooled results of trilaciclib in chemotherapy induced myelosuppression?
Dr Bunn: The pooled results of trilaciclib on chemotherapy induced myelosuppression, show tumor response rates were similar between both treatment groups. The objective response rate was 49.1% and 51.8% in patients receiving either trilaciclib or placebo, respectively. The median duration of response was 5.7 months in patients that received trilaciclib, and 4.6 [months] in patients that received placebo. The median PFS was 5.3 months in the trilaciclib group and 5 months in the placebo group, with a hazard ratio of 0.8 and a confidence interval of 0.6 to 1.06 which results in no statistical difference. The overall survival was 10.6 months for both arms and the hazard ratio for overall survival was 1.0. Again, [there] was no statistical difference in any of these efficacy endpoints.
Targeted Oncology™: FR is a 68-year-old man, who was recently diagnosed with extensive stage small cell lung cancer. He was started on carboplatin, etoposide and atezolizumab for treatment. But after receiving 2 cycles of treatment, FR has developed neutropenia. How would you manage this patient's neutropenia?
Dr Bunn: [Patients can experience] myelosuppression from chemotherapy treatment during any cycle. Most patients will experience neutropenia or febrile neutropenia in cycle 1. Before trilaciclib was an available treatment option, the only [treatment] choice was to provide supportive measures and consider reducing the dose [of chemotherapy]. One of the advantages of trilaciclib is that it will reduce myelosuppression, and therefore dose reductions are required far less frequently. In addition, supportive care [measures], such as G-CSF transfusions of red blood cells or of platelets are required less. Trilaciclib can be started at any point during a patient's chemotherapy regimen. Even with the addition of immunotherapy to chemotherapy, myelosuppression still remains an issue because the dose is not being altered. Even though the number of cycles administered for chemotherapy varies, myelosuppression tends to occur in the earlier cycles. The availability of trilaciclib reduces the requirement for dose reductions and for supportive care measures.
Targeted Oncology™: What advice do you have for community oncologists who are treating neutropenia in patients who have received chemotherapy?
Dr Bunn: One choice would be to add G-CSF at the onset of neutropenia. Another choice would be to consider ways to prevent neutropenia. The main options for [neutropenia prevention include] reducing the dose of the chemotherapy, which might reduce the efficacy [of chemotherapy] or add trilaciclib and continue with chemotherapy treatment at the same dose. If you choose to add trilaciclib, [then] most of the time, not always, but you have less myelosuppression in subsequent cycles allowing you to continue without a dose reduction in chemotherapy treatment.
Targeted Oncology™: Please comment on the incidence of neutropenia that was seen in the pooled results of trilaciclib.
Dr Bunn: In the pooled analysis of the trilaciclib studies, severe grade 4 neutropenia occurred in 53% of the patients who did not receive trilaciclib compared to 11% of the patients who received trilaciclib. Similarly, febrile neutropenia was reduced from 9.2% to 3.3%. Also, with respect to myelosuppression, G-CSF administration was given to 56% of the patients who did not receive neutropenia, and 28% of the patients receiving trilaciclib. Red [blood] cell transfusions were reduced from 26% to 15% and ESA administration was reduced from 12% to 3%. Grade 3 and grade 4 thrombocytopenia was reduced from 36% to 20%, and platelet transfusions were reduced from 9% to 8%. So all of these [results] indicate that trilaciclib was effective in reducing myelosuppression.
Targeted Oncology™: How did those numbers compare to what you might see in practice?
Dr Bunn: I would say that the use of G-CSF in my practice is a bit lower because I often dose reduce. As you know, carboplatin can be given at an AUC of six, AUC of five, or even lower. Obviously, myelosuppression is seen less when carboplatin is given at an AUC of five compared to an AUC of six. Many patients [diagnosed with] SCLC are previous smokers, elderly and not in good condition and so therefore we would start with a low dose of carboplatin for those patients. If trilaciclib is administered, then dose reductions for [chemotherapy] are not required. In my experience, when patients receive lower starting doses of carboplatin, the frequency of these toxicities is a bit lower than [what is reported] in the pooled analyses of trilaciclib.
Targeted Oncology™: How does chemotherapy induced myelosuppression affect the patient's health related quality of life?
Dr Bunn: It’s important that systemic therapy used to treat any type of cancer improves efficacy outcomes, while not impacting the patient’s quality of life. Side effects from systemic treatment can certainly affect quality of life. In these pooled analyses of the trilaciclib trials, quality of life was assessed. And interestingly enough, trilaciclib did not interfere with quality of life. In fact, in some measures the quality [of life] was superior. Patients who develop febrile neutropenia or require a blood transfusion often experience a diminished quality of life. Trilaciclib can prevent myelosuppression and therefore prevent reductions in quality of life.
Targeted Oncology™: How would the health-related quality of life factor into your decision making when you're deciding to give trilaciclib?
Dr Bunn: The question is should quality of life affect therapy [selection]? And the answer is [yes] it should because we're trying to make people live longer, and also live better. Certainly chemotherapy has a lot of side effects that can reduce [a] patients' quality of life. Trilaciclib helps to reduce myelosuppression associated with chemotherapy and therefore, improves the patient’s quality of life.
Targeted Oncology™: What were some of the patient reported outcomes that were measured from the pooled results of trilaciclib, and chemotherapy induced myelosuppression?
Dr Bunn: So the question is, what are quality of life assessments that can be done to determine whether a treatment is interfering with quality of life. In these trilaciclib studies, physical wellbeing was studied, as was fatigue, and functional activities. The results from these analyses favored trilaciclib. So trilaciclib in these trials prevented those quality-of-life impairments from chemotherapy.