Update on the use of granulocyte colony stimulating factor (G-CSF) in concurrent chemoradiotherapy. Administration in patients with small cell lung cancer may be safer than previously thought.
Small cell lung cancer (SCLC) accounts for less than one-fifth of all lung cancers. They are characterized by rapid growth or high cell division rate and early metastasis. Biologically, they are therefore suitable for chemo- and radiation primary therapy, so they react accordingly sensitively. For this purpose, they are classified as “very limited/limited/extensive disease”. In the first two stages, therapy is curative in intention, whereas in “extensive disease” it is palliative. Basically, the approach is multimodal, involves surgery, drugs and radiation treatment.
For “limited” SCLC, chemo in combination with radiation is recommended. Concurrent chemoradiotherapy is considered for patients with good performance status. Tolerability/safety of therapy is a challenge if one wants to maintain dose intensity and avoid dose reductions and delays. Controversy surrounds the use of granulocyte colony stimulating factor (G-CSF), which is currently not routine in concurrent chemoradiotherapy due to reports of higher toxicity.
The CONVERT study
The safety data need supplementation, the authors of a study presented at this year’s ELCC Congress found. Similarly, the use of prophylactic antibiotics could not be considered standardized. The researchers, led by English oncologist Fabio Gomes, MD, Manchester, hoped to clarify open questions on the topic with a subanalysis of the phase III CONVERT trial [1]. 547 patients with “limited” SCLC were randomized to receive chemotherapy (cisplatin/etoposide) plus either once daily (66 Gy, 33 fractions) or twice daily radiotherapy (45 Gy, 30 fractions).
Testing the different radiotherapy procedures was the main purpose of the study. To date, there is no international consensus on which standard radiochemo regimen should be preferred. Conventional fractionated is the daily single doses of 1.8 to 2.0 Gy and a total therapy dose of 60-66 Gy; hyperfractionated accelerated radiotherapy is the twice-daily regimen of 1.5 Gy to a total therapy dose of 45 Gy.
Due to safety concerns and logistics, twice-daily radiotherapy is sometimes omitted. The presentation on CONVERT at last year’s ASCO Annual Meeting concluded that there was no difference in either toxicity or survival between one- and two-day radiotherapy. Both therapy methods are appropriate.
Since the use of prophylactic measures such as G-CSF and antibiotics had been allowed in CONVERT, these could now also be evaluated in a subanalysis.
G-CSF do not worsen survival
G-CSF and antibiotic use in both arms were comparable-as was overall and progression-free survival (independent of G-CSF, although not independent of antibiotic use). If patients received prophylactic antibiotics, they had significantly worse overall (p=0.016) and progression-free survival (p=0.03) – possibly a selection bias, according to the authors.
G-CSF was used (prophylactically and/or therapeutically) in approximately 40% of patients, and with increasing frequency over time: while it was used in 11% of patients in the first cycle of therapy, the rate was 27% in the fourth cycle. For prophylactic antibiotics, the trend was in the opposite direction: overall, they were used in almost 50% of patients, but increasingly infrequently, initially in 41% and later in 20%.
Accompanying symptoms of blood cell stimulation
What particularly interested the researchers was the safety of neutrophil stimulation. Finally, the American Society of Clinical Oncology (ASCO) still advises against the use of CSF in the setting of concurrent chemoradiotherapy (especially mediastinal radiation) in its 2015 guideline update [2]. In principle, a risk assessment of the patient with regard to febrile neutropenia is recommended for prophylactic CSF administration. The ESMO guidelines on febrile neutropenia from 2016 [3] take a similar view.
In fact, the reason for the controversial position of G-CSF is mainly due to the results of a randomized phase III trial from the early 1990s. They had shown in 230 patients with “limited” SCLC not only a significant increase in the number of severe thrombocytopenias, but also severe anemias and pulmonary complications. Last but not least, more toxicity-related deaths occurred when granulocyte-macrophage CSF was used concurrently with chemoradiotherapy [4].
The new data from CONVERT go in a slightly different direction: although thrombocytopenias of grade 3-4 were also significantly more frequent under G-CSF, namely in 29.4% vs. 13% of cases (p<0.001). However, severe anemia occurred significantly more frequently under G-CSF only in the arm with twice-daily irradiation (here in 20.9% vs. 8.3% of cases; p=0.004) and with regard to acute pneumonitis or esophagitis of grade 3-4, there was no significant association with G-CSF use.
In summary, the authors highlighted that no disadvantage in survival was found and that the numbers of severe thrombocytopenias and anemias were lower than in previous studies. Moreover, the direct causal relationship between these events and the administration of G-CSF was unclear. It is obvious that myelosuppressive chemotherapies with G-CSF can be administered in higher doses or greater numbers, which may also increase the risk of thrombocytopenia and anemia.
What now?
The question of whether drugs that “boost” white blood cells, i.e., stimulate neutrophil survival, proliferation, and differentiation, can be safely used alongside chemoradiotherapy is unlikely to be conclusively answered by this. However, the basic idea that G-CSF can attenuate the (febrile) neutropenia expected with chemoradiotherapy, reduce the risk of infection-related complications, and thus accelerate patient recovery remains attractive. It’s important to remember that two things have changed fundamentally since the negative outcome study was published, Dr. Gomes said: First, radiotherapy techniques are now more advanced and precise than they were then, which also reduces the risk of toxicities. On the other hand, granulocyte-macrophage CSF was used at that time, which exerted its effect on several blood cells and whose use is no longer common today. Instead, G-CSF now target only neutrophils.
Overall, the results seem encouraging for primary/secondary prophylaxis of febrile neutropenia. The side effects of G-CSF were controlled by appropriate supportive measures. Caution is advised in patients at increased risk of thrombocytopenia. The selection of eligible patients must be made carefully, and monitoring is necessary.
In view of the fact that this was an unplanned post-hoc analysis and the study was not conducted for this purpose, one should not draw any hasty conclusions for practice, critical voices noted in the subsequent discussion round. Presenters and audience agreed on one point: there is still a need for research.
Take-Home Messages
Subanalysis of a large phase III trial provides new insights into neutropenia prophylaxis and treatment in small cell lung cancer. Is the use of
Granulocyte colony stimulating factor (G-CSF) with concurrent chemoradiotherapy perhaps safer than previously thought? Major societies currently advise against routine use; in previous studies, severe toxicities increased. But a lot has changed since then, the study authors found at this year’s European Lung Cancer Conference in Geneva.
Source: European Lung Cancer Conference, May 5-8, 2017, Geneva
Literature:
- Faivre-Finn C, et al: CONVERT: An international randomised trial of concurrent chemo-radiotherapy (cCTRT) comparing twice-daily (BD) and once-daily (OD) radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status (PS). J Clin Oncol 2016; 34(suppl; abstr 8504).
- Smith TJ, et al: Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015; 33(28): 3199-3212.
- Klastersky J, et al: Management of febrile neutropaenia: ESMO Clinical Practice Guidelines†. Ann Oncol 2016; 27(suppl 5): v111-v118. DOI: 10.1093/annonc/mdw325.
- Bunn PA Jr, et al: Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995; 13(7): 1632-1641.
InFo ONCOLOGY & HEMATOLOGY 2017; 5(3): 32-33.
