Discussion
intracranial hypertension, toxicity, malignancy, tumors, SD, pain, high-grade glioma, glioma, cerebral edema, toxic adverse
ADVERSE EVENTS, DISEASE, INDURATION, ADVERSE EFFECTS, GLIOMA, CEREBRAL EDEMA, EVENTS, TUMORS, INFLAMMATORY RESPONSE
Patients with recurrent high-grade glioma (grade 4 glioma is the most common) after standard chemotherapy or radiotherapy generally had a median OS of 5.7 to 7.5 monthsTo our knowledge, this article also provides the first report of CGA therapy in patients with recurrent high-grade (grade 3 and 4) glioma in a clinical trial setting. In this phase I trial, CGA was well tolerated and showed encouraging antitumor activity in patients with recurrent glioma. The MTD for CGA injection was determined to be 5.5 mg/kg. The most common drug-related adverse events were injection-related reactions (i.e., induration: 92%; pain: 12%). No grade 3 or 4 adverse events were observed for other adverse events except induration at the injection sites. The occurrence of these injection-related events correlated with the volume of the injected substance. Most adverse events were well tolerated by the patients, who recovered without medicinal intervention. Pharmacokinetic analysis indicated a linear pharmacokinetic profile with no accumulation after multiple injections; no CGA was detectable on days 9, 11, 13, 23, 25, 27, and 29 before CGA administration.In a preclinical Preclinical studies have shown that the T1/2 of CGA in animals is 40–50 minutes; and the T1/2 in this human clinical trial was approximately 1 h. Chlorogenic acid was rapidly eliminated In our preclinical study, the main metabolic pathway of CGA Although the size of this trial was small, the study did indicate that 52.1% of patients (12 of 23) achieved SD at the end of the first cycle of treatment. Importantly, the estimated median OS was 11.3 months for all patients and was 9.4 months for the 18 patients with grade 4 glioma. Furthermore, the 1-year survival rate was 47.8%, and 2 patients were alive at the cutoff day of February 11, 2022. With respect to the median OS (5.7 to 7.5 months) for patients with recurrent high-grade glioma treated with standard-of-care therapeutics, the median OS was prolonged after CGA treatment. These preliminary results are very encouraging and may aid in providing necessary care for a deadly malignancy.The localized reactions at the injection site might possibly have been due to 2 factors: (1) CGA (injection) is mildly acidic and may elicit local inflammatory reactions in the skin and muscle at the injection site, and (2) CGA is a small molecule immunomodulator. In addition to being absorbed into the blood, a small amount of the drug remaining in muscles may trigger a localized immune response at the injection site. In this clinical trial, a topical hot compress was used to facilitate drug absorption and decrease the local inflammatory response to mitigate the frequency and extent of these adverse events.No long-term adverse effects of CGA were observed in the long-term follow-up of the participants in this trial. The clinical observations were consistent with the preclinical animal safety evaluation of CGA, in which no apparent toxic adverse effects were found in long-term toxicity studies in rats (180 days) and beagle dogs (270 days), on the basis of analysis of hematological parameters and pathological tissue assessment at the end of treatment, thus indicating that CGA was well-tolerated.Notably, after the first 4 weeks (the first cycle) of CGA monotherapy, per protocol and physicians’ judgement, patients were eligible for treatment with CGA in combination with the standard-of-care therapeutic TMZ, because of the features of this advanced deadly disease. The combination of CGA and TMZ helped prolong OS. Patient 0005, who had survived as of the cutoff day, benefited from a treatment regimen moving from CGA monotherapy to CGA and TMZ in combination, and finally to triple combination therapy with metformin. This case study sheds light on the potential benefits of combining CGA with standard chemotherapy for glioma treatment. The underlying mechanism is currently under investigation.Our study has several limitations. This was a phase I study, and the sample size was too small to accurately assess the OS and progression-free survival of patients with recurrent high-grade glioma. Similarly, the protocol design allowed for combination treatment with CGA after the first cycle, thus complicating the assessment of efficacy or OS associated with CGA monotherapy. Beyond CGA, in the follow-up period, the combination of TMZ with PCV or bevacizumab could also be applied. Such combinations are recommended in clinical diagnosis and treatment guidelines.On the basis of our follow-up observations, patients who continued CGA monotherapy or combination treatment with standard-of-care therapy after the first cycle appeared to have good responses. This clinical observation is consistent with those from previous publications, in which patients with recurrent glioma have been found to respond to TMZ rechallengeDuring the trial period, 229 patients receiving supportive therapy beyond CGA or standard-of-care regimens, such as TMZ, were documented. The supportive medicines included steroid hormone drugs and recombinant human granulocyte colony stimulating factor (GCSF). Steroid hormone drugs were immunosuppressive, and were used in 21 cases during the trial, accounting for 9.1% of all patients receiving supportive therapies. However, the steroid treatment was short term, for 3–5 days, and was used primarily to control the symptoms of cerebral edema and intracranial hypertension; the drugs were discontinued after the symptoms had been controlled.In contrast, recombinant human GCSF is an immune-enhancing agent, which was applied in 6 cases and accounted for 2.6% of all patients receiving supportive therapies. GCSF was also administered short term, for 1–3 days, to balance granulocyte levels in patients with advanced tumors. Given that these immune-modulatory agents were used only as needed and for very short periods of time during the trial, their possible effects on CGA function cannot be excluded; however, such effects are expected to be minimal because of the reasons stated above.