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*Only for medical professionals to read and learn~Case A 72-year-old woman was diagnosed with right breast metastatic lobular carcinoma in November 2018 [estrogen receptor (ER)/progesterone receptor (PR) positive, human epidermis Growth factor receptor 2 (HER2) negative], with axillary lymph node, bone and spine metastasis, taking Ribociclib and letrozole for 1 year
.
On October 12, 2019, the patient presented to the emergency department due to acute abdomen and severe diarrhea.
He did not have nausea, vomiting, fever, cough, or dysuria
.
On physical examination, the patient had severe tenderness on palpation of the abdomen, and there was no obvious abnormality
.
Blood routine, liver function, and electrolytes were normal, and C-reactive protein was elevated
.
Stool culture: Clostridium difficile and bacterial/viral pathogens are negative
.
Abdominal X-ray showed no air liquid level or free air under the diaphragm
.
After symptomatic and supportive treatment, the symptoms did not improve significantly
.
CT of the abdomen and pelvis showed: colonic wall edema and thickening, high-density shadows in the colon, and a little exudation in the abdominal cavity.
Consider colitis caused by infection or inflammation
.
On October 22, the patient developed blood in the stool and his hemoglobin decreased significantly, and he was given a blood transfusion
.
Colonoscopy revealed an ulcer at the liver flexure, and histopathology revealed colitis
.
After admission and hospitalization, he was given intravenous fluids and anti-infective treatment, and Ribociclib was stopped, and hydrocortisone (100mg, bid, ivgtt) was given
.
After the symptoms improved, the glucocorticoid was reduced to two weeks after the drug was stopped, and the CT examination showed that there was no colitis symptom
.
The damage mechanism of CDK4/6 inhibitor-induced colitis is not clear, but it may be related to the aggregation of inflammatory cells
.
Since 2015, the FDA has approved three CDK4/6 preparations: Palbociclib (pipericlib), Ribociclib, and Abemaciclib (abexiclib), which have become the first-line treatment options for patients with metastatic HR+/HER2-phenotype, CDK4/6 inhibition The agent effectively and accurately inhibits the activity of CDK4 and CDK6 kinases in breast cancer cells, blocks Rb protein phosphorylation, thereby blocking the progression of the cell cycle from G1 phase to S phase, and inhibits tumor cell proliferation
.
At the same time, CDK4/6 inhibitors inhibit the expression of upstream estrogen receptor signaling pathways, and have a synergistic effect with endocrine therapy to delay and reverse endocrine resistance
.
Figure 1: CDK4/6 inhibitor drug name, pharmacokinetics and usage and dosage CDK4 / 6 inhibitors of the more common endocrine therapy after joint adverse reactions are: neutropenia, diarrhea, elevated liver transaminases, venous thrombosis, such as QT prolongation
.
There are also cases of interstitial lung disease (ILD) or pneumonia related to the treatment of CDK4/6 inhibitors
.
How to manage and respond to related adverse reactions? 1 Neutropenia: Neutropenia is the most common type of adverse reaction of CDK4/6 inhibitors.
Among them, piperacillil and Ribociclib have the highest proportion of neutropenia, and grade 3-4 neutropenia The ratio is 60%-66%: It is recommended that patients start CDK4/6 inhibitor treatment with a neutrophil count ≥1×109/L, and monitor blood routines on the 1st and 14th days of each cycle during the treatment period
.
Coping strategies: (1) If neutropenia ≤2 occurs, there is no need to adjust the dose; (2) If neutropenia occurs for the first time, there is no need to adjust the dose; (3) If there is a grade 3 neutropenia With fever or grade 4 neutropenia, the drug needs to be discontinued immediately, and the treatment should be reduced by one dose when it is restored to grade ≤ 2.
The granulocyte colony-stimulating factor (granulocyte colony-stimulating factor, G-CSF) treatment may be considered; (4) If grade 3 neutropenia reappears, the drug needs to be stopped until it is restored to ≤ grade 2 neutropenia, and the treatment is reduced by one dose
.
Patients after multiple chemotherapy or elderly patients are recommended to monitor blood routine weekly
.
2 Diarrhea: The most common adverse reaction of Abexicil is diarrhea.
The incidence of grade 3 diarrhea is 9%.
Diarrhea has an adverse effect on the quality of life of patients
.
Coping strategies: (1) Active anti-diarrhea treatments (such as loperamide) should be taken when loose stools appear for the first time, and oral fluid intake should be increased
.
(2) Eat soft and easy-to-digest foods, and seek medical advice in time when symptoms are severe
.
Prolonged 3QT interval: Patients with severe prolonged QT interval are at risk of sudden death
.
Ribociclib treatment can increase the risk of cardiotoxicity, including QTcF>480ms or QTcF>500ms, and QT prolongation>60ms compared with baseline; and QT interval prolongation usually leads to the interruption of Ribociclib treatment and the reduction of the dose
.
Coping strategies: (1) During the treatment of Ribociclib, it is necessary to monitor the ECG and serum electrolytes on the 1st and 15th days of the first cycle of treatment and the 1st day of the subsequent treatment cycle; (2) Avoid Ribociclib with known prolongation The combination of drugs with potential risks of the QT interval, especially antiarrhythmic drugs and other drugs known to prolong the QT interval
.
(3) Patients with advanced breast cancer may use tamoxifen, and it needs to be emphasized that Ribociclib is not suitable for combined use with tamoxifen; (4) Active interventions such as dose interruption or reduction are used to reverse or control
.
4 Venous thromboembolism: A meta-analysis compared CDK4/6 inhibitors or endocrine monotherapy in the treatment of advanced breast cancer.
Abexiride has the highest risk of VTE; the risks of pibaciclib and Ribociclib are similar
.
Coping strategies: During the treatment of CDK4/6 inhibitors, attention and prevention of the appearance of VTE should be paid attention to.
The symptoms and indications of deep vein thrombosis and pulmonary embolism should be monitored
.
5 Hepatotoxicity: Ribociclib has a higher incidence of grade 3-4 hepatotoxicity, followed by abecili
.
Pebacillil causes less liver toxicity, and liver function monitoring is usually not required
.
Coping strategy: monitor liver function on day 1 and day 15 of the first 2 cycles of Ribociclib or abecili treatment and on day 1 of subsequent treatment cycles
.
(1) Pay attention to the patient's combined medication, alcohol use status, and history of hepatitis; (2) Refer to the "Guidelines for the Diagnosis and Treatment of Drug-induced Liver Injury" to give silymarin, glycyrrhizic acid preparations, N-acetylcysteine (NAC) and other hepatoprotective treatments; (3) If hepatotoxicity is not tolerated after using a certain CDK4/6 inhibitor, it is recommended to try another CDK4/6 inhibitor with less hepatotoxicity; (4) For CDK4/6 inhibitors, there are existing causes before treatment.
For patients with liver metastases with abnormal liver function caused by tumors, liver function should be closely monitored during treatment, and the examination results should be compared with those before treatment.
If the abnormalities of various indicators or symptoms and signs are worse than before treatment, further imaging examinations should be performed if necessary.
Is it tumor progression or drug-induced liver toxicity
?
6ILD: The incidence of ILD related to CDK4/6 inhibitor treatment is extremely low, but there are still reports of ILD deaths caused by Ribociclib and Abexiclib
.
Therefore, the FDA specifically warns that there may be a risk of ILD during treatment with CDK4/6 inhibitors
.
Coping strategies: (1) If further intervention is needed, prednisolone 40mg can be taken orally at the beginning of treatment, once a day
.
Decrease the dose of 10 mg every 2 weeks, and after reducing to 20 mg, decrease 5 mg every week until it stops; (2) Give extra pneumocystis pneumonia preventive medication until prednisolone is stopped; (3) While waiting for the laboratory diagnosis result, Can be combined with empirical antibacterial therapy
.
In addition to the above-mentioned more common adverse reactions, searching the literature also found that the incidence of skin adverse reactions with piperacillil combined with endocrine therapy was also higher (14.
2%), including macular papules, steatosis, pruritus and urticaria, and bullous dermatitis There are also case reports about Stevens-Johnson syndrome.
The patient can recover after stopping the drug and strong topical steroids.
In severe cases, oral corticosteroids or hydroxychloroquine can be selected
.
Therefore, the possible adverse reactions of CDK4/6 inhibitors should be considered in the treatment of breast cancer, and the treatment should be actively dealt with to reduce the impact on patients
.
References: [1] National Cancer Quality Control Center Breast Cancer Expert Committee, Chinese Anti-Cancer Association Cancer Drug Clinical Research Professional Committee.
CDK4/6 inhibitors in the treatment of hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer Application consensus[J].
Chinese Journal of Oncology,2021,43(04):405-413.
[2]Qin Zemin, Yi Fan, Liu Manxiang, Guan Quanlin, Yuan Wenzhen.
Effectiveness of CDK4/6 inhibitor combined with endocrine in the treatment of advanced breast cancer Meta analysis of safety and safety[J].
Chinese Journal of Evidence-Based Medicine,2018,18(04):333-339.
[3]Chan OB,Su JC,Yazdabadi A,Chan A.
Drug induced vitiligo-like depigmentation from a CDK 4/6 inhibitor.
Asia Pac J Clin Oncol.
2021 Jun 28.
doi:10.
1111/ajco.
13585.
[4]Chawla S,Hill A,Fearfield L,et al.
Cutaneous toxicities occurring during palbociclib(CDK4/6 inhibitor) and endocrine therapy in patients with advanced breast cancer:a single-centre experience.
Breast Cancer Res Treat.
2021 Jul;188(2):535-545.
[5]Martel S,Maurer C,Lambertini M,PondéN,De Azambuja E .
Breast cancer treatment-induced cardiotoxicity.
Expert Opin Drug Saf.
2017 Sep;16(9):1021-1038.
[6]Widmer S,Grossman M.
Chemotherapy patient with Stevens-Johnson Syndrome presents to the Emergency Department:A case report.
Am J Emerg Med.
2018 Jul;36(7):1325.
e3-1325.
e4.
.
On October 12, 2019, the patient presented to the emergency department due to acute abdomen and severe diarrhea.
He did not have nausea, vomiting, fever, cough, or dysuria
.
On physical examination, the patient had severe tenderness on palpation of the abdomen, and there was no obvious abnormality
.
Blood routine, liver function, and electrolytes were normal, and C-reactive protein was elevated
.
Stool culture: Clostridium difficile and bacterial/viral pathogens are negative
.
Abdominal X-ray showed no air liquid level or free air under the diaphragm
.
After symptomatic and supportive treatment, the symptoms did not improve significantly
.
CT of the abdomen and pelvis showed: colonic wall edema and thickening, high-density shadows in the colon, and a little exudation in the abdominal cavity.
Consider colitis caused by infection or inflammation
.
On October 22, the patient developed blood in the stool and his hemoglobin decreased significantly, and he was given a blood transfusion
.
Colonoscopy revealed an ulcer at the liver flexure, and histopathology revealed colitis
.
After admission and hospitalization, he was given intravenous fluids and anti-infective treatment, and Ribociclib was stopped, and hydrocortisone (100mg, bid, ivgtt) was given
.
After the symptoms improved, the glucocorticoid was reduced to two weeks after the drug was stopped, and the CT examination showed that there was no colitis symptom
.
The damage mechanism of CDK4/6 inhibitor-induced colitis is not clear, but it may be related to the aggregation of inflammatory cells
.
Since 2015, the FDA has approved three CDK4/6 preparations: Palbociclib (pipericlib), Ribociclib, and Abemaciclib (abexiclib), which have become the first-line treatment options for patients with metastatic HR+/HER2-phenotype, CDK4/6 inhibition The agent effectively and accurately inhibits the activity of CDK4 and CDK6 kinases in breast cancer cells, blocks Rb protein phosphorylation, thereby blocking the progression of the cell cycle from G1 phase to S phase, and inhibits tumor cell proliferation
.
At the same time, CDK4/6 inhibitors inhibit the expression of upstream estrogen receptor signaling pathways, and have a synergistic effect with endocrine therapy to delay and reverse endocrine resistance
.
Figure 1: CDK4/6 inhibitor drug name, pharmacokinetics and usage and dosage CDK4 / 6 inhibitors of the more common endocrine therapy after joint adverse reactions are: neutropenia, diarrhea, elevated liver transaminases, venous thrombosis, such as QT prolongation
.
There are also cases of interstitial lung disease (ILD) or pneumonia related to the treatment of CDK4/6 inhibitors
.
How to manage and respond to related adverse reactions? 1 Neutropenia: Neutropenia is the most common type of adverse reaction of CDK4/6 inhibitors.
Among them, piperacillil and Ribociclib have the highest proportion of neutropenia, and grade 3-4 neutropenia The ratio is 60%-66%: It is recommended that patients start CDK4/6 inhibitor treatment with a neutrophil count ≥1×109/L, and monitor blood routines on the 1st and 14th days of each cycle during the treatment period
.
Coping strategies: (1) If neutropenia ≤2 occurs, there is no need to adjust the dose; (2) If neutropenia occurs for the first time, there is no need to adjust the dose; (3) If there is a grade 3 neutropenia With fever or grade 4 neutropenia, the drug needs to be discontinued immediately, and the treatment should be reduced by one dose when it is restored to grade ≤ 2.
The granulocyte colony-stimulating factor (granulocyte colony-stimulating factor, G-CSF) treatment may be considered; (4) If grade 3 neutropenia reappears, the drug needs to be stopped until it is restored to ≤ grade 2 neutropenia, and the treatment is reduced by one dose
.
Patients after multiple chemotherapy or elderly patients are recommended to monitor blood routine weekly
.
2 Diarrhea: The most common adverse reaction of Abexicil is diarrhea.
The incidence of grade 3 diarrhea is 9%.
Diarrhea has an adverse effect on the quality of life of patients
.
Coping strategies: (1) Active anti-diarrhea treatments (such as loperamide) should be taken when loose stools appear for the first time, and oral fluid intake should be increased
.
(2) Eat soft and easy-to-digest foods, and seek medical advice in time when symptoms are severe
.
Prolonged 3QT interval: Patients with severe prolonged QT interval are at risk of sudden death
.
Ribociclib treatment can increase the risk of cardiotoxicity, including QTcF>480ms or QTcF>500ms, and QT prolongation>60ms compared with baseline; and QT interval prolongation usually leads to the interruption of Ribociclib treatment and the reduction of the dose
.
Coping strategies: (1) During the treatment of Ribociclib, it is necessary to monitor the ECG and serum electrolytes on the 1st and 15th days of the first cycle of treatment and the 1st day of the subsequent treatment cycle; (2) Avoid Ribociclib with known prolongation The combination of drugs with potential risks of the QT interval, especially antiarrhythmic drugs and other drugs known to prolong the QT interval
.
(3) Patients with advanced breast cancer may use tamoxifen, and it needs to be emphasized that Ribociclib is not suitable for combined use with tamoxifen; (4) Active interventions such as dose interruption or reduction are used to reverse or control
.
4 Venous thromboembolism: A meta-analysis compared CDK4/6 inhibitors or endocrine monotherapy in the treatment of advanced breast cancer.
Abexiride has the highest risk of VTE; the risks of pibaciclib and Ribociclib are similar
.
Coping strategies: During the treatment of CDK4/6 inhibitors, attention and prevention of the appearance of VTE should be paid attention to.
The symptoms and indications of deep vein thrombosis and pulmonary embolism should be monitored
.
5 Hepatotoxicity: Ribociclib has a higher incidence of grade 3-4 hepatotoxicity, followed by abecili
.
Pebacillil causes less liver toxicity, and liver function monitoring is usually not required
.
Coping strategy: monitor liver function on day 1 and day 15 of the first 2 cycles of Ribociclib or abecili treatment and on day 1 of subsequent treatment cycles
.
(1) Pay attention to the patient's combined medication, alcohol use status, and history of hepatitis; (2) Refer to the "Guidelines for the Diagnosis and Treatment of Drug-induced Liver Injury" to give silymarin, glycyrrhizic acid preparations, N-acetylcysteine (NAC) and other hepatoprotective treatments; (3) If hepatotoxicity is not tolerated after using a certain CDK4/6 inhibitor, it is recommended to try another CDK4/6 inhibitor with less hepatotoxicity; (4) For CDK4/6 inhibitors, there are existing causes before treatment.
For patients with liver metastases with abnormal liver function caused by tumors, liver function should be closely monitored during treatment, and the examination results should be compared with those before treatment.
If the abnormalities of various indicators or symptoms and signs are worse than before treatment, further imaging examinations should be performed if necessary.
Is it tumor progression or drug-induced liver toxicity
?
6ILD: The incidence of ILD related to CDK4/6 inhibitor treatment is extremely low, but there are still reports of ILD deaths caused by Ribociclib and Abexiclib
.
Therefore, the FDA specifically warns that there may be a risk of ILD during treatment with CDK4/6 inhibitors
.
Coping strategies: (1) If further intervention is needed, prednisolone 40mg can be taken orally at the beginning of treatment, once a day
.
Decrease the dose of 10 mg every 2 weeks, and after reducing to 20 mg, decrease 5 mg every week until it stops; (2) Give extra pneumocystis pneumonia preventive medication until prednisolone is stopped; (3) While waiting for the laboratory diagnosis result, Can be combined with empirical antibacterial therapy
.
In addition to the above-mentioned more common adverse reactions, searching the literature also found that the incidence of skin adverse reactions with piperacillil combined with endocrine therapy was also higher (14.
2%), including macular papules, steatosis, pruritus and urticaria, and bullous dermatitis There are also case reports about Stevens-Johnson syndrome.
The patient can recover after stopping the drug and strong topical steroids.
In severe cases, oral corticosteroids or hydroxychloroquine can be selected
.
Therefore, the possible adverse reactions of CDK4/6 inhibitors should be considered in the treatment of breast cancer, and the treatment should be actively dealt with to reduce the impact on patients
.
References: [1] National Cancer Quality Control Center Breast Cancer Expert Committee, Chinese Anti-Cancer Association Cancer Drug Clinical Research Professional Committee.
CDK4/6 inhibitors in the treatment of hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer Application consensus[J].
Chinese Journal of Oncology,2021,43(04):405-413.
[2]Qin Zemin, Yi Fan, Liu Manxiang, Guan Quanlin, Yuan Wenzhen.
Effectiveness of CDK4/6 inhibitor combined with endocrine in the treatment of advanced breast cancer Meta analysis of safety and safety[J].
Chinese Journal of Evidence-Based Medicine,2018,18(04):333-339.
[3]Chan OB,Su JC,Yazdabadi A,Chan A.
Drug induced vitiligo-like depigmentation from a CDK 4/6 inhibitor.
Asia Pac J Clin Oncol.
2021 Jun 28.
doi:10.
1111/ajco.
13585.
[4]Chawla S,Hill A,Fearfield L,et al.
Cutaneous toxicities occurring during palbociclib(CDK4/6 inhibitor) and endocrine therapy in patients with advanced breast cancer:a single-centre experience.
Breast Cancer Res Treat.
2021 Jul;188(2):535-545.
[5]Martel S,Maurer C,Lambertini M,PondéN,De Azambuja E .
Breast cancer treatment-induced cardiotoxicity.
Expert Opin Drug Saf.
2017 Sep;16(9):1021-1038.
[6]Widmer S,Grossman M.
Chemotherapy patient with Stevens-Johnson Syndrome presents to the Emergency Department:A case report.
Am J Emerg Med.
2018 Jul;36(7):1325.
e3-1325.
e4.
