Clinically necessary PD-1/PD-L1 immune checkpoint inhibitors are recognized for safety in the clinical application of urogenital tumors

Introduction

In the field of urogenital tumors, several clinical trials have confirmed the excellent clinical efficacy
of immune checkpoint inhibitors (ICIs) in urothelial carcinoma (UC), renal cell carcinoma (RCC) and prostate cancer (PCa).
However, due to the particularity of the mechanism of action of immunotherapy, clinicians need to have a fuller and deeper understanding of the choice of treatment indications, the specification of drug regimen, the evaluation of efficacy and the management of related adverse reactions to ensure that patients maximize
the clinical efficacy and quality of life benefits in immunotherapy.

Therefore, the Urinary Health Promotion Branch of the Chinese Medical Promotion Association and the Urological Surgery Professional Committee of the Chinese Research Hospital Association have formulated this diagnosis and treatment safety consensus, hoping to escort the clinical application of immunotherapy in the population of urological male genital tumors
.
The consensus focuses on condition assurance, patient management, indication population selection, efficacy evaluation, monitoring and management of related adverse reactions, and the handling of complications/accidents
.

Contraindications to immunotherapy

Absolute contraindications: contraindicated
in patients with hypersensitivity to the active ingredient or any excipients.
Relative contraindications: (1) hepatic insufficiency: moderate/severe patients are not recommended, and mild patients should be used with caution under the guidance of a doctor; (2) Renal insufficiency: severe patients are not recommended, mild/moderate patients should be used with caution under the guidance of doctors; (3) Children and ≥ 70-year-old patients should be used with caution under the guidance of doctors
.

Safety assessment before and during treatment

ICI-related toxic side effects can affect multiple organs
of the body.
Therefore, patients should undergo a comprehensive and systematic pre-medication baseline assessment, co-existing disease status monitoring assessment, co-medication and drug interaction evaluation, and post-medication related toxic side effects
.

Table 1 Immunotherapy baseline evaluation table

Note: CT: computed tomography; BNP: type B natriuretic peptide; TSH: thyroid-stimulating hormone; T4: Thyroxine; ACTH: Adrenocorticotropic hormone
.

Consensus recommended

Particular attention should be paid to the baseline status and treatment changes of each vital organ of the patient before and during clinical application; It is recommended that special attention should be paid to the time point difference of the immunorelated toxicity reactivity of different organs, and the safety assessment interval can be adjusted according to different affected organs during follow-up, and the functional status of each organ can be assessed by the tumor MDT team if necessary, so as to maximize the safety of
immunotherapy.

Efficacy assessment

Immunotherapy efficacy evaluation criteria: The principle of tumor evaluation in immunotherapy patients before and during treatment is based on the efficacy evaluation criteria (irRECIST)
of immunorelated solid tumors.
For baseline assessment, the definition, localization, and quantification of target and non-target lesions, measurable and non-measurable lesions, and total tumor burden should be identified and documented according to the criteria for evaluating the immunoefficacy of solid tumors (iRECIST
).

Table 2 Immunotherapy baseline evaluation table

Note: PD: disease progression; SLD: sum of the length and diameter of the target lesion; iUPD: Progress to be confirmed; irPD: immune-associated disease progression
.

Quality of life assessment: Quality of life assessment is recommended every 3 to 4 weeks, and commonly used assessment scales include the assessment of cancer treatment function - Disease-related symptom scale (FKSI-DRS), the European Cancer Research and Treatment Tissue Cancer Patient Quality of Life Measurement Scale (EORTCQLQ-C30), the European Five-dimensional Health Scale Level 3 version (EQ-5D-3L), etc
.

Consensus recommended

Patients with urogenital neoplasmic tumors receiving immunotherapy need to assess the tumor baseline and treatment response according to iRECIST standards, tumor control and improvement in quality of life are equally important, and all experts recommend that regular assessments
of the patient's quality of life should be completed regularly during treatment.

Evaluation of adverse effects

Common immunotherapy adverse reactions include kidney, skin/mucosa, endocrine/metabolic, gastrointestinal/liver, lung, heart, nerve/muscle and blood-related adverse reactions, which can be assessed by the Efficacy Evaluation Standard (CTCAE) version 5.
0 of the Common Adverse Reaction Efficacy Evaluation Standard (CTCAE) according to international practice, and its clinical manifestations and treatment are detailed in the original text
.

Consensus recommended

Immunotherapy-related toxicity reactions focus on prevention, consensus experts unanimously agree, it is strongly recommended to do a good job in the pre-treatment baseline assessment and regular monitoring of related treatments during treatment, early detection of abnormalities, timely treatment
。 Most consensus experts believe that in principle, once a toxic reaction of grade 2 or above occurs, patients should be advised to suspend the use of immunotherapy drugs; All consensus experts agree that once a level 4 toxicity reaction occurs, even if it is fully recovered after treatment, in principle, it is recommended to permanently stop immunotherapy in the absence of exceptional circumstances; Most experts emphasize that in the event of a grade 3 to 4 toxicity, priority should be given to the appropriate clinical department with the affected organ system or individualized treatment through MDT
.

Adverse reaction monitoring

General principle: Regular monitoring of the course of adverse reactions, patient remission/progression of disease, and complications
through clinical manifestations, imaging tests, laboratory tests, etc.

Specifically, the following includes: (1) General: Clinical symptoms and adverse events should be evaluated
for each follow-up visit.
(2) Imaging examination: during immunotherapy, re-examine chest, abdomen and pelvic CT every 4 to 6 weeks; Brain MRI is rechecked every six months to 1 year, and patients with bone metastases are recommended to have a full-body bone scan
every six months.
(3) General hematological examination: during immunotherapy, it is repeated once every 2 to 3 weeks, and then every 6 to 12 weeks (blood routine, biochemistry, etc.
).

(4) Skin/mucous membranes: skin and mucous membrane examinations are carried out at each round-up or outpatient visit
.
(5) Pancreas: if asymptomatic, no routine monitoring is required; If symptomatic, blood and urine amylase and pancreatic imaging are performed
promptly.
(6) Thyroid: during immunotherapy, thyroid function tests (TFTs) are rechecked once every 4 to 6 weeks, and then every 12 weeks
.
(7) Adrenal glands and pituitary gland: during immunotherapy, morning plasma cortisol, adrenocorticotropic hormones (ACTH), TFTs are re-examined for 2 to 3 weeks, followed up
every 6 to 12 weeks.
(8) Lung: during immunotherapy, blood oxygen saturation is rechecked every 4 to 6 weeks, and lung imaging is routinely examined
.
(9) Cardiovascular: during immunotherapy, ECG/cardiomyoenological indicators are
reviewed every 2 to 4 weeks.
(10) Rheumatoid / skeletal muscle: if there is no symptoms, routine monitoring is not required; If there is a prior history, joint examinations/functional evaluations
are performed from time to time.

Immunotherapy in special populations

Patients with autoimmune diseases: such patients require close monitoring when receiving immunotherapy; Before starting immunotherapy, reduce the dose
of prednisone.
Patients with autoimmune neurological disorders or life-threatening, as well as patients whose condition cannot be controlled by immunosuppressive drugs, are not candidates for immunotherapy
.

Patients with a history of viral hepatitis: patients with hepatitis B and C can safely use immunotherapy within the scope of ensuring liver function safety, but should be used with
caution if severe liver function impairment occurs.

Patients who have undergone hematopoietic stem cell/organ transplantation: These patients are potential to avoid immunotherapy, but it has been reported that receiving immunotherapy can lead to graft-versus-host disease (GVHD) or transplant organ failure, so the risks
of treatment need to be discussed with the patient and the transplant surgeon before initiating immunotherapy.

Pregnant patients: Immunotherapy in these patients may break immune tolerance, leading to an increased
risk of miscarriage, stillbirth, and neonatal death.

Patients who change immunotherapy: This type of patient may increase the incidence
of irAEs.

Patients with poor general condition: the benefit of immunotherapy in these patients is limited and requires caution
.

Elderly patients: Current clinical trials do not have a clear limit on age, and should be carefully selected
according to the toxicity of different immunotherapy drugs.

People with HIV: Patients with a history of HIV may be potential for immunotherapy, but immunotherapy increases the risk of
inflammatory cytokine syndrome caused by Castleman's disease and Kaposi's sarcoma-associated herpes.

Immunized patients: live vaccination
during immunotherapy is not recommended.

Patients with common diseases such as hypertension and diabetes: clinical data are limited, and chronic diseases need to be standardized and used
with caution.

Consensus recommended

Due to the special mechanism of action of immune checkpoint inhibitor immunotherapy, it is determined that special populations with physiological/pathological immunosuppressive states need to be particularly cautious when receiving immunotherapy, and when facing special populations with the above characteristics, the suitability of immunotherapy is fully assessed by the tumor MDT team and the immunotherapy
is implemented under close monitoring.

References:

Urological Health Promotion Branch of the Chinese Medical Promotion Association, Urology Professional Committee of the Chinese Research Hospital Association.
Safety consensus on the clinical application of PD-1/PD-L1 immune checkpoint inhibitors in urogenital tumors[J].
Modern Journal of Urology,2022,27(1):7-15.

Editor: Wang Mumu

Reviewer: LR

Execution: Wang Mumu