Procalcitonin utilization in Cancer patients with Sepsis

Introduction
Diagnosing infection or Sepsis in cancer patients is challenging since it is difficult to differentiate between infection and fever of unknown origin. Also, the microbiological investigation takes time to get the result. However, in patients with hematological malignancies and solid tumors, the treatment and supportive care plan involves managing systemic and localized infections. Systemic and Localized infections are significant causes of excess morbidity and premature mortality among cancer patients with neutropenia. The risk of getting an infection is ten times higher in cancer patients than in those without malignancy. Thus, the utilization of specific biomarkers plays an essential role in the early diagnosis of Sepsis and appropriate antimicrobial treatment for survival and treatment of such patients. Techniques like the Polymerase Chain reaction are better in detecting microorganisms like intracellular bacteria, noncoding RNAs, and specific markers for infections such as procalcitonin (PCT). In this article, our center of discussion will be on Procalcitonin and its utilization in cancer patients with Sepsis.

Procalcitonin and its role in the human body
Procalcitonin is the precursor or prohormone of Calcitonin (CT). It constitutes 116 amino acids produced by the Parafollicular (C-cells) of the thyroid gland and neuroendocrine cells of the lungs & intestine. Procalcitonin is coded by the CALC-1 gene located on chromosome 11.
Procalcitonin is one of the valuable biomarkers in identifying bacterial infection because the level of Procalcitonin increases rapidly within two to four hours from the onset of a bacterial infection. Thus, procalcitonin is a biomarker that exhibits greater specificity in identifying Sepsis and can diagnose bacterial infection.
Procalcitonin as a biomarker has different roles in the human body, including:

• Diagnosing the severity of renal failure in urinary tract infection in children.
• Diagnosis and monitor medullary thyroid carcinoma
• Diagnose bacterial infections, stratify risk, and monitor the risk of septic shock.
• Monitoring the response to antibacterial therapy
• Diagnosis of septicemia and bacteremia in neonates, children, and adults.

The half-life of Procalcitonin is 34 hours; however, it increases during certain diseases involving bacterial infection. Procalcitonin level can also elevate even if there is no bacterial infection (false increase) during conditions involving:

• Severe trauma
• Liver cirrhosis
• Surgery
• Cardiac shock
• Malaria
• Burns
• Systemic vasculitis and intake of drugs that stimulate the release of cytokines.

Similarly, the level of procalcitonin can falsely decrease during conditions like osteomyelitis, abscess, and subacute endocarditis.
The normal values of Procalcitonin for different age groups that are also considered reference values include:

• ≤ 0.15 ng/mL in adults and children. In neonates, ≤ 0.15 ng/mL in ≥72 hours after birth is considered normal.
• For neonates within 72 hours of birth, the normal values are as follows:
• <2.0 ng/mL at birth
• Rises to ≤ 20 ng/mL at 18-30 hours after birth
• falls to ≤ 0.15 ng/mL by 72 hours of birth

Any decrease or increase in the reference values results in the possibility of local bacterial infection, a bacterial infection in the lower respiratory tract, bacterial meningitis, and end-stage chronic kidney disease.

Role of Procalcitonin in Cancer patients
The clinical interpretation of high PCT concentrations in the blood is difficult in cancer patients because their values can be modified by various circumstances, such as the existence of metastases or the neuroendocrine function of malignant tissue (e.g., small-cell lung cancer). Patients with medullary thyroid carcinoma (MTC) have higher procalcitonin levels. Both procalcitonin and calcitonin proteins are considered biomarkers for MTC.
Although PCT and CT both can be used in the diagnosis of MTC. However, PCT is preferred over CT due to the following reasons:

• First, PCT is stable and specific in both serum and plasma.
• PCT is cheaper and readily available in hospital laboratories

Here are the exciting facts scientific studies have found related to the role of procalcitonin in cancer patients:

• Patients with solid tumors, metastasis, and no evidence of infection had markedly elevated PCT levels, especially those with generalized metastatic disease.
• PCT may serve as an early indicator for the progression of neoplastic disease.
• Patients who experience massive tumor lysis and cytokine release following therapy with monoclonal antibodies increase PCT levels.
• A study found that patients with stage IV cancer or metastasis had significantly higher baseline PCT levels than patients with early-stage cancer or those in remission. The study concluded that not only is PCT specific for bacterial infection but that it also may be a predictor of metastasis and advanced cancer.
• Studies on PCT also concluded that procalcitonin could not be treated as a go-to biomarker for bacterial infection in patients with solid tumors. However, studies have found PCT superior to C-reactive protein in diagnosing and following infectious diseases in cancer patients. Scientific study has also shown that Procalcitonin is more useful in discriminating between bacterial and nonbacterial infections than CRP and WBC levels in neoplastic fever.
• Findings from scientific studies suggest PCT as a sensitive and specific early diagnostic marker to detect bacteremia in cancer patients with febrile neutropenia. In addition, scientific studies show that the median PCT values are higher in patients with febrile neutropenia with bacteremia than patients with a fever of unknown origin (FUO).
• Procalcitonin (PCT) sampling on the first day of chemotherapy and then following it up every four days until the end of neutropenia are essential tools that can predict bacteremia after chemotherapy.

Conclusion
Segal Abdul Aziz et al. carried out a study with 112 subjects to determine the procalcitonin levels in patients with metastatic tumors and discover the cut-off point for Sepsis in the study population. Out of the 112 enrolled subjects, 71 subjects had metastasis. Of those 71 subjects, 36 had Sepsis, and six experienced Sepsis and systemic inflammation response syndrome (SIRS). The study results found PCT levels high in patients with metastatic tumors in the absence of Sepsis. The study also showed the high cut-off point of the level of procalcitonin for diagnosing Sepsis in the meta-static solid tumor as compared to standard value.
Similarly, another retrospective study carried out by B.Vincenzi et al. found that a cut-off value of 1.52 ng/dL of PCT could be helpful in the management of antibiotic therapy, preventing delays of oncologic treatments.
In individuals with solid tumors, a combination of PCT and IL-6 measurements could be employed as indications of neoplastic disease progression, particularly liver metastasis. However, PCT levels should be considered a better marker in the differential diagnosis since it increases in cancer patients with bacterial infections and recovers to the normal range faster than CRP (due to its shorter half-life).
However, in the end, it should be remembered that PCT as a biomarker cannot replace the comprehensive clinical evaluation of the patient. Thus, PCT levels should only be measured in the context of a physical examination and when suitable microbiological diagnostics are conducted.

REFERENCES

1. Vincenzi, B., Fioroni, I., Pantano, F. et al. Procalcitonin as diagnostic marker of infection in solid tumors patients with fever. Sci Rep 6, 28090 (2016). https://doi.org/10.1038/srep28090
2. Durnaś, B., Wątek, M., Wollny, T., Niemirowicz, K., Marzec, M., Bucki, R., & Góźdź, S. (2016). Utility of blood procalcitonin concentration in the management of cancer patients with infections. OncoTargets and therapy, 9, 469–475. https://doi.org/10.2147/OTT.S95600
3. Aziz, S.A., Nelwan, E.J., Sukrisman, L. et al. Higher cut-off serum procalcitonin level for sepsis diagnosis in metastatic solid tumor patients. BMC Res Notes 11, 84 (2018). https://doi.org/10.1186/s13104-018-3204-1
4. Procalcitonin Frequently Asked Questions – Stanford Medicine. Accessed at
   https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/clinicalpathways/SHC-Procalcitonin-FAQ.pdf