This study highlights the specific role of HIPEC on the pathophysiology of postoperative serum inflammatory parameters. We observed that certain HIPEC protocols can suppress the WBC response to infection and may cause secondary and unspecific CRP elevations without underlining infection. This has a major impact on the sensitivity of WBC counts or the specificity of CRP values. We observed that this effect depends on the specific HIPEC protocol and seems more pronounced after prolonged perfusion for 60 min or more. To overcome this diagnostic limitation, we assessed the role of PCT, which was identified as a highly specific — although less sensitive — marker to diagnose infection. These findings may help to discriminate and diagnose infectious complications in the setting of CRS/HIPEC.
Due to the complexity of the procedure including HIPEC which induces additional tissue damage and inflammation, diagnosis of postoperative infection can be challenging. Knowledge about the potential suppression of the WBC reaction in response to infection after HPEC with mitomycinC and cisplatin is an important detail which should be known to any surgical oncologist in charge of these patients. Myelosuppression is a well-known hematologic side effect of doxorubicin, cisplatin, and mitomycinC [16,17,18]. Although is well known in the field, that HIPEC is overall well tolerated with acceptable myelosuppression rates compared to the systemic use of chemotherapeutic agents [18, 19], special care should be taken to this attenuated myelosuppressive effect which is not a clinical problem per se but may affect the diagnostic utility of WBC counts. This puts HIPEC treatment in line with other clinical situations, e.g., immunosuppression, old age, transplant patients, where the immune system is not able to react properly, and WBC counts or other serum parameters require critical evaluation.
While myelosuppression can be explained by the systemic effect of locoregional chemotherapy, the underlining mechanism of the secondary inflammation wave and CRP peak remains unclear. However, the clinical consequence is relevant. In the present study, 16% of patients after HIPEC with mitomycinC/doxorubicin underwent a CT scan due to increased CRP levels without diagnosing any postoperative infection. We speculated in a recent study, that prolonged perfusion protocols may trigger a systemic inflammatory response by translocation of intestinal bacterial components . The pathophysiologic mechanism behind this remains, however, still elusive. We observed in this study that patients treated with a 90-min protocol, who also shows depressed WBC and unspecific late CRP elevations, had more organ space infections compared to the short protocol with oxaliplatin. We do interpret this result with the highest care, due to the heterogeneity of groups which could explain this observed difference.
To improve diagnostic accuracy, PCT was introduced earlier for postoperative infection . We share the opinion of these authors that the diagnostic value of serum parameters in the first postoperative days is limited and is highly triggered by the amount and type of surgery. In this critical phase, the experience of the surgeon and particularly the clinical picture of the patient is more relevant, and serum parameters are of limited use to predict complications. However, towards the end of the first postoperative week, when the first peak of surgery-related inflammation flattens, these markers may help to improve patient management. PCT is produced by the C cells of the thyroidal gland and some other cell types upon bacterial infection and is stimulated by bacterial endotoxins and lipopolysaccharides, and indirectly by inflammatory markers, such as tumor necrosis factor-alpha, interleukin-6, and interleukin, and has a high specificity in the diagnosis of bacterial infections and sepsis . In this study, the high specificity of PCT to diagnose infectious complications could be confirmed and was independent from the applied HIPEC protocol. Despite its low sensitivity, the specificity of PCT, which remains unchanged by the perfusion protocol, is an important tool that may be helpful to discriminate between inflammation and infection in the sometimes challenging management of patients after CRS/HIPEC.
We would like to acknowledge the limitations of our study. Overall, the patient cohort includes different primary tumors and therefore the amount of surgery or CRS is not entirely comparable. Some differences in the early postoperative kinetics of the assessed parameters could also be related to this. For example, patients with pseudomyxoma were treated with mitomycinC, which translates into a longer operation time compared to the other protocols. However, the aim of the study, to look at the kinetics of blood and serum parameters, and to assess their diagnostic sensitivity and specificity, in the presence or absence of infection should not be influenced by this heterogeneity. The difference among groups with regard to ICU stay, hospital stay, and infectious complications should not influence the analysis of diagnostic parameters. While we assessed the most commonly used markers, it would be certainly interesting to assess the diagnostic potential of other inflammatory markers such as IL-6, IL-1, or TNF-a to get a deeper insight of the impact of HIPEC on a patient’s physiology.
In conclusion, we analyzed kinetics and the diagnostic value of CRP, WBC, and PCT after uncomplicated and complicated CRS/HIPEC. We identified a major impact on CRP levels and WBC counts, depending on the type of HIPEC protocol. In addition, we propose the use of PCT as a marker for infection which demonstrated to be independent from the treatment and offers a good specificity despite a still low sensitivity. Together our data highlight the complexity of HIPEC treatment which goes beyond technical excellence in the operating room but requires a dedicated holistic care of the surgical oncologist.