Doxorubicin as Risk Factor for Fascial Dehiscence After CRS-HIPEC for Peritoneal Metastases.

BACKGROUND/AIM: Among postoperative complications, fascial dehiscence (FD) is registered in up to 10% of patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). This study aimed to evaluate the risk factors related to FD after CRS-HIPEC. PATIENTS AND METHODS: A retrospective analysis of a prospectively maintained database of consecutive patients who underwent CRS-HIPEC between 2015 and 2023 was performed. For each patient, risk factors for postoperative fascial dehiscence were identified using multivariate analysis. RESULTS: During the study period (2018-2023), 217 patients were treated with CRS-HIPEC. The incidence of FD was observed in seven cases (3.2%), which were reoperated with direct fascial closure. In three cases, FD was associated with other grade III-IV complications. Body mass index, (BMI; p=0.024), doxorubicin-based HIPEC (p=0.005), and open technique (p=0.004) were identified as risk factors for FD in univariate analysis. Systemic chemotherapy, prior surgical score, and peritoneal cancer index (PCI) were not associated with an increased risk of FD. In multivariable regression analysis, doxorubicin-based HIPEC and open technique were confirmed as risk factors for FD. CONCLUSION: Although FD is a relatively rare event after CRS-HIPEC, open technique and doxorubicin-based HIPEC were significant predictors of this complication. Specific fascial closure techniques and proper wound care should be considered in high-risk patients.

HIPEC as a risk factor for postoperative coagulopathy after cytoreductive surgery for peritoneal metastases.

AIM OF THE STUDY: Postoperative coagulopathy is a poorly investigated condition after Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). This study aims to evaluate the occurrence and risk factors of coagulative disorders after surgery for peritoneal metastases. PATIENTS AND METHODS: The records were extracted from a prospectively maintained database of consecutive patients who underwent CRS between January 2018 and September 2020. The study was approved by the local Ethics Committee. For each patient, the coagulation profile (CP), which included international normalized ratio (INR), partial thromboplastin time (aPTT), and platelets (PLTS) before surgery, intensive care unit admission,1st, 3rd, 5th postoperative day (POD) and the day before discharge was collected. Risk factors for postoperative coagulopathy were identified at multivariate analysis. RESULTS: During the study period, 125 patients were included in the study. Among these, 48 (38.4%) underwent CRS only, and 77 (61.6%) CRS followed by HIPEC. Twenty-one patients (16.8%) developed severe coagulopathy, 5 (10.4%) after CRS and 16 (20.8%) after CRS-HIPEC. At multivariate analysis, HIPEC and blood loss ≥ 500 ml represented independent risk factors for severe alteration of INR > 1.5 (p = 0.05, OR 1.2) and PLTS < 75 109/L (p = 0.03, OR 1.3), respectively. CONCLUSION: HIPEC is an independent risk factor for postoperative coagulopathy after CRS. Further studies are necessary to assess the usefulness of the point-of-care test in patients treated with CRS-HIPEC.

Complete pathological response of colorectal peritoneal metastases in Lynch syndrome after immunotherapy case report: is a paradigm shift in cytoreductive surgery needed?

BACKGROUND: We report the first case of a patient affected by peritoneal metastases from colon cancer, arising in the context of Lynch syndrome with pathological complete response. The patient was treated with immunotherapy and cytoreductive surgery. This paper discusses the implications of these novel therapies for the management of PM. CASE PRESENTATION: A 50-year-old man affected by Lynch syndrome was referred to our institution for metachronous peritoneal recurrence of ascending colon adenocarcinoma. As a second-line treatment, he received Nivolumab therapy with stable disease. Patient underwent cytoreductive surgery with residual disease and a pathological complete response. Flow cytometry described a particular immune sub-population response. There was no evidence of disease progression after nine months. CONCLUSION: This is the first report of a Lynch patient affected by peritoneal metastases of colorectal cancer, treated with cytoreductive surgery (CRS) and resulting in a pathological complete response after immune checkpoint inhibitors treatment (ICIs). This case report may suggest that patients with peculiar immunological features could benefit from a tailored approach, since "classical" CRS paradigms may not effectively predict the clinical outcome. Further large-scale studies are needed to determine the correct operative management of such patients (tailored or "standard" CRS), defining the correct surgical timing and eventual discontinuation of ICI therapy after surgery.

Colic and rectal tumors with peritoneal metastases treated with cytoreductive surgery and HIPEC: One homogeneous condition or two different diseases? A systematic review and meta-analysis.

Colorectal cancer (CRC) peritoneal metastasis (PM) is one of the most important cause of cancer-related death in world. CRC PM is considered as a homogeneous disease without differentiating colonic or rectal origin. Aim of this study is to analyze survival of patients treated with cytoreductive surgery and HIPEC, according to the origin of PM. Literature search was performed to identify relevant articles. All meta-analysis were performed using mean difference and log of HR, when appropriate. The I2 statistic was used to determine the heterogeneity of included studies. Out of 349 selected records, 9 articles (1308 patients, 1153 colon PM and 155 rectal PM) have been included. OS and DFS is higher in patients affected by colon PM (OS mean difference: 24,49 months [95% CI: 14,70-34,28 months, p < 0,000001]; DFS mean difference: 7,75 months [95% CI: 1,37-14,13 months, p: 0,02]) and pooled Hazard Ratio for disease-related death in rectal PM is 1.62 [95% CI: 1,01-2,59, p: 0,05] compared to colon PM). Heterogeneity among selected studies is high in two subgroups and low in one (OS subgroup A I2: 98%, p < 0,000001; DFS subgroup I2: 91%, p < 0,000001; OS subgroup B I2: 25%, p: 0,26). Our analysis, with all the limitations related to included studies, suggests that peritoneal metastasis of rectal tumors treated with CRS and HIPEC have a worst prognosis of colon tumors PM. Larger studies are required to confirm those results and therefore we invite all Authors in considering also tumor localization when reporting data on CRC peritoneal metastasis treatment.

Iterative Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Peritoneal Metastases.

BACKGROUND: Our aim was to analyze the safety and efficacy of iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (iCRS-HIPEC) in patients with peritoneal recurrence from different tumor types. PATIENTS AND METHODS: Data on indications, intraoperative findings and postoperative outcome of all patients treated with iCRS-HIPEC at our Institution were reviewed. RESULTS: Between 2010-2018, 10 iCRS-HIPEC procedures for peritoneal recurrence in eight patients were performed. The median peritoneal cancer index was 14.5 (range=2-33). Completeness of cytoreduction was CC0-1 in most cases (9/10). Three grade III-IV complications (two intestinal fistulas, one bleeding) were recorded and there was no operative mortality. After a median follow-up of 19.5 months, six patients experienced recurrence after a median of 12.5 months. CONCLUSION: iCRS-HIPEC is a safe procedure in selected patients with recurrent peritoneal surface malignancies. Selection criteria still remain questionable and need to be further evaluated in large cooperative multi-institution studies.

Vitamin B6 and Cancer Risk: A Field Synopsis and Meta-Analysis.

Background: Vitamin B6 is involved in many biochemical reactions and might play a role in carcinogenesis. We summarized the evidence linking vitamin B6 to cancer risk. Methods: We conducted a systematic review of both observational and intervention studies investigating the relationship between vitamin B6 intake or blood levels of its bioactive form pyridoxal-5'-phosphate (PLP) and the risk of any type of cancer. Random-effects meta-analysis was used to calculate pooled relative risks (RRs) and their 95% confidence intervals (CIs) across studies for high vs low categories of vitamin intake or PLP levels. We also performed a random-effects dose-response meta-analysis. Results: We identified 121 observational studies (participants, n = 1 924 506; cases, n = 96 , 436) and nine randomized controlled trials (RCTs; participants, n = 34 911; cases, n = 2539) considering 19 tumor sites. High intake of dietary (food only) vitamin B6 was statistically significantly associated with lower risk of all cancers (relative risk [RR] = 0.78, 95% CI = 0.73 to 0.84) and specific tumors, with special regard to gastrointestinal carcinomas (RR = 0.68, 95% CI = 0.61 to 0.75). An inverse association was also observed between high PLP levels and the risk of all cancers (RR = 0.66, 95% CI = 0.58 to 0.76) and single tumor sites, the most consistent results being those for gastrointestinal tumors (RR = 0.56, 95% CI = 0.48 to 0.65). There was a statistically significant inverse linear relationship between cancer risk and both vitamin B6 dietary intake and PLP levels. When total (food and supplements) intake was considered, the associations were weaker or null. Findings from RCTs did not support a protective effect of vitamin B6 against cancer, although this evidence was graded as low level. Conclusions: Epidemiological evidence supports the potential of vitamin B6 as a cancer risk reduction agent and the role of PLP as a cancer screening biomarker, especially for gastrointestinal tumors. However, inconsistent findings from total intake and intervention studies suggest that vitamin B6 might also be an indicator of other dietary protective micronutrients.

Cyto-reductive Surgery combined with Hyperthermic Intra-peritoneal Chemotherapy for Peritoneal Surface Malignancies: current treatment and results.

Cyto-reductive Surgery (CS) combined with Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) as loco-regional treatment of Peritoneal Surface Malignancies (PSM) has increasingly gained acceptance in clinical practice. This review summarizes the more relevant studies on this topic. Indications, pre-operative work-up, technical aspects, outcome and future directions of this combined approach in the treatment of Peritoneal Surface Malignancies are discussed here and proposed in an informative and didactic manner.

Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease.

BACKGROUND: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement

Hyperthermic isolated perfusion with low-dose tumor necrosis factor alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcomas.

BACKGROUND: Tumor necrosis factor (TNF)-alpha-based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-alpha. METHODS: HILP with low-dose TNF-alpha (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF-alpha concentrations in plasma and perfusate were measured throughout perfusion. RESULTS: A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF-alpha was 56. CONCLUSIONS: HILP with low-dose TNF-alpha and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity.

True versus mild hyperthermia during isolated hepatic perfusion: effects on melphalan pharmacokinetics and liver function.

Hyperthermic antiblastic isolated hepatic perfusion (IHP) with melphalan has been recently proposed as an alternative therapeutic option for patients with unresectable liver tumors. Although melphalan-heat antiblastic synergism is at a maximum at temperatures higher than 41 degrees C, IHP has so far been performed in humans at lower temperatures. In this experimental work, we compared IHP under mild versus true hyperthermic conditions in terms of drug pharmacokinetics and liver function. Ten pigs were submitted to IHP with melphalan 1.5 mg/kg at a mean temperature of 40 degrees C (group A, n = 5) or 42 degrees C (group B, n = 5). After a 60-minute perfusion, a 15-minute washout was performed. Perfusate-to-plasma leakage was monitored using scintigraphy. Throughout perfusion, samples from the systemic blood, perfusate, and liver parenchyma were obtained to measure melphalan concentrations. Liver function was assessed using standard blood tests and the indocyanine green-based test. No deaths related to the IHP procedure were recorded. All animals had transient liver function impairment, with all liver function test results returning to normal within the observation period. At histologic examination, liver damage was similar under both hyperthermic conditions. Melphalan levels in the perfusate were not significantly different in the two study groups (the mean perfusate/plasma area under the curve from 0 to 60 minutes ratios were 463 and 501, respectively). These results correlated well with those obtained using the scintigraphic method. Liver drug concentrations remained unchanged after true hyperthermia IHP. Under true hyperthermic conditions, neither an increase in liver parenchyma toxicity nor changes in melphalan pharmacokinetics were observed. These findings support the use of true hyperthermia in the clinical setting to exploit fully the antitumor synergism between melphalan and heat.

Hyperthermic intraperitoneal intraoperative chemotherapy after cytoreductive surgery for the treatment of abdominal sarcomatosis: clinical outcome and prognostic factors in 60 consecutive patients.

BACKGROUND: Abdominal sarcomatosis is a rare nosologic entity with a poor prognosis. After a Phase I study on cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy (HIIC), the authors reported the results of the treatment of 60 patients using this novel multimodal approach. METHODS: Twenty-nine patients had multifocal primary disease and 31 patients had recurrent abdominal sarcoma. Tumor histology was represented by visceral (n = 26 [43%]) and retroperitoneal (n = 34 [57%]) sarcoma. All patients underwent cytoreductive surgery (with no or minimal residual disease) and 90-minute HIIC with doxorubicin (15.25 mg/L of perfusate) and cisplatin (43 mg/L). The clinical outcome and the prognostic value of 11 clinicopathologic variables were analyzed. RESULTS: No postoperative deaths occurred. The morbidity rate was 33% and the moderate to severe locoregional toxicity rate was 15%. The median time to local disease progression and the median overall survival were 22 months and 34 months, respectively. Using multivariate analysis, histologic grading and completeness of surgical cytoreduction predicted patient prognosis, indicating that both local progression-free and overall survival were affected significantly by tumor aggressiveness and local disease control. CONCLUSIONS: Although these results were encouraging, there was no definitive conclusion reached regarding the therapeutic activity of this locoregional treatment. In addition, the toxicity rate was substantial. In the absence of effective systemic agents, the therapeutic potential of cytoreductive surgery plus HIIC should be explored further in comparative trials.

Hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-alpha and melphalan for bulky in-transit melanoma metastases.

BACKGROUND: Melphalan (L-PAM) hyperthermic isolated limb perfusion (HILP) is currently considered the standard treatment for patients with in-transit metastases from cutaneous melanoma. We here report on the results of L-PAM and low-dose tumor necrosis factor (TNF)alpha HILP in patients with bulky disease. METHODS: Twenty patients underwent TNFalpha (1 mg) and L-PAM (10 mg/L) HILP. Perfusion was performed for 90 minutes, and systemic leakage was strictly monitored. Locoregional toxicity was evaluated according to Wieberdink's criteria, whereas tumor response was evaluated with physical examination and ultrasound scan with or without fine-needle aspiration of any suspected recurrence. RESULTS: In all cases, systemic leakage was <5%. No postoperative deaths occurred, and locoregional toxicity was mild (grade 1 or 2) in 95% of patients. A complete tumor response was obtained in 14 patients (70%), and partial responses were obtained in 5 patients (25%). After a median follow-up of 18 months, six patients are alive and disease free, seven are alive with local or distant recurrence or both, and seven have died of disease. CONCLUSIONS: Low-dose TNFalpha HILP can achieve tumor responses comparable with those reported with higher doses of cytokine. Moreover, this drug regimen is associated with acceptable local toxicity, carries a smaller risk of systemic toxicity, and incurs lower costs.

Hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from gastric adenocarcinoma.

BACKGROUND: Patients with peritoneal carcinomatosis from gastric carcinoma have a dismal prognosis. Hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) has been proposed to treat residual disease after cytoreductive surgery. PATIENTS AND METHODS: From January 1998 through July 2002, 13 patients with peritoneal carcinomatosis from gastric cancer underwent complete cytoreductive surgery followed by HIIC. Chemo-hyperthermia was performed using mitomicin C (3.3 mg/m2) and cisplatin (25 mg m2) for 90 minutes, at a mean intraperitoneal temperature of 41.7 degrees C. RESULTS: No postoperative death was observed. Moderate locoregional toxicity (ileus) was observed in eight cases (42%), while two patients (10%) experienced mild systemic toxicity (myelosuppression or fever). Postoperative complication rate was 26% (pleural effusion, n = 4; septicemia = 1). Median overall survival was 15 months, and the median local progression free survival was 10 months. CONCLUSIONS: Cytoreductive surgery followed by HIIC resulted a feasible procedure, the overall morbidity rate being acceptable. Although the study was conducted in a subset of patients with peritoneal carcinomatosis from gastric cancer (resectable disease), survival results are encouraging.

TNFalpha-based isolated perfusion for limb-threatening soft tissue sarcomas: state of the art and future trends.

The management of limb-threatening soft tissue sarcomas has not yet been standardized. Although local disease control does not affect overall survival, amputation or highly mutilating surgery may be required, which impairs the patient's quality of life. Various neoadjuvant approaches have been proposed to allow limb-sparing surgery for these locally advanced tumors. With TNFalpha-based hyperthermic isolated limb perfusion, the majority of patients can be spared amputation, with acceptable rates of locoregional and systemic complications. As yet, no other available treatment seems to give comparable results when applied to limb-threatening soft tissue sarcomas. Nevertheless, several issues remain to be addressed, such as the type and dose of drugs, repeatability of the procedure, association with radiotherapy, further indications, and evaluation of response. The authors describe the principles underlying TNFalpha-based hyperthermic isolated limb perfusion, review the worldwide experience so far published, and discuss the above issues. The potential future developments of this locoregional therapeutic approach will also be reported.

Cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from colon adenocarcinoma.

BACKGROUND: Hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) has been recently proposed to treat peritoneal carcinomatosis arising from colon adenocarcinoma, which is usually regarded as a lethal clinical entity. The purpose of this study was to evaluate the clinical outcome of this combined treatment. METHODS: A retrospective study of 46 patients treated for peritoneal carcinomatosis from colon adenocarcinoma was performed. Thirty-four patients were treated with complete cytoreductive surgery immediately followed by intraoperative HIIC with mitomycin C and cisplatin. The clinical outcome of these 34 patients was analyzed; the median follow-up period was 14.5 months. RESULTS: No postoperative deaths were reported. The postoperative morbidity rate was 35%. No severe locoregional or systemic toxicity was observed. The 2-year overall survival was 31%, and the median survival time and the median time to local disease progression were 18 and 13 months, respectively. Survival and local disease control in patients with well- and moderately differentiated colon adenocarcinoma were significantly better than in those with poorly differentiated tumors. CONCLUSIONS: Considering the dismal prognosis of this condition, HIIC seems to achieve encouraging results in a selected group of patients affected with resectable peritoneal carcinomatosis arising from colon adenocarcinoma. These findings support the conduction of formal phase III randomized trials.

Doxorubicin activity is enhanced by hyperthermia in a model of ex vivo vascular perfusion of human colon carcinoma.

There is little information on the pharmacokinetics and pharmacodynamics of doxorubicin (DXR) administered during locoregional treatments of colon carcinoma under hyperthermic conditions. The aim of this study was to evaluate distribution and activity of DXR in healthy tissue and tumor tissues under hyperthermic conditions by using an experimental model of ex vivo isolated vascular perfusion of human colon segments bearing primary carcinoma. The influence of topoisomerase-II alpha (TPI2 alpha) expression on the anti-cancer activity of DXR combined with heat was evaluated as well. Twenty seven colon segments surgically resected for primary carcinoma were perfused ex vivo under physiological conditions (group A, n = 7), with DXR (group B, n = 6), under hyperthermic conditions (group C, n = 6), and with the combination DXR-hyperthermia (group D, n = 8). Samples of perfusate and tissues (normal and pathologic) were collected during 90 minutes of perfusion. Doxorubicin concentration in perfusate and tissues was assessed with high-performance liquid chromatography. Protein expression of TPI2 alpha, the main molecular target of DXR, was measured by image analysis in normal mucosa and tumor samples. Drug uptake was increased by heat equally in healthy and diseased tissue. Under hyperthermic conditions, DXR activity was significantly higher in pathologic mucosa than in normal mucosa. Furthermore, the activity of DXR combined with heat correlated with baseline TPI2 alpha levels in tumor tissue. From these findings, it appears that heat sensitizes tumor cells-but not normal mucosa-to DXR activity. Furthermore, protein levels of TPI2 alpha in pretreatment samples could predict tumor sensitivity to DXR.

Hyperthermic intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin in patients who undergo cytoreductive surgery for peritoneal carcinomatosis and sarcomatosis: phase I study.

BACKGROUND: Hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) combined with cytoreductive surgery (CS) has been proposed as a new multimodal treatment mainly for carcinomatosis of gastrointestinal origin. To evaluate whether this regimen could be used for other tumor types, the authors conducted a Phase I study on HIIC with doxorubicin and cisplatin in patients with peritoneal carcinomatosis or sarcomatosis. PATIENTS AND METHODS: Thirty-one patients with peritoneal carcinomatosis or sarcomatosis (PCS) were enrolled for the study. After completion of CS, HIIC was administered with drug doses that were increased for each consecutive cohort following a three-patient cohort scheme. Thereafter, the accrual was stopped when Grade 4 locoregional or systemic toxicity was observed. The maximum tolerated dose (MTD) was considered the dose in the previous triplet. Drug pharmacokinetics and procedure costs also were analyzed. RESULTS: After CS, residual tumors were not present or measured less than or equal to 3 mm (in dimension) in all cases. Maximum tolerated dose was 15.25 and 43.00 mg L(-1) for doxorubicin and cisplatin, respectively. The perfusate/plasma area under the curve ratios were favorable for both drugs, at 162+/-113 and 20.6+/-6.0, respectively, for doxorubicin and cisplatin. Doxorubicin levels in the peritoneum were higher than in tumor or normal tissue samples. There were no postoperative deaths. Surgery-related complications were observed in 25% of cases. Findings at cost analysis showed that the length of stay in the operation room and intensive care unit were the major cost drivers. CONCLUSIONS: Cytoreductive surgery combined with HIIC is an expensive but feasible therapeutic approach for locally advanced abdominal tumors. Because our preliminary findings for local disease control are encouraging, a Phase II study is now advisable to verify the activity of this promising treatment.