Perioperative Systemic Chemotherapy Research Articles

Clinical Analysis of the Efficacy and Safety of Different Neoadjuvant Strategies in the Treatment of Locally Advanced Rectal Cancer

Objective In this study, we retrospectively analysed the efficacy and safety of three treatment models, namely, short-course radiotherapy sequential XELOX chemotherapy, neoadjuvant mFOLFOX6 concurrent radiotherapy and long-course concurrent radiotherapy with total mesorectal excision (TME) after treatment of locally advanced rectal cancer with high-risk factors. Methods We collected clinical data on 177 patients with locally advanced rectal cancer (cT3-4 and/or cN+) who were treated at the Department of Abdominal Oncology of the Affiliated Cancer Hospital of Guizhou Medical University from December 2017 to December 2022. All patients were associated with 2-3 risk factors [T4b, N2, Extramural Vascular Invasion (EMVI), Mesorectal Fascia (MRF) positivity], positive lateral lymph nodes. Among them, there were 45 cases in the short course radiotherapy sequential XELOX chemotherapy group (RT + XELOX group); 64 cases in the neoadjuvant mFOLFOX6 concurrent radiotherapy group (mFOLFOX6 + CRT group); and 68 cases in the long course concurrent radiotherapy group (CRT group). The RT + XELOX group and mFOLFOX6 + CRT group completed radiotherapy and 4 cycles of neoadjuvant chemotherapy, respectively, and then rested for 1-2 weeks before TME surgery; the CRT group completed concurrent radiotherapy and then rested for 6-8 weeks before TME surgery.Adjuvant chemotherapy was conducted after surgery in each of the three groups: 2 cycles of adjuvant chemotherapy with XELOX regimen in the RT + XELOX group, 4-6 cycles of adjuvant chemotherapy with mFOLFOX6 in the mFOLFOX6 + CRT group, and 8-12 cycles of adjuvant chemotherapy with mFOLFOX6 in the CRT group.The pathological complete response rate (pCR rate), tumour downstage rate, tumour complete resection rate (R0 resection rate), local recurrence rate, distant metastasis rate, overall survival rate, incidence of adverse reactions, surgical complications and completion rate of perioperative systemic chemotherapy were compared among patients in the three groups of cases after TME. Results The pCR rate (21.95% vs 17.24% vs 5.00%, p = 0.034) and and tumour downstage rate (78.05% vs 68.97% vs 53.33%, p = 0.029) were higher in the RT + XELOX group and mFOLFOX6 + CRT group compared to the CRT group. The RT + XELOX group had a lower 3-year distant metastasis rate (14.63% vs 36.67%, p = 0.048) and improved 3-year overall survival (76.57% vs 48.56%, p < 0.001) compared to the CRT group. There was no significant reduction in the 3-year distant metastasis rate in the mFOLFOX6 + CRT group versus the CRT group (27.59% vs 36.67%, p = 0.719), and the 3-year overall survival was similar (51.23% vs 48.56%, p = 0.35). Multi-logistic regression analysis and stratified analysis showed that patients in the RT + XELOX group and mFOLFOX6 + CRT group were more likely to achieve pCR than the CRT group (RT + XELOX group: OR 7.3, 95% CI [2.6-20.8], p < 0.001; mFOLFOX6 + CRT group OR 2.9, 95% CI [1.1-7.9], p = 0.036). The completion rates of perioperative systemic chemotherapy in the RT + XELOX, mFOLFOX6 + CRT, and CRT groups were 82.93% vs. 84.48% vs. 61.67% (χ2=9.95, p = 0.007), respectively. And there were significant differences in grade 3-4 leukopenia and thrombocytopenia (incidence of leukopenia: 15.50% vs. 7.81% vs. 1.47%, p = 0.045; incidence of thrombocytopenia: 13.33% vs 7.81% vs 1.47%, p = 0.027). There was no significant difference in the incidence of intraoperative and postoperative complications among the three groups (p > 0.05). Conclusions RT + XELOX group and mFOLFOX6 + CRT group significantly improved the near-term outcome (e.g., pCR rate) in patients with locally advanced rectal cancer with high-risk factors compared with CRT group. The RT + XELOX group also reduced the 3-year distant metastasis rate, increased the 3-year overall survival rate, and did not increase the incidence of perioperative surgical complications. It provides an effective means for the comprehensive treatment of locally advanced rectal cancer and has important clinical guidance and application value.

Preoperative chemotherapy response and survival in patients with colorectal cancer peritoneal metastases.

Treatment guidelines provided by PRODIGE-7 recommend perioperative systemic chemotherapy before cytoreductive surgery (CRS) for colorectal cancer peritoneal metastases (CRPM). Toxicity with multimodal treatment needs to be better defined. Chemotherapy response and impact on survival have not been reported. We assessed CRPM patients who received systemic oxaliplatin/irinotecan before CRS (preoperative) with Mitomycin C (35 mg/m2, 90 min) or Oxaliplatin (368 mg/m2, 30 min) heated intraperitoneal chemotherapy(HIPEC). Secondary analysis was performed from a prospective database. Overall survival (OS) in chemotherapy responders (R) and nonresponders (NR) was compared. Toxicity was assessed by rate of adverse events (AEs). From April 2005 to April 2021, 436 patients underwent CRS + HIPEC; 125 (29%) received preoperative chemotherapy. The 112 (90%) received oxaliplatin (64, 57%) or irinotecan (48, 43%). R, defined as complete (CR) or partial responseon preoperative imaging and/or postoperative histology, was seen in 71, 63% (53.8-72.3); 16, 14% (8.4-22.2) had CR. Median OS in R versusNR was 43.7 months (37.9-49.4) versus 23.9 (16.3-31.4) p = 0.007, HR 0.51 (0.31-0.84). OS multivariable analysis showed HR 0.48 (0.25-0.95), p = 0.03 for chemotherapy response corrected byperitoneal cancer index, completeness of cytoreduction score. CRS led to 21% grade 3-4 AEs versus 4% for preoperative chemotherapy. HIPEC grade 3-4 AEs were 0.5%. Preoperative chemotherapy response is an independent predictor for OS in CRPM.

Procollagen C-protein enhancer 1 (PCPE-1) as a potential serum biomarker for osteosarcoma.

e23518 Background: Osteosarcoma (OS) is the most common bone malignancy in children and young adults. Treatment with perioperative systemic chemotherapy has improved patient outcome but a third of patients will eventually develop incurable metastatic disease. Currently, there are no biomarkers for monitoring patients’ response to neo-adjuvant (NA) chemotherapy or for patients under active surveillance following treatments. Procollagen C-Proteinase Enhancer-1 (PCPE-1) is an extra-cellular matrix glycoprotein which promotes the maturation of pro-collagen into collagen in various tissues. Elevated serum levels of PCPE-1 are found in bone diseases such as Paget’s disease and Osteoporosis and in patients with breast cancer with bone metastases. Serum PCPE-1 has not been described in patients with OS. We aimed to describe PCPE-1 serum levels in patients with OS compared with healthy volunteers, and across different time points in their treatment and disease course. Methods: We collected serum samples from the Israeli national biobank of 18 adult OS patients. Serum samples were also collected from 6 healthy individuals. Additionally, we obtained serial samples from 4 OS patients prior to and after initiating NA therapy. Quantification of serum PCPE-1 levels was performed using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. Results: We successfully analyzed serum PCPE-1 levels from all patients and healthy volunteers. Mean PCPE-1 levels of 553ng/ml (range 479-614ng/ml) were observed in OS patients, compared with 313ng/ml (285-339ng/ml) in healthy volunteers. Of 4 patients undergoing treatment who had serial samples, a decrease in serum levels was observed 2 responding patients, while an increase in PCPE-1 levels were observed in one patient after NA treatment who had no response to treatment at the time of surgery. Of notice, serum levels nearly doubled in a patient during active surveillance who experienced local disease recurrence (274ng/ml and 423ng/ml, respectively). Conclusions: This is the first study to show elevated PCPE-1 serum levels in patients with OS. Our study also demonstrates potential changes in PCPE-1 levels in response to treatment. We are expanding our study to include a pediatric population to investigate the role of PCPE-1 as a potential tumor biomarker for monitoring treatment and surveillance of OS.

Systemic Chemotherapy in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery: Systematic Review and Meta-Analysis.

For patients with colorectal cancer (CRC) peritoneal metastases (PM) who are eligible for cytoreductive surgery (CRS), the indication and timing of systemic chemotherapy (SC) are still under debate. This study aims to analyze the role of pre, post or perioperative SC on the survival and surgical complications of patients treated with CRS-HIPEC. After a systematic search in MEDLINE, Cochrane Database of Systematic Reviews, Scopus, Web of Science and Embase, a meta-analysis was performed to compare postoperative complications, disease-free survival (DFS) and overall survival (OS) according to SC administration and timing. CRD42023478977. Of 1203 studies screened, 15 were included in the meta-analysis (4523 patients). Post-operative SC was associated with increased overall survival (post-SC vs. no post-SC: HR 0.81, p = 0.00001, I2 = 0%; pre-SC vs. post-SC: HR 0.65, p = 0.01, I2 = 28%), whereas SC (pre or post) or pre-SC compared to surgery alone was not (SC vs. no SC: p = 0.29, I2 = 80%; pre-SC vs. no pre-SC: p = 0.59, I2 = 58%). Similar results were seen for DFS. SC was not associated with an increased complication rate (p = 0.47, I2 = 64%). Systemic chemotherapy administration in patients undergoing radical surgery for colorectal peritoneal metastases is associated with increased survival only in the adjuvant/post-operative setting. Considering the limitations of the included studies, further trials are needed to answer this unresolved question.

Can neoadjuvant chemoradiotherapy before lateral pelvic lymph node dissection improve local control and prognosis in rectal cancer patients with clinically suspected lateral lymph node metastasis? A multicenter lateral node study in China

AimsSelective lateral pelvic lymph node (LPN) dissection (LPND) following neoadjuvant chemoradiotherapy (nCRT) for rectal cancer is widely recognized. This study aimed to determine the effects of nCRT before LPND on local control and prognosis of rectal cancer patients.Materials and methodsData were retrieved from a prospective database for rectal cancer patients with clinical LPN metastasis receiving total mesorectal excision and LPND at three institutions between January 2012 and December 2019. Selection bias was minimized using propensity score matching (PSM) and short-term and clinical outcomes were compared.ResultsPatients (n = 213) were enrolled and grouped as either nCRT (n = 97) or non-nCRT (n = 116). PSM was used to identify 83 matched pairs. In the matched cohort, nCRT patients had a longer operation duration (310.6 vs. 265.0 min, P = 0.001), lower pathological LPN metastasis rate (32.5% vs. 48.2%, P = 0.040), and fewer harvested lymph nodes (22 vs. 25, P = 0.018) compared to the non-nCRT group. However, after PSM, the two groups had similar estimated overall 3-year survival (79.5% vs. 80.7%, P = 0.922), 3-year disease-free survival (66.1% vs. 65.5, P = 0.820), and 3-year local recurrence-free survival (88.6% vs. 89.7%, P = 0.927). Distant metastasis was the predominant recurrence pattern in the overall (45/58, 77.6%) and matched (33/44, 75.0%) cohorts.ConclusionsLPND without nCRT is effective and sufficient in preventing local recurrence in patients with LPN metastases. Future prospective randomized controlled studies are warranted to confirm these findings. Since systemic metastasis is the predominant recurrence pattern in patients with LPN metastasis post-LPND, improved perioperative systemic chemotherapy is needed to prevent micrometastasis.

ASO Author Reflections: Perioperative Systemic Chemotherapy in Diffuse Malignant Peritoneal Mesothelioma treated with CRS-HIPEC.

ASO Author Reflections: Perioperative Systemic Chemotherapy in Diffuse Malignant Peritoneal Mesothelioma treated with CRS-HIPEC.

Metastatic Colorectal Cancer Treated with Combined Liver Resection, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Predictive Factors for Early Recurrence.

Selection of colorectal cancer patients with concomitant peritoneal (PM) and liver metastases (LM) for radical treatment with cytoreductive surgery (CRS), including liver resection and hyperthermic intraperitoneal chemotherapy (HIPEC), needs improvement. This retrospective, monocentric study was designed to evaluate the predictive factors for early recurrence, disease-free survival (DFS), and overall survival (OS) in such patients treated in a referral center. Consecutive colorectal cancer patients with concomitant LM and PM treated with curative intent with perioperative systemic chemotherapy, simultaneous complete CRS, liver resection, and HIPEC in 2011-2022 were included. Clinical, radiological (before and after preoperative chemotherapy), surgical, and pathological data were investigated, along with long-term oncologic outcomes. A multivariate analysis was performed to identify predictive factors associated with early recurrence (diagnosed <6 months after surgery), DFS, and OS. Of more than 61 patients included, 31 (47.1%) had pT4 and 27 (40.9%) had pN2 primary tumors. Before preoperative chemotherapy, the median number of LM was 2 (1-4). The median surgical PCI (peritoneal carcinomatosis index) was 3 (5-8.5). The median DFS and OS were 8.15 (95% confidence interval [CI] 5.5-10.1) and 34.1 months (95% CI 28.1-53.5), respectively. In multivariate analysis, pT4 (odds ratio [OR] = 4.14 [1.2-16.78], p = 0.032]) and pN2 (OR = 3.7 [1.08-13.86], p = 0.042) status were independently associated with an early recurrence, whereas retroperitoneal lymph node metastasis (hazard ratio [HR] = 39 [8.67-175.44], p < 0.001) was independently associated with poor OS. In colorectal cancer patients with concomitant PM and LM, an advanced primary tumor (pT4 and/or pN2) was associated with a higher risk of early recurrence following a radical multimodal treatment, whereas RLN metastases was strongly detrimental for OS.

Impact of Perioperative Systemic Chemotherapy on Survival for Patients Who have Diffuse Malignant Peritoneal Mesothelioma Treated with CRS-HIPEC.

The available data on the role of perioperative systemic chemotherapy (SC) for diffuse malignant peritoneal mesothelioma (DMPM) patients undergoing (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is heterogeneous and unstandardized. This study aimed to evaluate the impact of SC on the survival outcomes of DMPM patients undergoing CRS-HIPEC and to identify prognostic factors that affect the decision to administer SC. Patients who underwent CRS-HIPEC in the National Cancer Institute Milan (1995-2020) were retrospectively analyzed using propensity score-matching of known covariates. The patients were grouped into three groups: group A (neoadjuvant chemotherapy [NACT] and no-SC), group B (no-SC and adjuvant chemotherapy [ACT]), and group C (NACT and ACT). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meir method, and prognostic factors were calculated using the Cox-regression method. After a median follow-up period of 45 months (95% confidence interval [CI], 6.348-83.652 months) for group A, 115 months (95% CI, 44.379-185.621 months) for group B, and 88 months (95% CI, 3.296-172.704 months) for group C, the study analyzed 154 DMPM patients consisting of matched group A (NACT: 60 + no-SC: 52 = 112), group B (ACT: 38 + no-SC: 38 = 76), and group C (NACT: 31 + ACT: 31 = 62). The patients undergoing ACT had better 5-year OS and PFS than the patients undergoing NACT. In the multivariate analysis, ACT was significantly associated with improved OS by 48% (hazard ratio [HR], 0.52; 95% CI, 0.280-0.965, p = 0.038). For PFS, the association of ACT did not reach statistical significance (HR, 0.531; 95% CI, 0.266-1.058; p = 0.072). The optimum treatment sequence for DMPM is CRS-HIPEC followed by adjuvant chemotherapy for high-risk patients. Upfront surgery appears preferable to NACT for patients amenable to complete CRS.

The Effect of Histopathological Growth Patterns of Colorectal Liver Metastases on the Survival Benefit of Adjuvant Hepatic Arterial Infusion Pump Chemotherapy

BackgroundHistopathological growth patterns (HGPs) are a prognostic biomarker in colorectal liver metastases (CRLM). Desmoplastic HGP (dHGP) is associated with liver-only recurrence and superior overall survival (OS), while non-dHGP is associated with multi-organ recurrence and inferior OS. This study investigated the predictive value of HGPs for adjuvant hepatic arterial infusion pump (HAIP) chemotherapy in CRLM.MethodsPatients undergoing resection of CRLM and perioperative systemic chemotherapy in two centers were included. Survival outcomes and the predictive value of HAIP versus no HAIP per HGP group were evaluated through Kaplan–Meier and Cox regression methods, respectively.ResultsWe included 1233 patients. In the dHGP group (n = 291, 24%), HAIP chemotherapy was administered in 75 patients (26%). In the non-dHGP group (n = 942, 76%), HAIP chemotherapy was administered in 247 patients (26%). dHGP was associated with improved overall survival (OS, HR 0.49, 95% CI 0.32–0.73, p < 0.001). HAIP chemotherapy was associated with improved OS (HR 0.61, 95% CI 0.45–0.82, p < 0.001). No interaction could be demonstrated between HGP and HAIP on OS (HR 1.29, 95% CI 0.72–2.32, p = 0.40).ConclusionsThere is no evidence that HGPs of CRLM modify the survival benefit of adjuvant HAIP chemotherapy in patients with resected CRLM.

Extended pleurectomy/decortication and hyperthermic intraoperative intrapleural cisplatin perfusion for malignant pleural mesothelioma

ObjectiveTo evaluate the efficacy of multimodality treatment including extended pleurectomy/decortication (P/D) and hyperthermic intraoperative chemotherapy (HIOC) with cisplatin for malignant pleural mesothelioma (MPM), we investigated the pharmacokinetics of platinum, adverse events after HIOC, and survival outcome. MethodsFifty-three patients with pathologically diagnosed MPM (cT1-3N0-1M0, excluding sarcomatoid) underwent an extended P/D and HIOC (cisplatin 80 mg/m2 in saline 2 L, 42°C, 60 minutes) since 2011. The protocol includes postoperative 4 cycles of cisplatin and pemetrexed. Platinum concentrations in the perfusate (before and after) and the serum (1, 2, 4, 8, 24, 48, 72 hours after perfusion) were measured in 10 patients. Mortality and morbidity, especially adverse events of renal function, were investigated, and survival and affecting factors were examined. ResultsAll patients obtained macroscopic complete resection and pathologic staging revealed as follows: T1/2/3/4: 12/8/23/10, N0/1: 36/17, stage 1A/1B-3A/3B: 12/31/10, respectively. Platinum concentrations in the perfusate indicated that 28% of the dose remained in the pleural cavity, and the maximum concentration in the serum was 0.91 μg/mL. Six patients (11%) showed elevated max-creatinine (>2 mg/dL) postoperatively. Two patients (4%) received renal-replacement therapy, and one was weaned before discharge. There was no 30-day mortality and one in-hospital death (1.9%). Forty-six patients (87%) received multiple cycles of perioperative systemic chemotherapy. Median overall survival (OS) and disease-free survival (DFS) were 52.4 months and 18.7 months. Patents with stage 1A demonstrated a 5-year OS of 67.3% and a median DFS of 67.1 months, and patients with stage 1B-3A demonstrated a 5-year OS of 50.1% and a median DFS of 20.4 months. Univariate analysis showed histological subtype, p-T, p-stage, and multimodality treatment as significant factors affecting OS. Multivariate analysis revealed histology, p-stage, and multimodality as independent. ConclusionsExtended P/D and HIOC with cisplatin for MPM is acceptable with limited acute kidney injury. This multimodality protocol provides promising favorable survival for stage 1A-3A disease.

Survival Benefit of Perioperative Systemic Chemotherapy for Patients With N0 to N1 NSCLC Having Synchronous Brain Metastasis

IntroductionIn stage IV NSCLC with solitary or oligometastatic brain metastasis, surgical resection of the primary and definitive management of the brain metastasis is an accepted standard. However, the effect of systemic chemotherapy after surgical resection on overall survival is not well-established. MethodsWe used the National Cancer Database to retrospectively identify individuals with NSCLC as the primary tumor along with synchronous brain metastases who underwent thoracic resection with or without adjuvant chemotherapy. Chi-square and Wilcoxon rank sum tests were performed to compare categorical and continuous variables, respectively, across the treatment groups. Kaplan-Meier and Cox proportional modeling were done to determine the survival benefit. ResultsA total of 310 (71.9%) of the cohort received perioperative chemotherapy, most of whom (79.4%) received it in the adjuvant setting. Patients receiving chemotherapy were likely to be younger (p = 0.002), privately insured (p = 0.01), and receive radiation (p < 0.001). Perioperative chemotherapy was significantly associated with survival on both univariate (hazard ratio = 0.71[0.52 – 0.99]) and multivariable (hazard ratio = 0.66 [0.47 – 0.92]) in addition to age (p = 0.03), Charlson-Deyo score (p = 0.02), pathologic N stage (p = 0.02), and adenocarcinoma histology (p = 0.02). Kaplan-Meier analysis confirmed this result with a significantly better survival with perioperative chemotherapy (p = 0.02). Further subgroup analysis using pathologic N stage revealed similar effect in pN1 (p = 0.001), but not pN0 (p = 0.2) patients. ConclusionsPerioperative chemotherapy for pN0-1 NSCLC with synchronous brain metastasis is associated with improved OS in this analysis.

Abstract 5959: Dissecting the stromal drivers of gastroesophageal adenocarcinoma chemoresistance

Abstract Gastroesophageal adenocarcinoma (GEA) is the fastest rising cancer in North America. Over the course of five years, the survival rate is &amp;lt;20%, creating an urgent need for appropriate treatments against GEA. Currently, providing patients with peri-operative systemic docetaxel triplet-based chemotherapy (DCF or FLOT) is the most effective approach to treat GEA. Despite this, for 50% of patients that do present an initial response to therapy, the tumor returns due to pre-existing or newly acquired resistance (i.e., chemoresistance) by the cancer. Researchers have shifted their focus to the tumor microenvironment (TME) as one of the factors influencing chemoresistance in patients. The TME is composed of tumor cells, immune cells and their secreted products, as well as fibroblasts. The components of the TME have been shown to interact with one another to influence tumor growth and progression. Fibroblasts are wound-healing cells that can be transformed into cancer-associated fibroblasts (CAFs) in response to stress and the release of inflammatory products. CAFs are the most abundant cells in the TME, yet their role in the chemoresponse of GEA is still unclear. Previous studies on other cancer types demonstrated that CAF expression is distinct between chemoresistant and chemo-sensitive tumors and certain CAF subpopulations may confer this resistance. This project will investigate the role of CAFs in the chemo-response of GEA using patient-derived organoids (PDOs) and CAFs from &amp;gt;200 GEA patients. A single-cell RNA sequencing atlas developed from &amp;gt;30 GEA DCF- or FLOT-treated patient samples will be used to identify CAF markers and targetable processes. CAF sub-populations will then be elucidated and correlated to tumor response. IF, FACS, and ELISA will be performed for subsequent CAF marker validation and characterization. Ex vivo drug testing with DCF or FLOT will be conducted on PDO-CAF co-cultures to recapitulate their drug response. Citation Format: Kulsum Tai, Sanjima Pal, Julie Bérubé, Iris Kong, Adam Hoffman, Swneke Bailey, Aki Kirbizakis, Sui Huang, Michael Strasser, David Gibbs, Nicholas Bertos, Veena Sangwan, Lorenzo Ferri. Dissecting the stromal drivers of gastroesophageal adenocarcinoma chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5959.

Comparison of Neoadjuvant Systemic Chemotherapy Protocols for the Curative-Intent Management of Peritoneal Metastases from Colorectal Cancer, Regarding Morphological Response, Pathological Response, and Long-Term Outcomes: A Retrospective Study.

Selected patients with colorectal cancer peritoneal metastases (CRPM) could be offered a curative-intent strategy based on complete cytoreductive surgery (CRS), potentially combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and perioperative systemic chemotherapy. The impact of different neoadjuvant systemic chemotherapy (NACT) regimens remains unclear due to a lack of comparative data. Consecutive CRPM patients from a monocentric database who were treated with complete CRS after single-line NACT were included in this study. Chemotherapy regimens were tailored as a doublet drug (FOLFOX/FOLFIRI) with/without targeted therapy (anti-epidermal growth factor receptor/bevacizumab) and triplet-drug combination (FOLFIRINOX). Morphological response (MR) was assessed using the Response Evaluation Criteria in Solid Tumors criteria, and pathological response (PR) was assessed using the Peritoneal Regression Grading Score (PRGS). Long-term oncologic outcomes were compared. The cohort comprised 388 patients, including 127, 202, and 59 patients in the doublet, doublet+targeted, and triplet groups, respectively. MR rates were higher in the triplet (68.0%) and doublet+targeted groups (64.2%) when compared with the doublet group (42.4%, p=0.003). Complete and major PRs were observed in 13.6% and 32.0% of patients, respectively. Higher MR rates were observed after doublet+targeted or triplet regimens, while no difference was observed for PR rates. In multivariate analysis, FOLFIRINOX was independently associated with better overall survival (hazard ratio 0.49, 95% confidence interval 0.25-0.96; p=0.037). FOLFIRINOX also resulted in a higher rate of severe postoperative complications. In this retrospective study, a FOLFIRINOX regimen as NACT seemed to result in better long-term outcomes for CRPM patients after complete CRS/HIPEC, although with higher morbidity. Prospective studies are needed, including groups without NACT and those with FOLFIRINOX+bevacizumab.

Therapie peritonealer Metastasen

BackgroundPeritoneal carcinomatosis arising from gastrointestinal malignancies represents a major therapeutic challenge for oncological surgeons, oncologists and radiotherapists. The development of so-called multimodal therapy consisting of perioperative systemic chemotherapy, radical cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy (HIPEC) has resulted in significant prolongation of overall survival in these patients.AimSurvival data from prospective, randomized trials and register studies in recent years have established multimodal therapy as a treatment option for peritoneal metastatic colorectal as well as gastric cancer in the German guidelines. The current work on this complex topic ensures insight into the background of this topic.Materials and methodsThis paper is based on a selective literature search in the medical database PubMed on the keywords hyperthermic intraperitoneal chemotherapy, colorectal cancer, gastric cancer, multimodal therapy as well as on internal data from a reference center for the therapy of peritoneal malignancies from Germany.ResultsMultimodal therapy consisting of perioperative systemic chemotherapy, radical cytoreductive surgery, and HIPEC leads to better oncologic outcome in well-selected patients with peritoneal metastatic gastric and colorectal cancer in high-volume centers.

Perioperative chemotherapy in colorectal cancer with peritoneal metastases: A global propensity score matched study.

There is a paucity of studies evaluating perioperative systemic chemotherapy in conjunction with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colorectal cancer peritoneal metastases (CRCPM). The aim was to evaluate neoadjuvant and/or adjuvant systemic therapy in CRCPM. Patients with CRCPM from 39 treatment centres globally from January 1, 1991, to December 31, 2018, who underwent CRS+HIPEC were identified and stratified according to neoadjuvant/adjuvant use. Crude data analysis, propensity score matching (PSM) and Cox-proportional hazard modelling was performed. Of 2093 patients, 1613 were included in neoadjuvant crude evaluation with 708 in the PSM cohort (354 patients/arm). In the adjuvant evaluation, 1176 patients were included in the crude cohort with 778 in the PSM cohort (389 patients/arm). The median overall survival (OS) in the PSM cohort receiving no neoadjuvant vs neoadjuvant therapy was 37.0 months (95% CI: 32.6-42.7) vs 34.7 months (95% CI: 31.2-38.8, HR 1.08 95% CI: 0.88-1.32, p=0.46). The median OS in the PSM cohort receiving no adjuvant therapy vs adjuvant therapy was 37.0 months (95% CI: 32.9-41.8) vs 45.7 months (95% CI: 38.8-56.2, HR 0.79 95% CI: 0.64-0.97, p=0.022). Recurrence-free survival did not differ in the neoadjuvant evaluation but differed in the adjuvant evaluation - HR 1.04 (95% CI: 0.87-1.25, p=0.66) and 0.83 (95% CI: 0.70-0.98, p=0.03), respectively. Multivariable Cox-proportional hazard modelling in the crude cohorts showed hazard ratio 1.08 (95% CI: 0.92-1.26, p=0.37) for administering neoadjuvant therapy and 0.86 (95% CI: 0.72-1.03, p=0.095) for administering adjuvant therapy. Neoadjuvant therapy did not confer a benefit to patients undergoing CRS+HIPEC for CRCPM, whereas adjuvant therapy was associated with a benefit in this retrospective setting. None.

Oncological impact of intraperitoneal chemotherapy after cytoreductive surgery for patients with colorectal peritoneal metastasis: A bi-institutional retrospective analysis.

There is a paucity of evidence on the value of intraperitoneal chemotherapy (IPC) following cytoreductive surgery (CRS) for colorectal peritoneal metastasis. This study aimed to evaluate the association between mitomycin C-IPC and survival outcomes following CRS. The institutional databases of two tertiary hospitals were reviewed to identify patients who underwent CRS for colorectal peritoneal metastasis. The outcomes of patients who underwent CRS without IPC were compared with those of patients who underwent CRS plus early postoperative intraperitoneal chemotherapy(EPIC) or CRS plus hyperthermic intraperitoneal chemotherapy(HIPEC). The primary endpoints were cancer-specific survival (CSS), progression-free survival (PFS), and peritoneal PFS (P-PFS). In 149 patients with peritoneal metastasis alone, EPIC and HIPEC use was significantly associated with better CSS, PFS, and P-PFS in the multivariate analysis. CSS was also significantly associated with perioperative systemic chemotherapy. Among 42 patients with both peritoneal and extraperitoneal metastases, CSS was independently related to the completeness of cytoreduction score, location of extraperitoneal metastasis, and grade 3-4 complications. Mitomycin C-IPC after CRS was associated with better survival outcomes than CRS alone in patients with resectable peritoneal metastasis of colorectal cancer. This study found that IPC had beneficial effects regarding P-PFS in patients with both peritoneal and extraperitoneal metastases.

A single-center retrospective cohort study of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma.

BackgroundDiffuse malignant peritoneal mesothelioma (DMPM) is a rare variant of malignant mesothelioma, representing 10–15% of malignant mesothelioma cases. The preferred therapeutic approach is cytoreductive surgery (CRS) accompanied by hyperthermic intraperitoneal chemotherapy (HIPEC); the role of systemic chemotherapy is not well established. While some limited retrospective studies report worse outcomes with neoadjuvant chemotherapy, our institution has favored the use of neoadjuvant chemotherapy for symptom relief and surgical optimization. The aim of our study was to assess the outcomes of patients receiving neoadjuvant chemotherapy, compared to those receiving adjuvant or no perioperative chemotherapy.Patients and methodsWe conducted a single-center retrospective cohort study of treatment-naïve, non-papillary DMPM patients seen at our institution between 1/1/2009 and 9/1/2019. We explored the effect of type of systemic therapy on clinical outcomes and estimated median overall survival (mOS) using Kaplan-Meier curves. Hazard ratios (HR) calculated by Cox proportional hazard model were used to estimate effect of the exposures on overall survival.Results47 patients were identified with DMPM (median age at diagnosis 61.2 years, 76.6% epithelioid histology, 74.5% white race, 55.3% known asbestos exposure). CRS was performed in 53.2% of patients (25/47); 76.0% of surgical patients received HIPEC (19/25). The majority received systemic chemotherapy (37/47, 78.7%); among patients receiving both CRS and chemotherapy, neoadjuvant chemotherapy was more common than adjuvant chemotherapy (12 neoadjuvant, 8 adjuvant). Overall mOS was 84.1 months. Among neoadjuvant patients, 10/12 underwent surgery, and 2 were lost to follow-up; the majority (9/10) had clinically stable or improved disease during the pre-operative period. There were numerical more issues with chemotherapy with the adjuvant patients (4/8: 2 switches in platinum agent, 2 patients stopped therapy) than with the neoadjuvant patients (2/10: 1 switch in platinum agent, 1 delay due to peri-procedural symptoms). Neoadjuvant chemotherapy was not associated with worse mOS compared to adjuvant chemotherapy (mOS NR vs 95.1 mo, HR 0.89, 95% CI 0.18–4.5, p = 0.89).ConclusionsWhen used preferentially, the use of neoadjuvant chemotherapy in DMPM patients was not associated with worse outcomes compared to adjuvant chemotherapy. It was well-tolerated and did not prevent surgical intervention.

Advances in the management of peritoneal malignancies.

Peritoneal surface malignancies (PSMs) are usually associated with a poor prognosis. Nonetheless, in line with advances in the management of most abdominopelvic metastatic diseases, considerable progress has been made over the past decade. An improved understanding of disease biology has led to the more accurate prediction of neoplasia aggressiveness and the treatment response and has been reflected in the proposal of new classification systems. Achieving complete cytoreductive surgery remains the cornerstone of curative-intent treatment of PSMs. Alongside centralization in expert centres, enabling the delivery of multimodal and multidisciplinary strategies, preoperative management is a crucial step in order to select patients who are most likely to benefit from surgery. Depending on the specific PSM, the role of intraperitoneal chemotherapy and of perioperative systemic chemotherapy, in particular, in the neoadjuvant setting, is established in certain scenarios but questioned in several others, although more prospective data are required. In this Review, we describe advances in all aspects of the management of PSMs including disease biology, assessment and improvement of disease resectability, perioperative management, systemic therapy and pre-emptive management, and we speculate on future research directions.

Impact of perioperative chemotherapy on survival outcome of advanced colorectal cancer patients treated with cytoreduction and hyperthermic intraperitoneal chemotherapy: A retrospective study.

e15570 Background: Colorectal cancer (CRC) with peritoneal carcinomatosis (PC) is generally associated with poor prognosis. The present study aims to assess potential value of perioperative systemic chemotherapy in patients treated with cytoreductive surgery with HIPEC (CRS/HIPEC) in a single institute in Saudi Arabia. Methods: We included CRC with PC who underwent CRS/ HIPEC from January 2012 till December 2019. Different clinicopathological, treatment-related factors and dates of relapse/death, were retrospectively assessed. We checked the distribution of these factors in addition to survival outcome in those who received perioperative chemotherapy vs. none. Results: We recruited 127 eligible patients (79 patients [62.2%] received systemic chemotherapy). Patients with no perioperative chemotherapy were more likely to have grade 1 tumours (62.5% vs. 25.3%, p &lt; 0.0001), mucinous adenocarcinoma (41.7% vs. 12.7%, p = 0.002), normal CEA ≤5 ng/dl (70.2% vs. 47.4%, p = 0.016) and peritoneal-only metastasis (66.7% vs. 45.6%, p = 0.021). Median PFS and OS were 34 and 62.2 months, respectively. Patients with no perioperative systemic chemotherapy had significantly better PFS and OS (median PFS: not reached vs. 19 months, HR = 0.29, 95% CI = 0.15-0.59, p &lt; 0.0001, OS :HR = 4.3, 95% CI 1.3-14.3, p = 0.009). After adjustment of different prognostic factors, there was no significance difference in OS between the two groups (HR = 3.8, 95% CI = 0.98-14.71, p = 0.053), while PFS was still significantly better in the no chemotherapy group (HR = 2.52, 95% CI = 1.13-5.63, p = 0.024). Conclusions: CRS/HIPEC provided favourable survival outcome in our study cohort especially in patients with more favourable prognostic features. No survival benefit with perioperative chemotherapy could be demonstrated.

HER3 expression in metastatic colorectal cancer: Defining the clinicomolecular profile of an emerging target.

3588 Background: The success of tailored systemic therapies in treating distinct molecular subsets of patients (e.g., deficient mismatch repair, BRAF mutant, HER2 amplified) has spurred further exploration of novel targetable subsets within the heterogeneous landscape of metastatic colorectal cancer (mCRC). Human epidermal growth factor receptor 3 [HER3 (ErbB3)], a member of the HER (ErbB) receptor tyrosine kinase family, plays an important role in tumorigenesis and metastases and has emerged as a promising therapeutic target in a diverse array of cancers. For example, patritumab deruxtecan (U3-1402; HER3-DXd) is a HER3-directed antibody drug conjugate that has demonstrated clinically meaningful antitumor activity and acceptable safety profiles in metastatic breast cancer and EGFR-mutated non-small cell lung cancer. There is limited data, however, on the clinicopathological characterization of HER3 expression in mCRC. Methods: Tissue samples (surgical-metastatectomy) (N = 115) were obtained from a clinical cohort of patients (N = 99) with histologically proven mCRC and liver metastases who underwent liver resection with/without perioperative systemic chemotherapy. HER3 expression was analyzed on whole-mount preparations by immunohistochemistry (IHC). Staining was performed and visualized using the HER3 (D22C5) XP Rabbit-mAb (Cell Signaling Technology). Patients were categorized based on membranous intensity score as follows: Low with IHC 0 (absence of staining or staining in &lt; 10% of tumor cells), 1+ (faint/barely perceptible staining in ≥10% of tumor cells) or 2+ (weak to moderate staining in ≥10% of tumor cells), or High with IHC 3+ (strong staining in ≥10% of tumor cells). Clinicomolecular and treatment data, including gender, tumor sidedness, mutational status (RAS or BRAF), and prior chemotherapy were collected by review of patient electronic medical records. Chi-squared (or Fisher’s exact) test were used to determine associations between groups. Overall survival (OS) was calculated using Kaplan-Meier method and compared using log-rank tests. Results: Among 99 analyzed patients, 98 were evaluable for HER3 expression. Of these 25.5%, 26.5%, 40.8% and 7.2% showed HER3 IHC scores of 3+, 2+, 1+ and 0, respectively. No significant association was seen with HER3 expression and clinicopathological variables, mutational status, or prior treatment. Among patients with 2 samples analyzed from the same liver surgery, there was a moderate level of heterogeneity with concordance of 78.5% (kappa 0.43). Patients with high HER3 expression had poorer OS (5-year OS: 52%; median: 90.2 months) compared to low HER3 expression (5-year OS: 85%; median: not reached). Conclusions: In this large cohort of mCRC, HER3 expression was observed in 92.8% of patients and across diverse clinical and molecular features, supporting HER3 as a promising targetable biomarker in a large subset of mCRC.