Peritoneal metastases from colorectal cancer: Patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is an established treatment modality for patients with pseudomyxoma peritonei. The majority of patients with pseudomyxoma who have complete tumour removal and HIPEC are cured.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal and gastrointestinal origin shows acceptable morbidity and high survival

Background

Peritoneal carcinomatosis from colorectal origin carries a poor prognosis. Recent clinical studies show that cytoreductive surgery (CS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival of selected patients with a colorectal carcinoma and isolated peritoneal carcinomatosis in the absence of extra-abdominal metastases. Here, we report the clinical outcomes and survival after cytoreductive surgery and HIPEC of the first cohort of patients treated in our institution.

Methods

Sixty-seven patients underwent a laparotomy. Complete cytoreduction could be performed in 49 patients, who underwent a total of 53 CS–HIPEC procedures. All had peritoneal carcinomatosis originating from primary colorectal, cecal, appendiceal, and gastric tumors.

Results

In patients who underwent CS–HIPEC, an R0 resection could be achieved in 4%, R1 in 88%, and R2 in 8%. The 30-day mortality was 0; one patient died in-hospital after 10 weeks. The median hospital stay was 12 days (range 4–56). The overall morbidity was 43%, including extended gastroparesis (11%), anastomotic failure (11%) and intra-abdominal abscess (9%). Mean time to clinical recurrence was 12 months (range 4–22). The actuarial 1-year survival was 88% and 2-year survival was 75%.

Conclusion

In well-selected patients referred to a specialized institution, CS–HIPEC has an accep table morbidity and high survival rate.     

细胞减灭术联合腹腔热灌注化疗治疗结直肠癌腹膜转移的临床应用与展望

结直肠癌为我国常见恶性肿瘤之一, 其发病率逐年上升。腹膜为结直肠癌第2常见转移部位, 早期诊断困难, 预后不良。既往多采取全身性系统静脉化疗作为腹膜转移的主要治疗策略, 其全身不良反应明显, 且不能有效控制肿瘤进展。近年来, 外科技术、理念、设备的不断发展以及新的化疗药物与靶向药物的出现改善了结直肠癌腹膜转移患者的生存质量及预后。细胞减灭术(CRS)联合腹腔热灌注化疗(HIPEC)可在有效清除腹腔内游离癌细胞与亚临床病灶的同时, 减轻化疗药物带来的全身不良反应, 最大程度上实现宏观与微观的肿瘤根治, 目前, CRS+HIPEC已被国内外作为结直肠癌腹膜转移的一线治疗方案。文章分析总结了CRS+HIPEC治疗结直肠癌腹膜转移的生存疗效、预后因素分析、化疗安全性等问题, 探讨了HIPEC治疗目前存在的问题与争议。     

Peritoneal carcinomatosis and liver metastases from colorectal cancer treated with cytoreductive surgery perioperative intraperitoneal chemotherapy and liver resection

Background

An aggressive therapy comprising of cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) and liver resection/ablation is generally not offered to patients with both colorectal peritoneal carcinomatosis (CRPC) and liver metastases (LM) as it no longer represents a loco-regional disease. We review the outcomes of patients who underwent an aggressive treatment with a curative intent for both CRPC and LM as a prelude towards determining the suitability of this treatment.

Methods

Patients with CRPC were treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy in our institution. Patients with LM underwent additional treatment of liver resection/ablation. The characteristics and survival of patients with isolated CRPC and those with both CRPC and LM were compared.

Results

Fifty-five patients underwent complete cytoreductive surgery for treatment of CRPC, amongst which 16 patients had LM. The overall median survival was 36 months. Fourteen of the 16 patients treated for CRPC and LM underwent synchronous treatment. When patients with CRPC alone or CRPC with LM were compared, patients with CRPC and LM had a lower PCI (p = 0.03), received less HIPEC infusion (p < 0.001), received less of both HIPEC and EPIC infusion (p = 0.007), had a shorter procedural duration (p = 0.001) and required less blood transfusion (p = 0.02). There was no difference in survival between patients who had CRPC alone or CRPC with LM who underwent aggressive treatment (p = 0.77).

Conclusions

A curative procedure may be offered to selected patients with CRPC and LM, especially in those with a low peritoneal cancer index.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of gastrointestinal cancers with peritoneal metastases: Progress toward a new standard of care

Peritoneal metastases from gastrointestinal cancer was, in the past, accepted as an inevitable component of the natural history of these diseases. It is a major cause of intestinal obstruction, fistula formation, and bowel perforation as the recurrent malignancy progresses to a terminal condition. Peritoneal metastases may be caused by full thickness penetration of the bowel wall by the primary cancer or by spilled cancer cells released into the peritoneal space by surgical trauma. Two new surgical technologies that have evolved to manage peritoneal metastases are cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This combined treatment strategy uses peritonectomy procedures and visceral resections to reduce the disease in the abdomen and pelvis to a macroscopic volume. Then, HIPEC is used to preserve the complete cytoreduction by controlling the minimal residual disease. Since the extent of peritoneal metastases, as measured by the peritoneal cancer index (PCI), is crucial to a favorable outcome, prognostic indicators are used to select patients for treatment. The combined treatment may be used to prevent peritoneal metastases in gastrointestinal cancer patients having a resection of the primary malignancy. This is especially important in gastric cancer patients with serosal invasion. The combined treatment may be used synchronously with the primary cancer resection if peritoneal metastases are already apparent. The treatment is most frequently used with metachronous peritoneal metastases diagnosed in follow-up. Cure of peritoneal metastases is an option in selected patients and its knowledgeable use is progressing towards a new standard of care.     

Outcomes following synchronous liver resection,cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases: A bi-institutional study

PurposeSynchronous liver resection, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal liver (CRLM) and peritoneal metastases (CRPM) has traditionally been contraindicated. However, latest practice promotes specialist, multidisciplinary-led consideration for select patients. This study aimed to evaluate the perioperative and oncological outcomes of synchronous resection in the management of CRLM and CRPM from two tertiary referral centres.MethodThis bi-institutional, retrospective, cohort study included patients undergoing simultaneous liver resection, CRS and HIPEC for metastatic colorectal cancer from 2013 to 2020. Patients treated with ablative liver techniques, staged operative approaches and extra abdominal disease were excluded. Overall survival (OS) and disease-free survival (DFS) rates were assessed. Univariate and multivariate analyses identified variables associated with survival and major morbidity (Clavien-Dindo grade III/IV).ResultsTwenty-three patients were included. The median peritoneal carcinomatosis index (PCI) was 9 (range 0–22). There were two major liver resections and 21 minor resections. CC-0 resections were achieved in all patients. Major morbidity occurred in 7 patients. There were no deaths at 90 days. PCI was independently associated with morbidity (p = 0.04). PCI >10 (p = 0.069), major morbidity (p = 0.083) and presence of KRAS mutation (p = 0.052) approached significance for poor OS. Median follow up was 21 months (4–54 months). Median OS was 37 months, 3-year survival 54%, and median DFS 18 months.ConclusionSynchronous liver resection, cytoreductive surgery and HIPEC is feasible in selected patients with low-volume CRPM and CRLM. Increasing PCI is associated with postoperative major morbidity, and should be considered during operative planning.     

Outcomes for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the elderly

BackgroundCytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) has gained acceptance in the treatment of peritoneal carcinomatosis (PC) with reported morbidity and mortality rates of 27–56% and 0–11% respectively. The safety and outcome of such major operation in the elderly remains unclear. We report our experience at a high volume tertiary center.MethodA total of 170 consecutive patients underwent CRS-HIPEC for peritoneal carcinomatosis between March 2007 and July 2012. Mitomycin C (88.8%) was administered intraperitoneally at 42 °C for 90 min. Patients were categorized into two groups according to the age at the time of surgery: Group 1 (≤65 years-old) and Group 2 (>65 years-old). Differences between the groups were analyzed. Univariate and multivariate analyses were performed to identify variables associated with major morbidity.ResultsOf the 170 patients, 35 were older than 65 years. The two most common tumor sites were colorectal and appendiceal cancer. The perioperative morbidity and mortality rates in the elderly were 18.8% and 8.6% respectively. Gender, tumor type, estimated blood loss >400 mL, intraoperative blood transfusion, operative time >6 h, bowel anastomosis, intraoperative PCI >16, and extent of cytoreduction (Δ PCI) were not associated with major morbidity in the older group (p > 0.05). At a median follow-up of 15.7 months (0.2–53.5 months), recurrence rate for colorectal/appendiceal PC at 1 year was 48.0% in Group 1 and 44.3% in Group 2 (p = NS). Median survival for the colorectal/appendiceal carcinomatosis patients in Group 1 (n = 81) was 29.79 (SE 4.7) months and in Group 2 (n = 20) was 21.2 (SE 3.0) months, (p = 0.06, NS).ConclusionCRS-HIPEC procedures for peritoneal carcinomatosis in the elderly demonstrate comparable perioperative outcome in well-selected patients. Optimal cytoreduction was achieved in the majority of cases and survival was not significantly different from that of the younger group.     

Prognostic impact of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients: A meta-analysis of randomized controlled trials

Backgroundgastric cancer patients frequently develop peritoneal metastases (PM) with a poor long-term prognosis. A solid body of evidence underlines the beneficial role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on survival, but to date, there is a lack of consensus regarding the optimal strategy in the treatment of locally advanced primary tumors with or without peritoneal metastasis. The present meta-analysis aims to assess the impact of CRS + HIPEC on survival analyzing the results of randomized studies only.MethodsA systematic review of articles was conducted according to PRISMA guidelines. Twelve studies were included in qualitative and quantitative analysis.ResultsA survival benefit for patients treated with CRS + HIPEC at all time points was highlighted. However, difference in survival was significant at all time points for patients treated for prophylaxis of PM, but no difference was found when considering resection with a curative intent. The 1, 2, 3 and 5-year survival rates (SR) for patients undergoing CRS + HIPEC were 86.9%, 70.5%, 63.7% and 55.7% respectively. CRS + HIPEC for the treatment rather than prophylaxis of PM was the only predictor of a reduced 3y SR.ConclusionsCRS + HIPEC may lead to improved prognosis for patients suffering from locally advanced gastric cancer in both prophylactic and curative settings. However, due to far from negligible postoperative morbidity and mortality rates, a strict patient selection is crucial to achieve the best results. The presence of extraperitoneal disease strongly limits the indication of this kind of surgery.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of ovarian cancer

Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery and maximal regional chemotherapy, has been applied to treat ovarian cancer resulting in long-term survival rates in selected patients. However, the status of HIPEC in ovarian cancer remains an experimental procedure, given the many variables among the data and trials reviewed, to enable us to derive strong conclusions about its role from this overview. In this review we discuss treatment with HIPEC in patients with ovarian cancer and future prospective of its use in clinical setting. HIPEC is an effective tool in the treatment of selected patients with peritoneal carcinomatosis from ovarian cancer. Unfortunately, due to the lack of randomised trials, the evidence of HIPEC is very limited. Future randomised studies are awaited to define the role and clinical impact of HIPEC in ovarian cancer.     

Early and long-term postoperative management following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Peritoneal surface malignancies have been traditionally regarded as end-stage conditions amenable to merely palliative options. The combination of aggressive cytoreductive surgery (CRS), involving peritonectomy procedures and multivisceral resections, with intra-operative hyperthermic intra-peritoneal chemotherapy (HIPEC) and/or early postoperative intra-peritoneal chemotherapy (EPIC) to treat the microscopic residual tumor is a new concept. In recent years, promising results have been reported for peritoneal mesothelioma and carcinomatosis of gastrointestinal and gynaecologic origin treated by this combined protocol. However, CRS with HIPEC and/or EPIC is a complex procedure associated with high rates of potentially life-threatening complications. Furthermore, disease progression following comprehensive treatment is not uncommon and represents a relevant cause of treatment failure. The present paper reviews the available information on early postoperative management and long-term follow-up in patients treated with CRS and intraperitoneal chemotherapy. The peculiar clinical and biological alterations that can be expected during an uncomplicated postoperative course, as compared to standard digestive surgery, are discussed. Early recognition and appropriate management of the most common adverse events are addressed, in order to minimize the impact of treatment-related morbidity on survival and quality of life results. Since re-operative surgery with additional HIPEC, has proven to be useful in selected patients with recurrent disease, long-term surveillance aiming at early detection of postoperative disease progression has become a relevant issue. Current results on follow-up investigations are presented.     

Advanced cytoreduction as surgical standard of care and hyperthermic intraperitoneal chemotherapy as promising treatment in epithelial ovarian cancer

Favorable oncological outcomes have been reported in several trials with the introduction of Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the treatment of Advanced Epithelial Ovarian Cancer (EOC). However most of the studies testing the combined approach are observational and have been conducted in inhomogeneous series so that the evidence supporting the performance of this combined treatment is still poor. Median Overall and Disease Free Survivals of up to 64 months and 57 months, respectively have been reported. Although a rate of morbidity of up to 40% has been observed in some series the CRS + HIPEC continues to gain an increased popularity. Several prospective randomized trials are ongoing using the procedure in various time points of the disease.In this review several issues such as the impact of cytoreduction and residual disease (RD) on outcomes as well as the role of HIPEC will be updated from the literature evidence. Some controversial points HIPEC related will also be discussed.Recent experiences regarding the introduction of a more aggressive surgical approach to upper abdomen to resect peritoneal carcinomatosis (PC) allowed increased rates of optimal cytoreduction and has demonstrated an apparent better outcome. This evidence associated with the positive results phase III trial testing normothermic intraperitoneal as first-line chemotherapy is guiding some investigators to propose the CRS + HIPEC in the primary setting. Several prospective phase II and III trials have recently been launched to validate the role of the combined treatment in various time points of disease natural evolution.     

Oxaliplatin-based hyperthermic intraperitoneal chemotherapy with single drug versus multiple drug treatment for colorectal cancer with peritoneal metastases: an observational cohort study

BackgroundLong-term survival for selected patients with peritoneal metastases (PM) from colorectal cancer (CRC) is possible when treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The objective of this study was to compare three different oxaliplatin-based (OX)-HIPEC regimens. Primary end-point was disease-free survival (DFS), and secondary endpoints, morbidity and overall survival (OS).MethodsThis is a retrospective study of all patients with colorectal PM treated with CRS and HIPEC between 2004 and 2015 from the prospectively maintained Uppsala HIPEC database. One hundred and thirty-three patients were identified. Three HIPEC regimens were included: OX-HIPEC, OX-HIPEC + post-operative intraperitoneal chemotherapy (EPIC) with 5-fluorouracil (5-FU), and oxaliplatin-irinotecan-based (OXIRI)-HIPEC. Multivariable Cox regression for DFS was performed.ResultsSixty-one patients received OX-HIPEC, 24 patients received OX-HIPEC + 5-FU EPIC, and 48 patients received OXIRI-HIPEC. The DFS for the OX-HIPEC group was 10.5 months, OX-HIPEC + EPIC 11.9 months, and OXIRI-HIPEC 13.4 months (OX-HIPEC vs. OXIRI HIPEC, P=0.049). The morbidity and OS did not differ between the groups. In the multivariable analysis, low peritoneal cancer index (PCI), absence of liver metastases, low completeness of cytoreduction (CC) score, and multiple drug (EPIC or OXIRI) HIPEC regimen were independent prognostic factors for DFS.ConclusionsThis study showed improved DFS with an intensification of HIPEC by adding irinotecan or EPIC compared to oxaliplatin alone without an increase in morbidity or mortality.     

Prognostic scores for colorectal cancer with peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Background: Selecting colorectal patients for HIPEC-surgery needs improvement. The study aim was to improve the colorectal peritoneal score (COREP) and to compare it with three other scores: peritoneal-surface disease-severity score (PSDS), colorectal-peritoneal metastases prognostic-surgical-score (COMPASS), and the CEA/PCI ratio.

Method: Twelve preoperative factors were chosen to evaluate for COREP score modification. Criteria from logistical analyses were set to qualify for the modified COREP score (mCOREP). Odds ratios were used to assign score points for the eligible factors with open/close laparotomy prediction as endpoint. mCOREP was applied internally and compared with the original COREP, PSDS, COMPASS, and CEA/PCI ratio. Odds ratios, hazard ratios, and Kaplan–Meier curves were used for comparison.

Results: Seven factors qualified for mCOREP: CEA, CA 19-9, CA-125, C-reactive protein, albumin, platelet count and signet-cell histology. mCOREP was superior to the original COREP. mCOREP and COMPASS scores were the only scores with independent prognostic value. The mCOREP had the best discriminatory ability between its prognostic groupings. mCOREP 11?+?had 9?months survival with half of patients being open/close surgery.

Conclusion: The mCOREP has successfully been simplified while still improving its prognostic ability. The mCOREP and COMPASS scores have independent prognostic value. Patients with mCOREP 11?+?may not benefit from treatment.     

Systemic inflammatory response after hyperthermic intraperitoneal chemotherapy (HIPEC): The perfusion protocol matters!

BackgroundCRS/HIPEC gained acceptance as a treatment for selected patients with peritoneal metastasis. However, the pathophysiology behind HIPEC is poorly understood, and a variety of regimens are currently in use. In this study, we describe for the first-time changes in the postoperative systemic inflammatory reaction, highly different among HIPEC treatment protocols.MethodsHIPEC was performed with three protocols, different with regard to perfusion times and drugs: (mitomycinC/doxorubicin, 90min), (cisplatin, 90min) (oxaliplatin, 30min). Serial blood samples were assessed for C-reactive protein (CRP), white blood cells (WBC), pancreatic stone protein (PSP) and bacterial component (16s rDNA). The study was approved by the local ethics committee and registered at clinicaltirals.gov (NCT02741167).ResultsOverall, 140 patients from two European centers were included. In patients without postoperative complications, a secondary peak of inflammatory parameters, CRP (p = 0.015) and PSP (p = 0.004) was observed after HIPEC for 90 min with mitomycinC/doxorubicin or cisplatin but not after 30 min oxaliplatin. In patients after 90 min HIPEC, postoperative serum bacterial 16srDNA level were 2.1 times higher (95% CI 0.646–3.032, p = 0.015) compared to 30 min oxaliplatin.DiscussionIn conclusion, we identified a secondary inflammatory reaction after 90 min HIPEC, either with mitomycinC/doxorubicin or cisplatin, not observed after short course HIPEC with oxaliplatin. This protocol dependent physiology of acute phase proteins should be known in the clinical management of patients after HIPEC.     

Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases

The peritoneal cavity must be oncologically considered as an organ in its own right and peritoneal metastases (PM) must be treated with the same curative intent (and the same results) as liver metastases. The package combining complete cytoreductive surgery (CCRS) (treating the visible disease) plus hyperthermic intraoperative peritoneal chemotherapy (HIPEC) (treating the remaining non-visible disease) achieves cure in many patients. Twenty years of publication allow us to assemble sufficient background information and data to point out the good and poor indications for CCRS + HIPEC.HIPEC is the standard of care for the treatment of peritoneal pseudomyxomas and peritoneal mesotheliomas and also, recently for the treatment of colorectal PM with limited peritoneal extension.HIPEC is in the evaluation phase for gastric PM and ovarian PM after initially disappointing results, but it is highly probable that it will be useful in particular settings. PM from neuroendocrine tumours are in the same situation.HIPEC is not currently indicated for the treatment of PM from sarcomas, from GIST, and for small round-cell desmoplastic tumours, given the poor results obtained.HIPEC can be useful, on a case-by-case basis, to treat rare tumours complicated by isolated peritoneal diffusion (e.g. Frantz’s tumours).HIPEC can be used in the prophylactic setting to prevent PM in patients with a high risk of developing PM, and the first results of the ‘second-look’ approach are promising.Finally, CCRS + HIPEC appear to be indispensable tools in the oncologist’s armentarium.     

Quality of life in patients with peritoneal surface malignancies after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Background

An increasing number of patients are presenting with peritoneal carcinomatosis and more centers are performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). While morbidity and mortality are shown to be acceptable, quality of life after surgery should be assessed.

Methods

63 patients who had CRS and HIPEC from 2001 to 2012 and who were still alive and on follow up were included. The EORTC-QLQ-C30 was administered to the patients.

Results

Median age was 53 years (14–71). 44% had ovarian primaries, 21% had appendicael primaries and 19% had colorectal primaries. Median follow-up was 1.08 years (0.06–9.8). The median time from surgery to the questionnaire was 1.3 years (0.24–10.18). There was no statistical difference in scores when comparing by age, gender, recurrence, gender, PCI score, presence of a complication and type of primary cancer. Scores were highest less than 6 months after surgery, dropped subsequently but rose again after 2 years. Our patients had better scores compared to a control group of outpatient cancer patients at our institution as well as the reference EORTC group.

Conclusions

In keeping with previous quality of life studies done for CRS and HIPEC patients, we have shown that our patients can achieve a good quality of life after CRS and HIPEC even with recurrent disease.