Advances in therapeutics for peritoneal metastases from colorectal cancer: a narrative review

Introduction

Colorectal cancer (CRC) caused nearly 900,000 deaths and was newly diagnosed in 1.8 million patients worldwide in 2018, making it the 2^nd leading cause of cancer deaths and the 3^rd most diagnosed cancer (1,2). Carrying significant morbidity and mortality, it is estimated that anywhere from 55–75% of CRC patients will ultimately die from their cancer (3,4).

While patients with localized CRC can expect a 5-year survival as high as 90% (5,6), it is estimated that 4–8% of CRC patients have peritoneal metastasis (PM) at the time of diagnosis and nearly 20% develop metachronous peritoneal disease, making the peritoneum the third most common site of CRC metastasis after the liver and lungs (7-11). Furthermore, PM from CRC is likely under-diagnosed and understudied, as peritoneal nodules are often too small to be detected on standard computed tomography (CT) or positive emission tomography (PET) (12,13), exploratory laparoscopy often leaves intra- and extra-peritoneal regions unexamined (14), symptoms may present late, and CRC patients with PM have historically been excluded from clinical trials due to their poor response to systemic chemotherapy relative to CRC patients without PM (15-17). Indeed, autopsy evidence suggests that the true incidence of PM from CRC is as high as 40% (18-20).

We present the following article in accordance with the Narrative Review reporting checklist (available at https://dmr.amegroups.com/article/view/10.21037/dmr-21-88/rc).

Methods

A systematic literature search was conducted using the MEDLINE/PubMed database. To identify relevant studies, the following search terms were used: “intraperitoneal chemotherapy”, “colorectal cancer”, “peritoneal carcinomatosis”, “advanced colorectal cancer”, “HIPEC”, “EPIC”, “novel therapies”, and “adjuvant chemotherapy”. Data regarding the study design, patient population, treatments received, safety and tolerability, and primary outcomes were assessed and recorded, and studies conducted or published prior to 1980 were excluded (Table 1). The quality of studies was independently evaluated by all researchers, with any disagreements regarding inclusion resolved through thorough assessment and discussion. The quality of relevant studies was noted in the manuscript.

Current treatments

The most common operative treatment for CRC with PM is cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC). While this treatment was first developed in the 1980’s and 1990’s, it gained wide use following several studies demonstrating an overall survival (OS) and progression-free survival (PFS) benefit compared to other modalities of treatment (21-29). One of the most notable of these studies was conducted in 2003, in which Verwaal et al. randomly assigned 105 patients with PM from CRC to either a “standard therapy” arm, consisting of systemic chemotherapy with or without palliative surgery, or an “experimental therapy” arm, consisting of CRS/HIPEC (22). After a median follow-up of 21.6 months, the median survival was 22.4 months in the experimental arm and 12.6 months in the standard arm. The authors also noted that the 2-year survival was more than twice as high in the CRS/HIPEC group, further demonstrating a significant survival benefit to CRS/HIPEC.

More recently however, the PRODIGE trial called into question the benefit of adding HIPEC to CRS (30). In this randomized, open-label, phase 3 trial conducted in France (NCT00769405), patients with PM from CRC either underwent CRS with oxaliplatin-based HIPEC or CRS alone, and all received perioperative systemic chemotherapy. After a median follow-up of 63.8 months no significant difference in OS or PFS was noted between the two groups, with the CRS/HIPEC group demonstrating median OS and PFS of 41.7 and 13.1 months, and the CRS-alone group demonstrating median OS and PFS of 41.2 and 11.1 months. However, there are several important findings to highlight from these results. Patients in both the CRS alone and the CRS/HIPEC group achieved a durable survival benefit from their treatment, with both groups experiencing a median overall survival exceeding 3 years. Further, the negative results from this trial may be attributable in part to the selected HIPEC regimen, as oxaliplatin was the only agent used in the trial and it was delivered at a lower dose and over a shorter perfusion time of 30 minutes compared to standard protocols used in the United States. Finally, a subsequent subgroup analysis demonstrated that HIPEC with oxaliplatin perhaps did improve OS and PFS in patients with an intermediate peritoneal cancer index (PCI) score between 11 and 15, and it is thus possible that HIPEC may provide a benefit in select patients.

Systemic chemotherapy in itself is also a standard treatment for PM from CRC, although systemic therapy alone has been historically associated with limited survival benefit. Various studies from the 1990s and early 2000s found that patients with PM of CRC origin treated with 5-fluorouracil and leucovorin had a median survival of 5.2 to 7.7 months (7,31-33). The addition of irinotecan and platinum-based analogs such as oxaliplatin to chemotherapeutic regimens has significantly improved this prognosis, with more recent studies demonstrating median survivals ranging from 6 to 24 months (28,34-38). However, a 2017 systematic review found little evidence in seven studies to support the use of neoadjuvant systemic chemotherapy in treating PM from CRC, although its analysis of 14 studies using adjuvant chemotherapy did demonstrate limited evidence of improved survival (39). Klaver et al. in 2013 found a significant OS and PFS benefit from the addition of 5-fluorouracil-based chemotherapy with oxaliplatin alongside targeted therapy of CRS or CRS/HIPEC, with the benefits even more pronounced when biological therapies, such as bevacizumab, panitumumab, or cetuximab, were incorporated as a first line treatment (40). Yet, few studies have directly compared biological agents and different timelines of administration against each other, making broad conclusions about the efficacy of systemic chemotherapy in treating PM from CRC difficult.

Today, most referral centers use a multidisciplinary approach of CRS/HIPEC alongside systemic chemotherapy, both adjuvant and neoadjuvant (41), in the treatment of PM from CRC. Regardless, even with optimal treatment, nearly half of patients experience disease progression or local recurrence in the 1^st year after surgery, the 5-year overall survival is estimated at around 40%, and treatment itself may be associated with significant morbidity and mortality (24,25,42-50). Thus, it is imperative that novel therapies be investigated to better treat this debilitating and deadly disease.

Additional modalities of intraperitoneal and systemic chemotherapy delivery

One of the primary areas of investigation in the treatment of PM from CRC involves modifying and improving upon existing surgical techniques and administration of intraperitoneal or systemic chemotherapy, as summarized in Table 2.

Pressurized intraperitoneal aerosolized chemotherapy (PIPAC)

PIPAC laparoscopically delivers chemotherapy, most commonly oxaliplatin, as a pressurized aerosol, which theoretically should produce better tissue penetration and distribution of the cytotoxic agent compared to the traditional delivery system used in HIPEC (51,52). While early evidence suggests that it is safe with low toxicity and can stimulate disease regression in select patients with PM from CRC (53-56), a recent single-arm, phase II trial in patients with unresectable colorectal peritoneal metastases did report a high number of major and minor adverse events (57). Five clinical trials (NCT03868228, NCT03246321, NCT03280511, NCT03210298, and NCT02604784) are currently investigating the safety and efficacy of this novel procedure in PM from CRC (49).

Early post-operative intraperitoneal chemotherapy (EPIC)

EPIC administers chemotherapy, typically mitomycin C or 5-fluorouracil, for 5 days following surgery. Introduced in the 1990s in an attempt to reduce peritoneal recurrence following cytoreduction (58,59), current research on its use in patients with PM from CRC is entirely retrospective in nature and its benefits are inconclusive (60). For example, a 1:2 matched case-control study found that the administration of EPIC in patients undergoing CRS for PM from CRC improved OS and PFS compared to controls who did not receive EPIC (61). Conversely, when EPIC has been compared head to head with HIPEC, it has not shown superiority in regard to OS or PFS and has been associated with worse side effects across patients with various primary tumors, including colorectal (23,24,62-64). While current evidence does not support the addition of EPIC to CRS/HIPEC, Chua et al. showed that the combination of the two improved OS and PFS in patients with colorectal peritoneal carcinomatosis compared to either treatment alone (65), and the combination has also produced favorable results in patients with peritoneal dissemination from primary tumors of appendiceal origin (66). However, this combination has been associated with an increased risk of postoperative complications, with one study finding that EPIC + HIPEC produced higher rates of grade III/IV complications compared to HIPEC alone (44.7% vs. 31.0%), and that on multivariate logistic regression it was associated with increased complications in patients with peritoneal malignancies (67). The ongoing ICARuS trial (NCT01815359) is the first randomized control trial to prospectively compare EPIC, which will use floxuridine and leucovorin, and HIPEC with mitomycin C, for treatment of peritoneal metastasis of appendiceal and colorectal origin.

Sequential postoperative intraperitoneal chemotherapy (SPIC)

SPIC is a form of sequential EPIC administered for 6 months post-CRS. While it has demonstrated a survival benefit in treating PM from ovarian cancer (68), it has only been sparsely investigated in PM from CRC origin, with just a handful of trials and case-control studies in the literature. A randomized trial that was terminated prematurely along with a non-randomized comparative study found that CRS/SPIC did confer a survival benefit compared to systemic chemotherapy alone (69,70), but the role of SPIC cannot be extrapolated from these studies as there were no control groups undergoing CRS without SPIC. SPIC has been compared to HIPEC alone in both a case-control and a cohort study, both of which demonstrated superior OS and PFS in the HIPEC group (71,72). Nonetheless, its use should be evaluated in conjunction with the standards of care to determine whether it has any use as an adjuvant therapy to CRS/HIPEC.

“Bidirectional” chemotherapy

A “bidirectional” chemotherapy approach involves the simultaneous use of intraperitoneal chemotherapy and systemic chemotherapy preoperatively in patients with advanced, unresectable tumors with the goal of making complete surgical resection possible. One pilot study evaluated a bidirectional regimen of oxaliplatin-based intraperitoneal chemotherapy and FOLFIRI-based systemic chemotherapy in six patients with unresectable PM from CRC (73). The study reported several side effects and complications, but overall the regimen was tolerated well and the researchers recommended a phase I or II trial to determine the optimal oxaliplatin dose and the regimen’s efficacy. This approach has also been investigated in gastric cancer, with promising results (74).

2^nd-look and prophylactic/adjuvant HIPEC

Second-look laparotomy and prophylactic HIPEC has been investigated in patients at a high risk for recurrence or metastasis. Elias et al. found that in patients who were asymptomatic and had no signs of recurrence or metastasis on imaging studies 13 months after resection of an aggressive primary tumor, a second-look operation was able to detect and diagnose peritoneal metastasis in approximately 55% of cases (75,76). Several other studies have found a benefit to prophylactic HIPEC in local tumors at a high-risk for peritoneal dissemination (77,78).

However, two clinical trials, the COLOPEC (NCT02231086) trial and more recently the PROPHYLOCHIP (NCT01226394), failed to find a difference in OS or PFS in this high-risk patient population (79,80). The COLOPEC trial aimed to determine whether adjuvant HIPEC could prevent the development of PM in patients with colon cancer at a high risk for peritoneal spread (80). Conducted in 9 Dutch centers, 204 patients were randomly assigned to receive either adjuvant systemic chemotherapy alone or adjuvant HIPEC followed by standard adjuvant systemic chemotherapy. Progression to PM did not significantly differ between the two groups, with 19% of patients in the experimental arm developing PM compared to 23% in the control arm. During diagnostic laparoscopy at 18 months there was no statistically significant difference in peritoneal-free survival (80.9% for the experimental group vs. 76.2% in the control group.) PROPHYLOCHIP (NCT01226394) was conducted in 23 hospitals in France and randomized 150 patients with CRC at a high risk for developing PM and who had already received 6 months of standard systemic adjuvant chemotherapy to either surveillance or second-look surgery plus HIPEC (79). After a median follow-up of 50.8 months the 3-year disease-free survival was 53% in the surveillance group and 44% in the second-look surgery group, demonstrating no benefit to exploratory laparotomy and HIPEC over surveillance alone. Additionally, 41% of patients in the second-look surgery group had grade 3–4 complications, the most common of which were abdominal hemorrhage or digestive leakage.

Various clinical trials, including the ongoing HIPECT4 (NCT02614534) trial, which uses mitomycin C as adjuvant HIPEC as opposed to the oxaliplatin used in the PROPHYLOCHIP and COLOPEC trials, will further investigate the utilization of HIPEC in preventing PM from CRC in high-risk patients (49).

Perioperative chemotherapy with CRS/HIPEC

While the role of adjuvant and neoadjuvant systemic chemotherapy in treating PM from CRC has already been discussed, another area of investigation is the use of perioperative systemic chemotherapy in conjunction with CRS/HIPEC.

The CAIRO6 (NC02758951) study, an open-label, phase 2 randomized clinical trial performed in Dutch tertiary referral centers, was the first to prospectively compare perioperative systemic chemotherapy in conjunction with CRS/HIPEC versus CRS/HIPEC alone in patients with resectable colorectal peritoneal metastases (76,81). With 40 patients randomized to each arm, the trial found no significant differences in proportion of macroscopic complete CRS/HIPEC between the two groups (89% in the experimental group vs. 86% in the control group). Similarly, post-operative morbidity did not differ significantly between the two groups (22% in the experimental group vs. 33% in the control group). Most of the intraoperative and postoperative characteristics did not significantly differ between the two groups as well, although the experimental group did show a lower median PCI score (5 vs. 12), a lower rate of ostomy formation (19% vs. 43%) and reduced median length of hospital stay (8 vs. 11 days). Despite these negative results, the authors noted that the addition of perioperative systemic chemotherapy was considered safe and capable of inducing a response in patients, and felt that their results justified a phase 3 trial.

Immunotherapy

Intraperitoneal immunotherapy is a novel approach in the treatment of PM from CRC, and while most studies in the field are still nascent and inconclusive and have been primarily performed in animal models, they nonetheless represent exciting first steps. These studies are summarized in Table 3.

CAR-T cell therapy

CAR-T immunotherapy involves collecting and modifying T-cells to target cancer-specific antigens (82) and is currently being investigated in both localized and disseminated solid tumors (83). Upregulated in CRC (84), CEA has arisen as a potential target for this type of immunotherapy (85). Early studies in patients with metastatic CRC not limited to the peritoneum demonstrated the feasibility of this approach, though sample sizes were small and significant side effects were noted in certain patients (86,87). In 2016, Katz et al. investigated intraperitoneal administration of CAR-T cells in a murine model of PM from CRC. The researchers found that the treatment induced significant cancer cell lysis and provided prolonged protection against CEA positive peritoneal tumors, especially when administered in conjunction with antibodies that suppressed myeloid-derived suppressor cells and regulatory T cells that had proliferated in the peritoneal tumors (88). Another potential target of CAR-T therapy in PM from CRC is the surface antigen folate receptor-α (FRα) (89). In a murine model of ovarian, colorectal and breast cancer, however, Song et al. found that while a combination of CAR-T cells with a co-stimulatory molecule designed to target FRα did improve T-cell persistence, it did not produce adequate anti-tumor activity and did not demonstrate consistent localization (90).

Cancer vaccines

Cancer vaccines represent another potential immunotherapy, sensitizing the immune system to cancer cells. In a murine model of PM from CRC, Alkayyal et al. found that intraperitoneal injection of tumor cells infected with an oncolytic Rhabdovirus, Maraba virus, induced the recruitment of cytotoxic natural killer cells to the peritoneal cavity and was associated with reduced tumor burden and improved OS, even in mice with bulky peritoneal carcinomatosis (91). Similarly, Liang et al. evaluated the intraperitoneal administration of a recombinant plasmid that targeted FRα (the same antigen targeted by Song et al.) in a colon cancer murine model, and found that the treatment induced a significant response by natural killer cells and CD8⁺ T cells and led to substantial tumor reduction (92).

Oncolytic vaccinia virus

Immune checkpoint inhibitors when used alone have shown limited efficacy in treating CRC (93-95), and some researchers have therefore turned to oncolytic virotherapy, a novel type of immunotherapy that essentially acts as an in-situ cancer vaccine, to treat this deadly malignancy. The oncolytic vaccinia virus mJX-594 (JX) is armed with granulocyte-macrophage colony-stimulating factor (GM-CSF), which is upregulated in various cancers and has been shown to stimulate immune cell maturation and activity (96,97). Having demonstrated oncolytic and immunostimulatory activity in preclinical models and clinical models of liver cancer (98,99), Lee et al. tested JX in a murine model of PC from MC38 colon cancer. The researchers found that the oncolytic vaccinia virus suppressed peritoneal cancer progression and malignant ascites formation, activated peritoneal dendritic cells and CD8⁺ T cells, selectively destroyed peritoneal colon cancer cells, and even potentiated the activity of immune checkpoint inhibitors and anti-cancer immune cells (100).

Monoclonal antibodies

While three biologic agents—Bevacizumab, Cetuximab, and Panitumumab—are currently approved as first-line treatments for metastatic CRC, several other monoclonal antibodies are under investigation as potential treatments for PM from CRC, as summarized in Table 4.

MOC31PE immunotoxin

MOC31PE immunotoxin is composed of two parts: a monoclonal antibody that targets epithelial cell adhesion molecule (EpCAM), an antigen commonly expressed in CRCs, and pseudomonas exotoxin A. MOC31PE can enter cancer cells that express EpCAM, upon which its toxin causes cell death by inactivating vital cell processes. It demonstrated anti-cancer activity in preclinical testing (101-103) and was tested in patients with PM from CRC in the ImmunoPeCa trial (NCT02219893), a dose-escalating phase 1 trial conducted in 2017 (104). In this trial, 21 patients undergoing CRS/HIPEC for PM from CRC were administered the MOC31PE immunotoxin intraperitoneally the day after surgery at four different dose levels. The researchers found that the drug was safe and well-tolerated, with no dose-limiting toxicity observed. MOC31PE concentrations in the peritoneal fluid were considered to be in the cytotoxic range, though it was not absorbed systemically in any appreciable amount. All patients developed neutralizing antibodies. At 34 months follow-up, the estimated 3-year OS was 78% and the median PFS was 21 months, and the researchers concluded that these results warrant further investigation into the efficacy of MOC31PE immunotoxin at treating PM from CRC (105).

Catumaxomab

Catumaxomab is a rat-mouse hybrid monoclonal antibody that targets EpCAM. With demonstrable antineoplastic activity (106,107), in 2009 it was approved in Europe for treating malignant ascites caused by peritoneal carcinomatosis (108,109). While several studies have shown its efficacy in treating malignant ascites from primary ovarian and gastric cancers (110), its use in CRC and PM from CRC is still largely unexplored. However, a single case report of a 78-year-old patient with peritoneal carcinomatosis of colonic origin treated with catumaxomab found that it suppressed malignant ascites and may have even had systemic antitumor effects (111), and perhaps it warrants further investigation as an adjuvant treatment for PM from CRC.

Other

Radspherin

Radspherin is an alpha-emitting radioactive microparticle drug created by the privately held Norwegian pharmaceutical company Oncoinvent. Designed to distribute localized radiation to cancer cells, Oncoinvent hopes that it will be able to treat metastatic cancers in body cavities. The company claims that in pre-clinical models it has demonstrated anti-cancer activity, has increased overall survival, and has produced little to no toxicity. It is currently being investigated in two separate phase 1 open label clinical trials: RAD-18-001 (NCT03732768) for the treatment of peritoneal carcinomatosis from ovarian cancer and RAD-18-002 (NCT03732781) for the treatment of peritoneal carcinomatosis from colorectal carcinoma. In the RAD-18-002 trial, Radspherin will be administered as an intraperitoneal injection following CRS/HIPEC.

Conclusions

Peritoneal metastases from CRC remains a challenging disease process that, even when treated with a multidisciplinary approach including CRS/HIPEC and systemic chemotherapy, carries significant morbidity and mortality. Various novel therapies are currently being tested to aid in treating this disease, with some promising results, although preliminary. The continued development of these therapies and others will move the paradigm forward with the hope of impacting outcomes in years to come.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Digestive Medicine Research for the series “Peritoneal Carcinomatosis: History and Future”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://dmr.amegroups.com/article/view/10.21037/dmr-21-88/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dmr.amegroups.com/article/view/10.21037/dmr-21-88/coif). The series “Peritoneal Carcinomatosis: History and Future” was commissioned by the editorial office without any funding or sponsorship. OSE served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Digestive Medicine Research from August 2020 to September 2022. OSE received grants from Appendix Cancer Pseudomyxoma Peritonei Foundation Research Grant with the payment made for his institution. OSE had a participation on Verywell Health-Medical Advisory Board. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol 2019;14:89-103. [Crossref] [PubMed]
2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
3. Riihimäki M, Thomsen H, Sundquist K, et al. Colorectal cancer patients: what do they die of? Frontline Gastroenterol 2012;3:143-9. [Crossref] [PubMed]
4. Jones OM, John SK, Horseman N, et al. Cause and place of death in patients dying with colorectal cancer. Colorectal Dis 2007;9:253-7. [Crossref] [PubMed]
5. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 2009;22:191-7. [Crossref] [PubMed]
6. Moghimi-Dehkordi B, Safaee A. An overview of colorectal cancer survival rates and prognosis in Asia. World J Gastrointest Oncol 2012;4:71-5. [Crossref] [PubMed]
7. Jayne DG, Fook S, Loi C, et al. Peritoneal carcinomatosis from colorectal cancer. Br J Surg 2002;89:1545-50. [Crossref] [PubMed]
8. Lemmens VE, Klaver YL, Verwaal VJ, et al. Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study. Int J Cancer 2011;128:2717-25. [Crossref] [PubMed]
9. Segelman J, Granath F, Holm T, et al. Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer. Br J Surg 2012;99:699-705. [Crossref] [PubMed]
10. Koppe MJ, Boerman OC, Oyen WJ, et al. Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg 2006;243:212-22. [Crossref] [PubMed]
11. van Gestel YR, Thomassen I, Lemmens VE, et al. Metachronous peritoneal carcinomatosis after curative treatment of colorectal cancer. Eur J Surg Oncol 2014;40:963-9. [Crossref] [PubMed]
12. Koh JL, Yan TD, Glenn D, et al. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis. Ann Surg Oncol 2009;16:327-33. [Crossref] [PubMed]
13. Sugarbaker PH. Preoperative Assessment of Cancer Patients with Peritoneal Metastases for Complete Cytoreduction. Indian J Surg Oncol 2016;7:295-302. [Crossref] [PubMed]
14. Jayakrishnan TT, Zacharias AJ, Sharma A, et al. Role of laparoscopy in patients with peritoneal metastases considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). World J Surg Oncol 2014;12:270. [Crossref] [PubMed]
15. Tseng J, Bryan DS, Poli E, et al. Under-representation of peritoneal metastases in published clinical trials of metastatic colorectal cancer. Lancet Oncol 2017;18:711-2. [Crossref] [PubMed]
16. Franko J. Therapeutic efficacy of systemic therapy for colorectal peritoneal carcinomatosis: surgeon’s perspective. Pleura and Peritoneum 2018;3:20180102. [Crossref] [PubMed]
17. Franko J, Shi Q, Goldman CD, et al. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol 2012;30:263-7. [Crossref] [PubMed]
18. Hugen N, van de Velde CJH, de Wilt JHW, et al. Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol 2014;25:651-7. [Crossref] [PubMed]
19. Gilbert JM, Jeffrey I, Evans M, et al. Sites of recurrent tumour after 'curative' colorectal surgery: implications for adjuvant therapy. Br J Surg 1984;71:203-5. [Crossref] [PubMed]
20. Russell AH, Pelton J, Reheis CE, et al. Adenocarcinoma of the colon: an autopsy study with implications for new therapeutic strategies. Cancer 1985;56:1446-51. [Crossref] [PubMed]
21. Elias D, Faron M, Iuga BS, et al. Prognostic similarities and differences in optimally resected liver metastases and peritoneal metastases from colorectal cancers. Ann Surg 2015;261:157-63. [Crossref] [PubMed]
22. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737-43. [Crossref] [PubMed]
23. Glehen O, Kwiatkowski F, Sugarbaker PH, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study. J Clin Oncol 2004;22:3284-92. [Crossref] [PubMed]
24. Elias D, Gilly F, Boutitie F, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol 2010;28:63-8. [Crossref] [PubMed]
25. Ihemelandu C, Sugarbaker PH. Management for Peritoneal Metastasis of Colonic Origin: Role of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy: A Single Institution's Experience During Two Decades. Ann Surg Oncol 2017;24:898-905. [Crossref] [PubMed]
26. Cao CQ, Yan TD, Liauw W, et al. Comparison of optimally resected hepatectomy and peritonectomy patients with colorectal cancer metastasis. J Surg Oncol 2009;100:529-33. [Crossref] [PubMed]
27. Cao C, Yan TD, Black D, et al. A systematic review and meta-analysis of cytoreductive surgery with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol 2009;16:2152-65. [Crossref] [PubMed]
28. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009;27:681-5. [Crossref] [PubMed]
29. Franko J, Shi Q, Meyers JP, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol 2016;17:1709-19. [Crossref] [PubMed]
30. Quénet F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:256-66. [Crossref] [PubMed]
31. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 2000;88:358-63. [Crossref] [PubMed]
32. Chu DZ, Lang NP, Thompson C, et al. Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer 1989;63:364-7. [Crossref] [PubMed]
33. Köhne CH, Cunningham D, Di Costanzo F, et al. Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann Oncol 2002;13:308-17. [Crossref] [PubMed]
34. Klaver YL, Lemmens VE, Creemers GJ, et al. Population-based survival of patients with peritoneal carcinomatosis from colorectal origin in the era of increasing use of palliative chemotherapy. Ann Oncol 2011;22:2250-6. [Crossref] [PubMed]
35. Meulenbeld HJ, van Steenbergen LN, Janssen-Heijnen ML, et al. Significant improvement in survival of patients presenting with metastatic colon cancer in the south of The Netherlands from 1990 to 2004. Ann Oncol 2008;19:1600-4. [Crossref] [PubMed]
36. Chua TC, Morris DL, Saxena A, et al. Influence of modern systemic therapies as adjunct to cytoreduction and perioperative intraperitoneal chemotherapy for patients with colorectal peritoneal carcinomatosis: a multicenter study. Ann Surg Oncol 2011;18:1560-7. [Crossref] [PubMed]
37. Klaver YL, Simkens LH, Lemmens VE, et al. Outcomes of colorectal cancer patients with peritoneal carcinomatosis treated with chemotherapy with and without targeted therapy. Eur J Surg Oncol 2012;38:617-23. [Crossref] [PubMed]
38. Gallagher DJ, Kemeny N. Metastatic colorectal cancer: from improved survival to potential cure. Oncology 2010;78:237-48. [Crossref] [PubMed]
39. Waite K, Youssef H. The Role of Neoadjuvant and Adjuvant Systemic Chemotherapy with Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Systematic Review. Ann Surg Oncol 2017;24:705-20. [Crossref] [PubMed]
40. Klaver YL, Leenders BJ, Creemers GJ, et al. Addition of biological therapies to palliative chemotherapy prolongs survival in patients with peritoneal carcinomatosis of colorectal origin. Am J Clin Oncol 2013;36:157-61. [Crossref] [PubMed]
41. Klaver CE, Groenen H, Morton DG, et al. Recommendations and consensus on the treatment of peritoneal metastases of colorectal origin: a systematic review of national and international guidelines. Colorectal Dis 2017;19:224-36. [Crossref] [PubMed]
42. Glehen O, Gilly FN, Boutitie F, et al. Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy: a multi-institutional study of 1,290 patients. Cancer 2010;116:5608-18. [Crossref] [PubMed]
43. Verwaal VJ, Bruin S, Boot H, et al. 8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol 2008;15:2426-32. [Crossref] [PubMed]
44. Kuijpers AM, Mirck B, Aalbers AG, et al. Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol. Ann Surg Oncol 2013;20:4224-30. [Crossref] [PubMed]
45. Hallam S, Tyler R, Price M, et al. Meta-analysis of prognostic factors for patients with colorectal peritoneal metastasis undergoing cytoreductive surgery and heated intraperitoneal chemotherapy. BJS Open 2019;3:585-94. [Crossref] [PubMed]
46. Nadler A, McCart JA, Govindarajan A. Peritoneal Carcinomatosis from Colon Cancer: A Systematic Review of the Data for Cytoreduction and Intraperitoneal Chemotherapy. Clin Colon Rectal Surg 2015;28:234-46. [Crossref] [PubMed]
47. Verwaal VJ, van Tinteren H, Ruth SV, et al. Toxicity of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy. J Surg Oncol 2004;85:61-7. [Crossref] [PubMed]
48. Wu W, Yan S, Liao X, et al. Curative versus palliative treatments for colorectal cancer with peritoneal carcinomatosis: a systematic review and meta-analysis. Oncotarget 2017;8:113202-12. [Crossref] [PubMed]
49. Sánchez-Hidalgo JM, Rodríguez-Ortiz L, Arjona-Sánchez Á, et al. Colorectal peritoneal metastases: Optimal management review. World J Gastroenterol 2019;25:3484-502. [Crossref] [PubMed]
50. Mogal H, Chouliaras K, Levine EA, et al. Repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: review of indications and outcomes. J Gastrointest Oncol 2016;7:129-42. [PubMed]
51. Reymond MA, Hu B, Garcia A, et al. Feasibility of therapeutic pneumoperitoneum in a large animal model using a microvaporisator. Surg Endosc 2000;14:51-5. [Crossref] [PubMed]
52. Khosrawipour V, Khosrawipour T, Kern AJ, et al. Distribution pattern and penetration depth of doxorubicin after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a postmortem swine model. J Cancer Res Clin Oncol 2016;142:2275-80. [Crossref] [PubMed]
53. Demtröder C, Solass W, Zieren J, et al. Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin in colorectal peritoneal metastasis. Colorectal Dis 2016;18:364-71. [Crossref] [PubMed]
54. Ellebæk SB, Graversen M, Detlefsen S, et al. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC)-directed treatment of peritoneal metastasis in end-stage colo-rectal cancer patients. Pleura Peritoneum 2020;5:20200109. [Crossref] [PubMed]
55. Kim G, Tan HL, Sundar R, et al. PIPAC-OX: A Phase I Study of Oxaliplatin-Based Pressurized Intraperitoneal Aerosol Chemotherapy in Patients with Peritoneal Metastases. Clin Cancer Res 2021;27:1875-81. [Crossref] [PubMed]
56. Alyami M, Gagniere J, Sgarbura O, et al. Multicentric initial experience with the use of the pressurized intraperitoneal aerosol chemotherapy (PIPAC) in the management of unresectable peritoneal carcinomatosis. Eur J Surg Oncol 2017;43:2178-83. [Crossref] [PubMed]
57. Rovers KP, Wassenaar ECE, Lurvink RJ, et al. Pressurized Intraperitoneal Aerosol Chemotherapy (Oxaliplatin) for Unresectable Colorectal Peritoneal Metastases: A Multicenter, Single-Arm, Phase II Trial (CRC-PIPAC). Ann Surg Oncol 2021;28:5311-26. [Crossref] [PubMed]
58. Sugarbaker PH, Cunliffe WJ, Belliveau J, et al. Rationale for integrating early postoperative intraperitoneal chemotherapy into the surgical treatment of gastrointestinal cancer. Semin Oncol 1989;16:83-97. [PubMed]
59. Cunliffe WJ, Sugarbaker PH. Gastrointestinal malignancy: rationale for adjuvant therapy using early postoperative intraperitoneal chemotherapy. Br J Surg 1989;76:1082-90. [Crossref] [PubMed]
60. Soucisse ML, Liauw W, Hicks G, et al. Early postoperative intraperitoneal chemotherapy for lower gastrointestinal neoplasms with peritoneal metastasis: a systematic review and critical analysis. Pleura Peritoneum 2019;4:20190007. [Crossref] [PubMed]
61. Park SY, Choi GS, Park JS, et al. Efficacy of Early Postoperative Intraperitoneal Chemotherapy After Complete Surgical Resection of Peritoneal Metastasis from Colorectal Cancer: A Case-Control Study from a Single Center. Ann Surg Oncol 2016;23:2266-73. [Crossref] [PubMed]
62. Lam JY, McConnell YJ, Rivard JD, et al. Hyperthermic intraperitoneal chemotherapy + early postoperative intraperitoneal chemotherapy versus hyperthermic intraperitoneal chemotherapy alone: assessment of survival outcomes for colorectal and high-grade appendiceal peritoneal carcinomatosis. Am J Surg 2015;210:424-30. [Crossref] [PubMed]
63. Elias D, Benizri E, Di Pietrantonio D, et al. Comparison of two kinds of intraperitoneal chemotherapy following complete cytoreductive surgery of colorectal peritoneal carcinomatosis. Ann Surg Oncol 2007;14:509-14. [Crossref] [PubMed]
64. Tan GH, Ong WS, Chia CS, et al. Does early post-operative intraperitoneal chemotherapy (EPIC) for patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) make a difference? Int J Hyperthermia 2016;32:281-8. [Crossref] [PubMed]
65. Chua TC, Liauw W, Zhao J, et al. Comparative analysis of perioperative intraperitoneal chemotherapy regimen in appendiceal and colorectal peritoneal carcinomatosis. Int J Clin Oncol 2013;18:439-46. [Crossref] [PubMed]
66. Huang Y, Alzahrani NA, Liauw W, et al. Early Postoperative Intraperitoneal Chemotherapy for Low-Grade Appendiceal Mucinous Neoplasms with Pseudomyxoma Peritonei: Is it Beneficial? Ann Surg Oncol 2017;24:176-83. [Crossref] [PubMed]
67. McConnell YJ, Mack LA, Francis WP, et al. HIPEC+EPIC versus HIPEC-alone: differences in major complications following cytoreduction surgery for peritoneal malignancy. J Surg Oncol 2013;107:591-6. [Crossref] [PubMed]
68. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34-43. [Crossref] [PubMed]
69. Cashin PH, Mahteme H, Spång N, et al. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. Eur J Cancer 2016;53:155-62. [Crossref] [PubMed]
70. Mahteme H, Hansson J, Berglund A, et al. Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study. Br J Cancer 2004;90:403-7. [Crossref] [PubMed]
71. Cashin PH, Graf W, Nygren P, et al. Intraoperative hyperthermic versus postoperative normothermic intraperitoneal chemotherapy for colonic peritoneal carcinomatosis: a case-control study. Ann Oncol 2012;23:647-52. [Crossref] [PubMed]
72. Cashin PH, Graf W, Nygren P, et al. Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis: prognosis and treatment of recurrences in a cohort study. Eur J Surg Oncol 2012;38:509-15. [Crossref] [PubMed]
73. Sgarbura O, Samalin E, Carrere S, et al. Preoperative intraperitoneal oxaliplatin for unresectable peritoneal carcinomatosis of colorectal origin: a pilot study. Pleura Peritoneum 2016;1:209-15. [Crossref] [PubMed]
74. Yonemura Y, Elnemr A, Endou Y, et al. Effects of neoadjuvant intraperitoneal/systemic chemotherapy (bidirectional chemotherapy) for the treatment of patients with peritoneal metastasis from gastric cancer. Int J Surg Oncol 2012;2012:148420. [Crossref] [PubMed]
75. Elias D, Goéré D, Di Pietrantonio D, et al. Results of systematic second-look surgery in patients at high risk of developing colorectal peritoneal carcinomatosis. Ann Surg 2008;247:445-50. [Crossref] [PubMed]
76. Elias D, Honoré C, Dumont F, et al. Results of systematic second-look surgery plus HIPEC in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis. Ann Surg 2011;254:289-93. [Crossref] [PubMed]
77. Baratti D, Kusamura S, Iusco D, et al. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the Time of Primary Curative Surgery in Patients with Colorectal Cancer at High Risk for Metachronous Peritoneal Metastases. Ann Surg Oncol 2017;24:167-75. [Crossref] [PubMed]
78. Sloothaak DA, Mirck B, Punt CJ, et al. Intraperitoneal chemotherapy as adjuvant treatment to prevent peritoneal carcinomatosis of colorectal cancer origin: a systematic review. Br J Cancer 2014;111:1112-21. [Crossref] [PubMed]
79. Goéré D, Glehen O, Quenet F, et al. Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): a randomised, phase 3 study. Lancet Oncol 2020;21:1147-54. [Crossref] [PubMed]
80. Klaver CEL, Wisselink DD, Punt CJA, et al. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. Lancet Gastroenterol Hepatol 2019;4:761-70. [Crossref] [PubMed]
81. Rovers KP, Bakkers C, Nienhuijs SW, et al. Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial. JAMA Surg 2021;156:710-20. [Crossref] [PubMed]
82. Lim WA, June CH. The Principles of Engineering Immune Cells to Treat Cancer. Cell 2017;168:724-40. [Crossref] [PubMed]
83. Wagner J, Wickman E, DeRenzo C, et al. CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality? Mol Ther 2020;28:2320-39. [Crossref] [PubMed]
84. Tiernan JP, Perry SL, Verghese ET, et al. Carcinoembryonic antigen is the preferred biomarker for in vivo colorectal cancer targeting. Br J Cancer 2013;108:662-7. [Crossref] [PubMed]
85. Hartmann J, Schüßler-Lenz M, Bondanza A, et al. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 2017;9:1183-97. [Crossref] [PubMed]
86. Katz SC, Burga RA, McCormack E, et al. Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases. Clin Cancer Res 2015;21:3149-59. [Crossref] [PubMed]
87. Parkhurst MR, Yang JC, Langan RC, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 2011;19:620-6. [Crossref] [PubMed]
88. Katz SC, Point GR, Cunetta M, et al. Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery. Cancer Gene Ther 2016;23:142-8. [Crossref] [PubMed]
89. Ledermann JA, Canevari S, Thigpen T. Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments. Ann Oncol 2015;26:2034-43. [Crossref] [PubMed]
90. Song DG, Ye Q, Carpenito C, et al. In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res 2011;71:4617-27. [Crossref] [PubMed]
91. Alkayyal AA, Tai LH, Kennedy MA, et al. NK-Cell Recruitment Is Necessary for Eradication of Peritoneal Carcinomatosis with an IL12-Expressing Maraba Virus Cellular Vaccine. Cancer Immunol Res 2017;5:211-21. [Crossref] [PubMed]
92. Liang X, Luo M, Wei XW, et al. A folate receptor-targeted lipoplex delivering interleukin-15 gene for colon cancer immunotherapy. Oncotarget 2016;7:52207-17. [Crossref] [PubMed]
93. Chon HJ, Kim H, Noh JH, et al. STING signaling is a potential immunotherapeutic target in colorectal cancer. J Cancer 2019;10:4932-8. [Crossref] [PubMed]
94. Liu Z, Ravindranathan R, Kalinski P, et al. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat Commun 2017;8:14754. [Crossref] [PubMed]
95. Ma Z, Li W, Yoshiya S, et al. Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18. Clin Cancer Res 2016;22:2969-80. [Crossref] [PubMed]
96. van de Laar L, Coffer PJ, Woltman AM. Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy. Blood 2012;119:3383-93. [Crossref] [PubMed]
97. Shirota H, Klinman DM. CpG-conjugated apoptotic tumor cells elicit potent tumor-specific immunity. Cancer Immunol Immunother 2011;60:659-69. [Crossref] [PubMed]
98. Heo J, Reid T, Ruo L, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 2013;19:329-36. [Crossref] [PubMed]
99. Breitbach CJ, Bell JC, Hwang TH, et al. The emerging therapeutic potential of the oncolytic immunotherapeutic Pexa-Vec (JX-594). Oncolytic Virother 2015;4:25-31. [Crossref] [PubMed]
100. Lee YS, Lee WS, Kim CW, et al. Oncolytic vaccinia virus reinvigorates peritoneal immunity and cooperates with immune checkpoint inhibitor to suppress peritoneal carcinomatosis in colon cancer. J Immunother Cancer 2020;8:e000857. [Crossref] [PubMed]
101. Wiiger MT, Bideli H, Fodstad O, et al. The MOC31PE immunotoxin reduces cell migration and induces gene expression and cell death in ovarian cancer cells. J Ovarian Res 2014;7:23. [Crossref] [PubMed]
102. Flatmark K, Guldvik IJ, Svensson H, et al. Immunotoxin targeting EpCAM effectively inhibits peritoneal tumor growth in experimental models of mucinous peritoneal surface malignancies. Int J Cancer 2013;133:1497-506. [Crossref] [PubMed]
103. Andersson Y, Engebraaten O, Fodstad Ø. Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo. Br J Cancer 2009;101:1307-15. [Crossref] [PubMed]
104. Frøysnes IS, Andersson Y, Larsen SG, et al. Novel Treatment with Intraperitoneal MOC31PE Immunotoxin in Colorectal Peritoneal Metastasis: Results From the ImmunoPeCa Phase 1 Trial. Ann Surg Oncol 2017;24:1916-22. [Crossref] [PubMed]
105. Frøysnes IS, Andersson Y, Larsen SG, et al. ImmunoPeCa trial: Long-term outcome following intraperitoneal MOC31PE immunotoxin treatment in colorectal peritoneal metastasis. Eur J Surg Oncol 2021;47:134-8. [Crossref] [PubMed]
106. Ströhlein MA, Heiss MM. Intraperitoneal immunotherapy to prevent peritoneal carcinomatosis in patients with advanced gastrointestinal malignancies. J Surg Oncol 2009;100:329-30. [Crossref] [PubMed]
107. Jäger M, Schoberth A, Ruf P, et al. Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3). Cancer Res 2012;72:24-32. [Crossref] [PubMed]
108. Ströhlein MA, Heiss MM. Immunotherapy of peritoneal carcinomatosis. Cancer Treat Res 2007;134:483-91. [PubMed]
109. Chelius D, Ruf P, Gruber P, et al. Structural and functional characterization of the trifunctional antibody catumaxomab. MAbs 2010;2:309-19. [Crossref] [PubMed]
110. Thadi A, Khalili M, Morano WF, et al. Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis. Vaccines (Basel) 2018;6:54. Erratum in: Vaccines (Basel) 2019;7 PMID: 30103457. [Crossref] [PubMed]
111. Bezan A, Hohla F, Meissnitzer T, et al. Systemic effect of catumaxomab in a patient with metastasized colorectal cancer: a case report. BMC Cancer 2013;13:618. [Crossref] [PubMed]