Pegsitacianine Informs Surgery in Peritoneal Carcinomatosis

Targeted Therapies in OncologyAugust I
Volume 12
Issue 11
Pages: 14

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Currently, cytoreductive surgery remains a pillar of modern treatment for peritoneal carcinomatosis.

Treating peritoneal carcinomatosis remains a significant problem in a wide variety of malignancies, including gastrointestinal, gynecologic, or primary peritoneal. Because the peritoneum is sequestered to some degree from the systemic circulation, traditional systemic treatment options have limited delivery to this region; as such, peritoneal carcinomatosis often has a poor response to intravenous chemotherapy.1 Currently, cytoreductive surgery (CRS) remains a pillar of modern treatment for peritoneal carcinomatosis.

During this procedure, all visible peritoneal disease and involved intra-abdominal organs are removed. The disease is quantified by a peritoneal carcinomatosis index, or PCI, and the residual disease remaining following cytoreduction is quantified by the completeness of cytoreduction (CC) score. These scores are consistently identified as critical prognostic factors for patients undergoing CRS.2 Additionally, patients with complete cytoreduction demonstrate improved overall survival compared with patients with incomplete cytoreduction.3 To improve completeness of cytoreduction, molecular imaging of malignant tissue has been an expanding area of innovation.4,5 To address this need, our center participated in a multi- institutional phase 2 clinical trial using pegsitacianine as an adjunct for detecting disease during CRS, and has been submitted for publication. A previous phase 1 study demonstrated both a favorable safety profile and clinical utility.6

Pegsitacianine is a micellar nanoparticle designed as an activatable fluorescent probe for use as an intraoperative adjunct to oncologic surgery in solid tumors. This agent is composed of a hydrophilic polyethylene glycol exterior, with an inner hydrophobic polymethyl methacrylate core to which the near-infrared (NIR) fluorophore, indocyanine green 2, is covalently conjugated. At physiologic pH, the fluorophore is quenched within the nanoparticle core, keeping it in a fluorescence-“off” state. Exposure to acidic conditions, such as the tumor microenvironment, causes the hydrophobic exterior to dissociate and release the fluorophore from quenching, enabling visualization upon excitation with NIR light.6

FIGURE. Preparation for the Use of the Nanoprobe1

FIGURE. Preparation for the Use of the Nanoprobe1

In our trial, eligible participants included those with imaging and/or biopsy confirmed peritoneal metastatic disease with a PCI of 10 or greater who were eligible surgical candidates. Two groups were created, one group with tumors containing 50% or less mucin and one group with 50% or more mucin pegsitacianine content. Approximately 48 hours prior to surgery, patients received an infusion of 1mg/kg of pegsitacianine. On the day of their cytoreductive surgery, surgeons imaged up to 10 individual suspected tumor specimens and 5 normal specimens for fluorescence analysis using a near-infrared (NIR) camera. Then, following standard-of-care CRS, a CC score was determined, and the camera was again used to re-evaluate each region of the peritoneal cavity for evidence of occult residual disease. Residual fluorescent deposits were resected at the surgeon’s discretion, and all specimens were correlated with final pathology.

In total, 40 patients were included in this trial. PCI ranged from 10 to 36, and following cytoreductive surgery, most patients had a CC0 or CC1 cytoreduction, with only 1 patient having a CC2 reduction. Our primary clinical outcome was resection of initially undetected residual disease that was subsequently detected using the NIR camera, leading to either further resection or a revision of the assessment of completeness. Impressively, this occurred in 50% of patients studied. In these patients, 33 additional pathology confirmed tumors were resected following NIR camera imaging, and 13 patients had their CC score increased. Residual disease was identified in all the studied tumor types, and there was no discernible anatomic pattern of distribution of the missed lesions.

A total of 650 samples were obtained during this trial, with 69% of specimens being either true positives or true negatives when assessed by a pathologist. This conferred a sensitivity and specificity of 83% and 59%, respectively, with the EleVision NIR camera and 86% and 45%, respectively, with the PDE Neo II camera. These numbers are remarkable, considering that CT and MRI, which are used for initial staging and to detect peritoneal disease, have a specificity for lesions of 0.5 cm or less of only 11% to 28%, respectively, with sensitivities being dependent on tumor type.7,8 In our study, no difference was noted in NIR camera performance by primary tumor type or between mucinous and nonmucinous pathology.

No treatment-related serious adverse events occurred in any patients, but 28% of patients experienced a grade 1 or grade 2 infusion reaction. Only 2 patients dosed with pegsitacianine needed to have the drug discontinued.

Though peritoneal surface malignancies present a significant challenge to surgical oncologist, this study shows promise for molecular imaging in improving onclogic outcomes for this patient population. These agents have a favorable safety profile, now demonstrated in both phase 1 and phase 2 studies. Utilization of these imaging agents stands to not only augment a surgeon’s ability to detect occult tumors but could also allow for more accurate staging of a patient with cancer and improved completeness of cytoreduction. Because adequate treatment and completeness of cytoreduction are key to improved outcomes in these patients, ultimately, this improvement in detection of tumor and staging of patients could increase survival. Further studies with this technology are on the horizon and could become an essential component of modern treatment of patients with peritoneal surface malignancies.

1. Harper MM, Kim J, Pandalai PK. Current trends in cytoreductive surgery (crs) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal disease from appendiceal and colorectal malignancies. J Clin Med. 2022;11(10):2840.. doi:10.3390/jcm11102840
2. 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(24):5608-5618. doi:10.1002/ cncr.25356
3. Levine EA, Stewart JH 4th, Shen P, Russell GB, Loggie BL, Votanopoulos KI. Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1,000 patients. J Am Coll Surg. 2014;218(4):573-585. doi:10.1016/j. jamcollsurg.2013.12.013
4. Nguyen QT, Tsien RY. Fluorescence-guided surgery with live molecular navigation--a new cutting edge. Nat Rev Cancer. 2013;13(9):653-662. doi:10.1038/nrc3566
5. Nagaya T, Nakamura YA, Choyke PL, Kobayashi H. Fluorescence-Guided Surgery. Front Oncol. 2017;7:314. . doi:10.3389/fonc.2017.00314
6. Voskuil FJ, Steinkamp PJ, Zhao T, et al. Exploiting metabolic acidosis in solid cancers using a tumor-agnostic pH-activatable nanoprobe for fluorescence-guided surgery. Nat Commun. 2020;11(1):3257. doi:10.1038/s41467-020-16814-4
7. Sugarbaker PH. Preoperative assessment of cancer patients with peritoneal metastases for complete cytoreduction. Indian J Surg Oncol. 2016;7(3):295-302. doi:10.1007/ s13193-016-0518-0
8. Jacquet P, Jelinek JS, Steves MA, Sugarbaker PH. Evaluation of computed tomography in patients with peritoneal carcinomatosis. Cancer. 1993;72(5):1631-1636. doi:10.1002/1097-0142(19930901)72:5<1631::aid-cncr2820720523>;2-i
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