Productive research in patients with peritoneal carcinomatosis has moved slowly over several decades. In large part this was due to lack of standardized assessments by which cancer responses could be quantitated in a reliable and statistically evaluable manner. Recently, both laboratory and clinical assessments have been developed. Clinical research has shown that the prognosis of patients with peritoneal carcinomatosis is dependent upon preoperative and intraoperative variables [1]. These are the histologic grade of the malignancy, the preoperative tumor volume as assessed at surgery, the distribution of tumor at surgery, and the completeness of cytoreductive surgery. Also the preoperative abdominal and pelvic computed tomography (CT) scan has shown predictive value in assessment of the completeness of cytoreduction in patients with mucinous carcinomatosis [2]. The clinical research tools that are currently used in peritoneal carcinomatosis studies are reviewed in this manuscript.

Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis

PURPOSEA phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 125-labeled monoclonal antibody A33 (125I-mAb A33), its limiting organ toxicity, and the uptake and retention of radioactivity in tumor lesions.PATIENTS AND METHODSPatients (N = 21) with advanced chemotherapy-resistant colon cancer who had not received prior radiotherapy were treated with a single 125I-mAb A33 dose. 125I doses were escalated from 50 to 350 mCi/m2 in 50-mCi/m2 increments. Radioimmunoscintigrams were performed for up to 6 weeks after 125I-mAb A33 administration.RESULTSAll 20 patients with radiologic evidence of disease showed localization of 125I to sites of disease. Twelve of 14 patients, who underwent imaging studies 4 to 6 weeks after antibody administration, had sufficient isotope retention in tumor lesions to make external imaging possible. No major toxicity was observed, except in one patient with prior exposure to mitomycin who developed transient grade 3 thrombocytopenia. Although the isot...

Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer.

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology.

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A comprehensive overview of radioguided surgery using gamma detection probe technology

Intraoperative probes have been employed to assist in the detection and removal of tumors for more than 50 years. For a period of about 40 years, essentially every detector type that could be miniaturized had been tested or at least suggested for use as an intraoperative probe. These detectors included basic Geiger-Muller (GM) tubes, scintillation detectors, and even state-of-the-art solid state detectors. The radiopharmaceuticals have progressed from 32PO4- injections for brain tumors to sophisticated monoclonal antibodies labeled with iodine-125 for colorectal cancers. The early work was mostly anecdotal, primarily interdisciplinary collaborations between surgeons and physical scientists. These collaborations produced a few publications, but never seemed to result in an ongoing clinical practice. In the mid 1980s, several companies offered basic gamma-detecting intraoperative probes as products. This led to the rapid development of radioimmunoguided surgery (RIGS) and sentinel node detection as regularly practiced procedures to assist in the diagnosis and treatment of cancer. In recent years intraoperative imaging probes have been developed. These devices add the ability to see the details of the detected activity, giving the potential of using the technique in a low-contrast environment. Intraoperative probes are now established as clinical devices, they have a commercial infrastructure to support their continued use, and there is ongoing research, both commercial and academic, that would seem to ensure continued progress and renewed interest in this slowly developing field.

Intraoperative probes and imaging probes.

In previous studies, we have compared the immunochemical properties, the in vivo pharmacokinetics, and the tumor penetrance of a radioiodinated single-chain Fv (sFv) in comparison with other immunoglobulin (Ig) forms (intact IgG, F(ab')2, and Fab') (Cancer Res., 51: 6363-6371, 1991). Biodistribution studies demonstrated a higher percent injected dose/g in the liver and spleen for the intact IgG and F(ab')2. Renal uptake was observed with the Fab' and F(ab')2, whereas the sFv demonstrated no specific localization in either of these organs. The 125I-labeled sFv also demonstrated a more even distribution throughout the tumor xenografts as compared to the other Ig forms (Cancer Res., 52: 3402-3408, 1992). Subsequent studies utilizing the sFv conjugated with a radiometal (177Lu) demonstrated that the sFv was being metabolized by the kidney, and a significantly higher percent injected dose/g was obtained with a 177Lu-labeled sFv as compared to a 125I-labeled sFv (Cancer Res., 52: 6413-6417, 1992). These previous studies indicated the potential utility of radioiodinated sFv and other Ig fragments for use in radioimmunoguided surgery with a hand-held probe, diagnostic imaging, and possibly therapy. The present study compares the distribution in normal tissues of the 4 Ig forms of monoclonal antibody (MAb) CC49, which is directed against a pancarcinoma antigen (tumor-associated glycoprotein-72). 125I-labeled sFv, Fab', F(ab')2, and IgG of MAb CC49 were administered to athymic mice either bearing or not bearing the tumor-associated glycoprotein-72 positive human colon carcinoma xenograft (LS-174T). At various intervals following the i.v. injection of the Ig forms, the liver, spleen, kidneys, and lungs were removed for autoradiographic analyses. Dramatic differences were observed in the kidney; the IgG was found only in the renal vasculature, whereas the Fab', F(ab')2, and sFv showed a high density of grains in the cortical tubules. In the liver, the IgG and F(ab')2 were found in association with hepatocytes, Kupffer cells, and in the sinusoids; the Fab' and sFv were primarily associated with the Kupffer cells. In the spleen, the Ig forms localized to the marginal zones surrounding the lymphoid follicles. No specific accumulation of grains for any of the Ig forms was observed in the lung. In each of the tissues, the clearance rates were related to the size of the Ig form. The localization in the liver and spleen was determined to be antigen-mediated.(ABSTRACT TRUNCATED AT 400 WORDS)

https://cancerres.aacrjournals.org/content/canres/53/16/3776.full.pdf

Microautoradiographic Analysis of the Normal Organ Distribution of Radioiodinated Single-Chain Fv and Other Immunoglobulin Forms

Radioimmunoguided surgery (RIGS) has been employed intraoperatively in cases of colorectal cancer to assess the extent of local tumor spread and metastatic disease. This technique uses radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens, and a hand-held gamma-detection probe to detect the radiolabel fixed to tumor tissue. Recently introduced is an MAb directed against tumor-associated glycoprotein (anti-TAG), CC49. Sixty patients were entered into the initial study. Eighteen of 21 (86%) primary tumors were localized by the CC49 MAb and the gamma-detecting probe. Twenty-nine of 30 (97%) recurrent tumors were localized. Antibody dose did not affect localization. Specimens were divided into tissue types I through IV, based on antibody localization and hematoxylin and eosin (HE type II, RIGS (-) and histologically (+); type III, RIGS (+) and histologically (-); type IV, RIGS (+) and histologically (+). Type IV tissue were further classified by whether they were grossly apparent, IVa, or grossly inapparent, IVb (occult). Occult tumor found by RIGS and confirmed by H&E staining (type IV) had localization ratios similar to RIGS-positive, histology-negative tissue (type III). Traditionally found cancer (type IV) had significantly higher ratios. In 12 of 24 patients (50%) with primary tumors and 14 of 30 patients (47%) with recurrent tumors, RIGS with CC49 altered the planned operative procedure. Radioimmunoguided surgery with CC49 provides useful, immediate intraoperative information not available by other techniques.

Shlomo Schneebaum

Papers

Intraoperative detection of colorectal cancer with radioimmunoguided surgery and CC49, a second-generation monoclonal antibody.