Recent insights into the pathophysiology of omental metastases.

Although, useful in inflammatory conditions, the greater omentum represents an important site of metastasis in peritoneal carcinomatosis and is therefore frequently removed as a staging or therapeutic tool. Apart from the milky spots, omental adipose stem cells, and adipocytes have recently been identified to play a role in the preferential homing of tumor cells to the omentum. The extent of omentectomy and whether a routine omentectomy should be done are still known unknowns.

Radioimmunotherapy is an effective adjuvant treatment after cytoreductive surgery of experimental colonic peritoneal carcinomatosis.

UNLABELLED: Because tumor targeting with radiolabeled monoclonal antibodies is more efficient in small lesions, radioimmunotherapy is considered most suitable for minimal or microscopic residual disease. The aim of the present studies was to assess the efficacy of adjuvant radiommunotherapy using radiolabeled monoclonal antibodies after cytoreductive surgery in rats with peritoneal carcinomatosis of colonic origin. METHODS: We used a tumor model, in which peritoneal carcinomatosis was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in Wag/Rij rats. The biodistribution of the (125)I-/(111)In-labeled anti-CC-531 MG1 monoclonal antibody after intraperitoneal administration was assessed. Subsequently, the efficacy of (177)Lu-MG1 (74 MBq per rat) was compared with that of unlabeled MG1 or phosphate-buffered saline-bovine serum albumin in this model. Finally, rats with resectable intraperitoneal CC-531 tumors were subjected to exploratory laparotomy only, cytoreductive surgery only, exploratory laparotomy + radiommunotherapy (56 MBq (177)Lu-MG1 per rat), or cytoreductive surgery + radiommunotherapy. Survival was the primary endpoint. RESULTS: Both (125)I- and (111)In-labeled MG1 preferentially accumulated in intraperitoneal CC-531 tumors. The uptake of (111)In-MG1 in tumor was higher than that of (125)I-MG1 (4.1 +/- 2.3 %ID/g vs. 1.1 +/- 0.5 %ID/g [%ID/g is percentage of injected dose per gram], 72 h after injection; P = 0.053). Radiommunotherapy with 74 MBq (177)Lu-MG1 almost completely eradicated tumor growth, whereas unlabeled MG1 had no effect. In the surgery study, both cytoreductive surgery and radiommunotherapy were well tolerated. The median survival of the control rats that underwent exploratory laparotomy only was 41 d. The median survival of the rats that were treated with cytoreductive surgery only, exploratory laparotomy + radiommunotherapy, or cytoreductive surgery + radiommunotherapy was 51 d (P = 0.05 compared with control rats), 61.5 d (P = 0.03), and 88 d (P = 0.0001), respectively, which suggests an additive effect of both treatment modalities. There was a highly significant trend toward improved survival of cytoreductive surgery + radiommunotherapy compared with both monotherapies (P = 0.0004). CONCLUSION: This study provides proof of principle that radiommunotherapy can be an effective treatment modality when applied as an adjuvant treatment after resection of tumors with a high risk of recurrence, such as after cytoreductive surgery of peritoneal carcinomatosis.

Combination therapy using gemcitabine and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin.

INTRODUCTION: Gemcitabine has been shown to exert a radiosensitizing effect in various epithelial cancers. The aim of the present studies was to investigate whether the efficacy of radioimmunotherapy (RIT) using the (131)I-labeled anti-CEA monoclonal antibody (MAb) MN-14 could be enhanced by coadministration of gemcitabine in nude mice with small (1-3 mm) peritoneal metastases of colonic origin. MATERIALS AND METHODS: Firstly, the maximum tolerated dose (MTD) of gemcitabine was determined, when administered intraperitoneally at two different dosing schedules (0.11-3.0 mg/mouse/administration on days 0, 3, 6, and 9, or 0.022-0.60 mg/mouse/administration on days 0, 1, 2, 3, and 4). In two separate therapy studies in which these two administration regimens were applied, the efficacy of gemcitabine monotherapy was compared to that of RIT alone (125 muCi (131)I-MN-14/mouse) or RIT combined with gemcitabine. RESULTS: When administered every 3rd day for a total of 4 administrations, or daily for 5 consecutive days, the gemcitabine was considered safe at 0.33 mg/mouse/administration and 0.066 mg/mouse/administration, respectively. In the first therapy study, median survival of the control mice was 39 days. Gemcitabine monotherapy at 0.11 mg or 0.33 mg/mouse/administration every 3rd day (total, 4 administrations) resulted in a median survival of 52 and 57 days, respectively (p = 0.0003, compared to controls). RIT alone resulted in a median survival of 66 days (p < 0.0001, compared to controls). The combination of RIT and gemcitabine coadministration resulted in a median survival of 73 and 94 days, respectively (p = 0.12, for trend). In the second therapy study, median survival of the control mice was 48 days, which was similar to the median survival of the mice treated with daily administrations of gemcitabine monotherapy at 0.022 mg/mouse/administration on 5 consecutive days (49 days; p = 0.17). RIT alone resulted in a significantly improved median survival of 66 days (p= = 0.0010, compared to controls). Combination therapy using RIT and gemcitabine resulted in a median survival of 64 days, which did not differ significantly from the survival of the mice treated with RIT alone (p = 0.43). CONCLUSIONS: At the dose regimens employed, gemcitabine did not enhance the efficacy of RIT of experimental small-volume peritoneal carcinomatosis of colonic origin.

Biodistribution and therapeutic efficacy of (125/131)I-, (186)Re-, (88/90)Y-, or (177)Lu-labeled monoclonal antibody MN-14 to carcinoembryonic antigen in mice with small peritoneal metastases of colorectal origin.

UNLABELLED: Therapeutic efficacy in radioimmunotherapy depends, among other things, on the choice of the radionuclide. The aim of the present study was to determine the most suitable radionuclide for radioimmunotherapy with monoclonal antibody MN-14 to carcinoembryonic antigen in an experimental model of small peritoneal metastases of colorectal origin. METHODS: In nude mice with intraperitoneal LS174T tumors (diameter, 1-3 mm), the biodistributions of MN-14 labeled with (131)I ((131)I-MN-14), (186)Re-mercaptoacetyltriglycine ((186)Re-MN-14), and (88)Y-diethylenetriaminepentaacetic acid (DTPA) ((88)Y-MN-14) after intravenous and intraperitoneal administration were determined. Subsequently, the therapeutic efficacies of equally toxic activity doses of (131)I-MN-14 (9.25 MBq per mouse), (186)Re-MN-14 (9.25 MBq per mouse), (90)Y-MN-14 (3.15 MBq per mouse), and MN-14 labeled with (177)Lu-DTPA ((177)Lu-MN-14) (8.33 MBq per mouse) after intraperitoneal administration were determined. RESULTS: Each of the radioimmunoconjugates preferentially accumulated in tumor nodules, both after intravenous administration and after intraperitoneal administration. Values for clearance from blood were similar for all radioimmunoconjugates. The uptake of (88)Y-MN-14 in the liver and spleen was significantly higher than the uptake of (131)I-MN-14 or (186)Re-MN-14. Maximal uptake values (mean +/- SD) in tumors were 58 +/- 7 percentage injected dose per gram of tissue (%ID/g) for (131)I-MN-14 (24 h after administration), 83 +/- 19 %ID/g for (186)Re-MN-14 (72 h after administration), and 148 +/- 89 %ID/g for (88)Y-MN-14 (192 h after administration). Dosimetric analysis of the biodistribution data estimated that the radiation doses guided to the tumor by intraperitoneally administered (131)I-MN-14, (186)Re-MN-14, (90)Y-MN-14, and (177)Lu-MN-14 were 150, 100, 45, and 200 Gy, respectively. The median survival time of control mice, treated with unlabeled MN-14, was 42 d, whereas the median survival times of mice treated with (131)I-MN-14, (186)Re-MN-14, (90)Y-MN-14, and (177)Lu-MN-14 were 100 d (range, 58-142; P < 0.0001), 72 d (range, 46-84; P = 0.0002), 82 d (range, 46-142; P < 0.0001), and 136 d (range, 56-142; P < 0.0001), respectively. At the completion of the experiment (142 d after tumor cell inoculation), no residual disease was found in 8 of 9 long-term survivors ((131)I, n = 3; (90)Y, n = 1; and (177)Lu, n = 4). CONCLUSION: The uptake of (88)Y-MN-14 in small peritoneal LS174T xenografts was higher than the uptake of (131)I-MN-14 or (186)Re-MN-14. The present study indicates that (131)I and (177)Lu are the most suitable radionuclides for the radioimmunotherapy of small peritoneal metastases.

Radionuclide therapy of cancer with radiolabeled antibodies.

Radioimmunotherapy (RIT) using radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens has evolved from an appealing concept to one of the standard treatment options for patients with non-Hodgkin's lymphoma (NHL). Inefficient localization of radiolabeled MAbs to nonhematological cancers due to various tumor-related factors, however, limits the therapeutic efficacy of RIT in solid tumors. Still, small volume or minimal residual disease has been recognized as a potentially suitable target for radiolabeled antibodies. Several strategies are being explored aimed at improving the targeting of radiolabeled MAbs to solid tumors thus improving their therapeutic efficacy. In this review, various aspects of the application of radiolabeled MAbs as anti-cancer agents are discussed, and the clinical results of RIT in patients with hematological and various solid cancers (colorectal, ovarian, breast and renal carcinomas) are reviewed.

Timing of adjuvant radioimmunotherapy after cytoreductive surgery in experimental peritoneal carcinomatosis of colorectal origin.

BACKGROUND: Treatment of patients with peritoneal carcinomatosis (PC) of colorectal cancer (CRC) includes cytoreductive surgery (CS) in combination with (hyperthermic) intraperitoneal chemotherapy (HIPEC), resulting in a limited survival benefit with high morbidity and mortality rates. Radioimmunotherapy (RIT) as adjuvant therapy after CS of CRC has been shown to prolong survival in preclinical studies. However, the optimal setting of RIT remains to be determined. METHODS: PC was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in Wag/Rij rats. Animals were subjected to exploratory laparotomy (Sham), CS only or CS + RIT at different time points after surgery. RIT consisted of 55 MBq lutetium-177-labelled anti-CC531 antibody MG1 (183 mug). The primary endpoint was survival. RESULTS: Cytoreductive surgery with or without RIT was well tolerated. Median survival of animals in the Sham and CS group was 29 days and 39 days, respectively (P < 0.04). Compared to CS alone, median survival of rats after adjuvant RIT was 77 days (P < 0.0001), 52 days (P < 0.0001) and 45 days (P < 0.0001) when given directly, 4 and 14 days after surgery, respectively. CONCLUSION: The efficacy of adjuvant RIT after CS for the treatment of PC of colonic origin decreases when the administration of the radiolabelled MAbs is postponed. This study shows that adjuvant RIT should be given as early as possible after surgery.

Interposition of polyglactin mesh does not prevent adhesion formation between viscera and polypropylene mesh.

BACKGROUND: The use of intra-peritoneal polypropylene mesh (PPM) to repair incisional hernia carries the risk of adhesions and damage to the intra-abdominal viscera. Polyglactin 910 mesh (PGM) is advocated to avoid contact between PPM and the intra-abdominal viscera. An experimental study in rats was performed to determine if interposition of a resorbable prosthesis between the PPM and viscera alters biocompatibility, adhesion formation, and herniation. MATERIALS AND METHODS: A 2- x 3-cm abdominal wall defect was created in 80 rats. Rats were randomly assigned for repair with 2.5- x 3.5-cm PPM (n = 40) or 2.5- x 3.5-cm PPM plus polyglactin 910 mesh (PPM-PGM) (n = 40). The rats were sacrificed at 1, 2, 3, and 6 months (n = 10), and an autopsy was performed to determine herniation and adhesion rates. Mesh-fascia interface was taken for histology. RESULTS: In the PPM group, 1 rat died before the end of the experiment, and at 6 months one of the 10 rats had a herniation. In the PPM-PGM group, two rats died before the end of the experiment, and two rats had a herniation after 1 month and three rats after 6 months. At 1, 2, and 3 months the adhesion score in the PPM group (median, 3; range, 2-3) did not differ from the score in the PPM-PGM group (median, 3; range, 2-3). Also, at 6 months the adhesion score in the PPM group (median, 2; range, 2-3) did not differ from the score in the PPM-PGM group (median, 3; range, 2-3). At microscopy a capsule was formed around the PP fibers, which matured over months in the PPM group. In the first month after implantation an inflammatory response was seen. Histology was similar in both groups, although in the early PPM-PGM group the inflammatory response was more evident. CONCLUSION: Interposition of PGM between PPM and viscera does not alter adhesion formation nor influences herniation rate.

Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies.

OBJECTIVE: To review the literature with regard to the incidence and prognostic significance of peritoneal seeding during surgery for primary colorectal cancer (CRC), the incidence of intraperitoneal recurrence of CRC, and the current treatment strategies of established PC of colorectal origin, with special focus on cytoreductive surgery and intraperitoneal chemotherapy (IPEC). SUMMARY BACKGROUND DATA: Although hematogenous dissemination forms the greatest threat to patients with CRC, peritoneal carcinomatosis (PC), presumably arising from intraperitoneal seeding of cancer cells, is a relatively frequent event in patients with recurrent CRC. METHODS: The PubMed and Medline literature databases were searched for pertinent publications regarding the incidence and prognostic significance of exfoliated tumor cells in the peritoneal cavity during curative surgery for primary CRC, the incidence of intraperitoneal recurrence of CRC, and the therapeutic results of systemic chemotherapy or cytoreductive surgery followed by IPEC. RESULTS: The incidence of peritoneal seeding during potentially curative surgery for primary CRC, as reported in 12 patient series, varied widely, from 3% to 28%, which may be explained by differences in methods to detect tumor cells. PC is encountered in approximately 7% of patients at primary surgery, in approximately 4% to 19% of patients during follow-up after curative surgery, in up to 44% of patients with recurrent CRC who require relaparotomy, and in 40% to 80% of patients who succumb to CRC. The reported median survival after systemic 5-fluorouracil-based chemotherapy for PC varies from 5.2 to 12.6 months. Median survival after aggressive cytoreductive surgery followed by (hyperthermic) IPEC in selected patients, as reported in 16 patient series, tends to be better and varies from 12 to 32 months at the cost of morbidity and mortality rates of 14% to 55% and 0% to 19%, respectively. One randomized controlled trial has been published confirming the superiority of aggressive surgical cytoreduction and intraperitoneal chemotherapy over strictly palliative treatment. CONCLUSIONS: Peritoneal seeding of cancer cells possibly leading to PC is a rather common phenomenon in patients with CRC. Cytoreductive surgery and adjuvant (hyperthermic) IPEC have been shown to be efficacious in selected patients and should therefore be considered in patients with resectable PC of colorectal origin.

Combination therapy using the cyclooxygenase-2 inhibitor Parecoxib and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin.

BACKGROUND: Inhibition of the COX-2 enzyme has been shown to have a radiosensitizing effect in epithelial cancers. The aim of this study was to investigate whether the efficacy of radioimmunotherapy (RIT) using 131I-labeled anti-CEA monoclonal antibody MN-14 could be enhanced by co-administration of the selective COX-2 inhibitor Parecoxib in mice with small volume (1-3 mm) peritoneal carcinomatosis of colonic origin. METHODS: First, the efficacy of 14 daily injections of Parecoxib monotherapy (0-0.2-1.0-5.0-25.0 mg/kg) was determined in mice with intraperitoneal LS174T xenografts. Second, the influence of Parecoxib (1.0 or 5.0 mg/kg) on the biodistribution of 125I-MN-14 was assessed. Finally, the efficacy of RIT alone [125 microCi 131I-MN-14/mouse approximately 1/4 of the maximal tolerated dose (MTD)] was compared with that of Parecoxib monotherapy and RIT combined with daily injections of Parecoxib (1.0 or 5.0 mg/kg). RESULTS: Parecoxib had no measurable antitumor effect up to the highest dose level (25 mg/kg). Parecoxib had no effect on the uptake of 125I-MN-14 in the intraperitoneal tumor xenografts or on normal tissue distribution. Median survival of the control mice and the mice treated with Parecoxib monotherapy (1.0 or 5.0 mg/kg) was 48.5 days, 52 days and 52 days (P=0.47). RIT alone significantly delayed the growth of the intraperitoneal xenografts resulting in a median survival of 87 days (P<0.0001). Mice treated with RIT + Parecoxib at 1.0 or 5.0 mg/kg had a median survival of 73.5 days and 76 days, respectively, which was not statistically different from survival after RIT alone (P=0.15). CONCLUSION: The COX-2 inhibitor Parecoxib does not enhance the therapeutic efficacy of RIT of experimental small volume peritoneal carcinomatosis of colonic origin.

Antibody-guided radiation therapy of cancer.

Radioimmunotherapy (RIT) using radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens has evolved from an appealing concept to one of the standard treatment options for patients with non-Hodgkin's lymphoma (NHL). Inefficient localization of radiolabeled MAbs to nonhematological cancers due to various tumor-related factors, however, has refrained RIT from outgrowing the experimental stage in solid tumors. Still, small volume or minimal residual disease has been recognized as a potentially suitable target for radiolabeled antibodies. Several strategies are being explored aimed at improving the targeting of radiolabeled MAbs to solid tumors thus improving their therapeutic efficacy. In this review, a historical overview of the application of RIT is given and various aspects of the application of radiolabeled MAbs as anti-cancer agents are discussed. Finally, the clinical results of RIT of NHL, colorectal cancer, ovarian cancer, breast cancer, and renal cell cancer are reviewed.

Experimental radioimmunotherapy of small peritoneal metastases of colorectal origin.

Radioimmunotherapy using radiolabeled monoclonal antibodies (MoAbs) directed against tumor-associated antigens might be an effective treatment modality for small volume disease. Our aim was to optimize an experimental model of radioimmunotherapy for small peritoneal metastases of colorectal origin using the anti-CEA MoAb MN-14. In nude mice with intraperitoneal (i.p.) LS174T tumors, a protein dose-escalation study was carried out to determine the maximal dose of radioiodinated MN-14 to be used in radioimmunotherapy. The biodistribution of radioiodinated MN-14 was determined after intravenous (i.v.) and i.p. administration. Finally, the therapeutic efficacy of escalating activity doses of (131)I-labeled MN-14 (62.5-500 microCi) was assessed and compared to that of unlabeled MN-14 or 500 microCi of (131)I-labeled irrelevant control antibody. At protein doses higher than 25 microg, uptake in tumor was reduced, presumably due to saturation of tumor antigen. During the first 24 hours i.p. administration led to higher tumor uptake and higher tumor:blood ratios than i.v. administration. Median survival of the control groups was 38 days (unlabeled MN-14) and 52 days ((131)I-labeled nonspecific antibody). Median survival of the groups treated with increasing activity doses of (131)I-labeled MN-14 was 42 days (62.5 microCi), 49 days (125 microCi), 63 days (250 microCi) and 101 days (500 microCi), respectively (p < 0.0001 compared to unlabeled MN-14). The present study shows that the anti-CEA-antibody MN-14 preferentially accumulates in i.p. LS174T tumor xenografts after both i.p. and i.v. administration. Intraperitoneal radioimmunotherapy using (131)I-labeled MN-14 delays significantly the outgrowth of peritoneal LS174T metastases, even at relatively low activity doses.