Number of retrieved lymph nodes and survival in node-negative patients undergoing laparoscopic colorectal surgery for cancer.

BACKGROUND: The number of retrieved lymph nodes in colorectal cancer resection may have an impact on staging and survival. Examination of at least 12 nodes has become a quality measure for adequate surgical practice. To evaluate the impact of the number of retrieved lymph nodes in laparoscopic colorectal surgery for cancer on node-negative patients' survival. METHODS: Evaluation of our prospective in-hospital collected data of patients that underwent laparoscopic surgery for curable colorectal cancer over a 5-year period. Long-term data were collected from our outpatient's clinic data and personal contact when necessary. RESULTS: During a 5-year period since September 2003,173 patients were operated laparoscopically for curable colorectal cancer. Of the 117 patients who were node negative, 85 node-negative patients (72%) had 12 or more evaluated lymph nodes (mean, 18.3 + 2.4), while 32 node-negative patients had less than 12 (mean, 8.3 + 6.2). Patients with fewer than 12 nodes evaluated had significantly more left-sided tumors, while patients with 12 nodes or more had more right-sided tumors. A comparison of 5-year disease free and overall Kaplan-Meier survival curves revealed no statistically significant difference between the two groups. CONCLUSIONS: Evaluation of less than 12 nodes may not necessarily impact patients' survival in node-negative patients undergoing laparoscopic resection for curable colorectal cancer. A lower number of nodes may be sufficient.

Benefits of radioimmunoguided surgery for pelvic recurrence.

AIM: Surgery for recurrent rectal cancer is usually traumatic and of questionable curative value. The use of radioimmunoguided surgery (RIGS) in enhancing the surgeon's assessment of the extent of disease in these patients was investigated. METHODS: Twenty-one patients diagnosed with recurrent pelvic cancer were operated using the RIGS(O)system. Preoperative assessment included CTs of chest, abdomen and pelvis as well as colonoscopy. Patients were injected with CC49, a monoclonal antibody (MoAb) labelled with 125I. Surgical exploration was followed by survey with the gamma-detecting probe. RESULTS: Surgical exploration identified eight intra-colorectal recurrences, nine extra-colonic pelvic recurrences and five extra-pelvic lymph node metastases. RIGS exploration confirmed all intra-colonic recurrences except for one (patient with no MoAb localization), identified 13 pelvic recurrences and 10 lymph node metastases. There were seven patients with occult findings (33%), resulting in a modified surgical procedure. Surgery included five abdomino-perineal resections, six low anterior resections, seven excisions of presacral tumour, eight total abdominal hysterectomy and bilateral salpingo-oophorectomy, one pelvic exenteration and one post-exenteration. There were no operative deaths. Eight patients had minor complications, and one patient had a major complication with reoperation due to urinary leak. The mean follow-up was 18 months. Ten patients died of disease. CONCLUSION: Although not curative, RIGS can help the surgeon in the decision-making process through better disease staging.

Immunoguided lymph node dissection in colorectal cancer: a new challenge?

Knowledge of lymphatic involvement in patients with colorectal cancer is important in surgery and in the postoperative decision-making process. Fifty-eight patients with recurrent colorectal cancer underwent operation with the RIGS/(Radioimmunoguided Surgery) technology. Preoperatively, patients were injected with 1 mg monoclonal antibody (MoAb) CC49 (anti-TAG-72-tumor-associated glycoprotein) labeled with 2 mCi of iodine 125. Traditional surgical exploration was followed by survey with a gamma-detecting probe. Localization of MoAb on tumor was noted in 54/58 patients (93%). Traditional exploration identified 117 suspected tumor sites. With RIGS, 177 suspected tumor sites were detected. In 17 of the 58 patients (27.5%), at least one occult tumor site identified by RIGS was confirmed by pathology with hematoxylin & eosin (H & E) staining. This finding resulted in 16 major changes in surgical plan. RIGS performance varied between lymphatic and non-lymphatic tissue, with a positive predictive value (PPV) of 95.6% and negative predictive value (NPV) of 90% in non-lymphoid tissue compared to PPV of 40% and NPV of 100% in lymphoid tissue. In patients with tumors that localize, no RIGS activity in lymph nodes signifies no tumor, while decisions based on RIGS activity in lymph nodes requires H & E confirmation. Using this guideline, additional information acquired by RIGS can help the surgeon in making an informed decision during surgery and in planning postoperative therapy.

Radioimmunoguided surgery for recurrent colorectal cancer manifested by isolated CEA elevation.

BACKGROUND: Carcinoembryonic antigen (CEA) is a sensitive marker for detecting recurrent colorectal carcinoma. An asymptomatic rise of CEA can precede by several months the detection of recurrent cancer by standard imaging modalities. Yet, surgeons are hesitant to operate solely on the basis of an observed increase in CEA. We investigated the ability of radioimmunoguided surgery to enhance the surgeon's capability of detecting intraabdominal disease in these patients. METHODS: Nineteen patients who underwent radioimmunoguided surgery for suspected tumor recurrence based solely on elevated CEA were included in the study. They underwent colonoscopy and CT of the abdomen and chest, all of which were negative. They then underwent scintigraphy scan with an anti-CEA monoclonal antibody (MoAb) labeled with (99m)Tc or Indium I-111. All patients were injected with the CC49 MoAb (an anti-TAG-72 tumor-associated glycoprotein) labeled with (125)I three weeks before surgery. During surgery, traditional exploration was followed by survey with a gamma-detecting probe. RESULTS: Traditional surgical exploration identified 26 recurrent tumors: 7 hepatic, 8 pelvic, 6 retroperitoneal, 3 colonic, 1 splenic, and 1 anastomotic. Radioimmunoguided surgical exploration confirmed all recurrent tumors and identified additional tumor sites in seven patients that resulted in changing the surgical plan. CEA scans correlated with intraabdominal findings in seven patients. Abdominal pathology did not correlate completely with the scans in three patients, and CEA scan results were undetermined in two patients. CONCLUSION: Patients with elevated CEA and no other findings should be operated upon without delay, and radioimmunoguided surgery should be used to enhance the surgeon's knowledge of the extent of disease.

Identification of lymph node metastases in recurrent colorectal cancer.

Lymph node metastases are an important prognostic prediction factor in patients with recurrent colorectal cancer, particularly those with liver metastasis. Fifty-six patients with recurrent colorectal cancer were operated by us using the RIGS (radioimmunoguided surgery) technology. Patients were injected with 1 mg monoclonal antibody (MoAb) CC49 labeled with 2 mCi 125I. In surgery, traditional exploration was followed by survey with a gamma-detecting probe. Sixty of 151 patients enrolled in the Neo2-14 Phase III study for recurrent colorectal cancer were diagnosed with liver metastases based on preoperative CT. In 17/56 patients (30%), RIGS identified at least one tumor site confirmed by pathology (H&E). This resulted in 16 major changes in surgical plan. RIGS performance varied between lymphatic and non-lymphatic tissue, with positive predictive value (PPV) of 100% and negative predictive value (NPV) of 94% for non-lymphoid tissue, compared to PPV of 46.5% and NPV of 100% for the lymphoid tissue. Thirty-five out of 60 patients were considered resectable after traditional evaluation. RIGS identified occult tumor in 10 of these patients (28.5%). 7/10 occult patients expired (70%), while only 7/25 of the non-occult patients expired (28%) (P = 0.046). In localizing patients, no RIGS activity in lymph nodes signifies no tumor, while H&E confirmation is needed for decisions based on RIGS activity in the lymph nodes. RIGS provides important staging information, identifying patients for whom surgery may be done with curative intent.

Effect of photodynamic therapy on normal fibroblasts and colon anastomotic healing in mice.

Photodynamic therapy as an adjuvant modality to surgical resection of colon cancer is feasible provided that it does not affect healing of the anastomosis. The aim of this study was to evaluate the effects of photodynamic therapy on the viability of normal fibroblasts and on the healing process of colonic anastomosis in mice. Both in vitro and in vivo methods were employed. For in vitro study, 2 x 10(to the fifth power); human fibroblasts were incubated in triplicate with 5-aminolevulinic acid (2.5 microg/well) for 48 hours. Cells then underwent photoradiation at light doses of 50, 100, and 200 joules/cm(2) using a nonlaser light source. Viability was assessed by methylene blue dye exclusion. For in vivo studies, 60 mice were randomized into study and control groups and underwent laparotomy involving colonic anastomosis. The anastomosis underwent photodynamic therapy using 5-aminolevulinic acid (60 mg/kg) as a photosensitizer and a nonlaser light (40 joules/cm(2)). On postoperative days 1, 4, 7, 14, and 21, six mice were killed and subjected to bursting pressure and histologic examinations. Results of in vitro study showed pretreatment cell viability to be 96% to 99% in both groups. Photodynamic therapy caused no significant change in fibroblast viability at all light doses. Results of in vivo studies showed that the mean bursting pressure of both groups dropped to a low peak on day 4. Subsequently there was a gradual increase in bursting pressure along the examined time points (P <0. 001). There was no difference in bursting pressure between the two groups for all time points examined. It was concluded that photodynamic therapy has no effect on viability of normal human fibroblasts and no adverse effects on healing of colonic anastomosis.

Clinical applications of gamma-detection probes - radioguided surgery.

Radioguided surgery (RGS) is a surgical technique that enables the surgeon to identify tissue "marked" by a radionuclide before surgery, based on the tissue characteristics, the radioactive tracer and its carrying molecule, or the affinity of both. Thus, yet another tool has been added to the inspection and palpation traditionally used by the surgeon. Current clinical applications of radioguided surgery are: radioimmunoguided surgery (RIGS) for colon cancer, sentinel-node mapping for malignant melanoma (which has become state-of-the-art), sentinel-node mapping for breast, vulvar and penile cancer, and detection of parathyroid adenoma and bone tumour (such as osteid osteoma). Although the same gamma-detecting probe (GDP) may be used for all these applications, the carrier substance and the radionuclide differ. MoAb and peptides are used for RIGS, sulphur colloid for sentinel-node mapping, iodine-125 for RIGS, technetium-99m for sentinel node, parathyroid and bone. The mode of injection also differs, but there are some common principles of gamma-guided surgery. RIGS enables the surgeon to corroborate tumour existence, find occult metastases, and assess the margins of resection; this may result in a change on the surgical plan. Sentinel lymph-node (SLN) scintigraphy for melanoma guides the surgeon to find the involved lymph nodes for lymph-node dissection. SLN for breast cancer is being investigated with promising results. This procedure has also changed the outlook of lymph-node pathology by giving the pathologist designated tissue samples for more comprehensive examination. Gamma-guided surgery will result in more accurate and less unnecessary surgery, better pathology and, hopefully, in better patient survival.

Gamma probe-guided sentinel node biopsy--optimal timing for injection.

AIMS: We initiated a Phase I feasibility study using a gamma-detecting probe (GDP) and radiolabelled colloid to localize the sentinel lymph node (SLN) in breast cancer. The aim of the study was to establish the ideal timing for injection and examine any possible exclusion criteria for this method. METHODS: Thirty breast cancer patients diagnosed by fine needle aspiration (FNA) were included in this study. All were injected with 60 MBq rhenium colloid labelled with 99mTc (Tck-17). Scintigraphy was done 20 min, 2, 6 and 25 hours post-injection. Patients were then taken to surgery where they were injected with patent blue dye. During surgery, the SLN was located with a GDP (Neoprobe Model 1000). In 28 patients, the SLN was identified by scintigraphy 2 hours after injection, identical to the images seen after 24 hours. RESULTS: In all 28 patients, the SLN was found by the GDP during surgery. In 26 patients the SLN was dyed blue. The two patients with no SLN localization had received prior radiation. Pathology disclosed SLNs with metastases in seven patients. Two patients had a negative SLN but had an axillary lymph node replaced by tumour. CONCLUSIONS: Two to 24 hours prior to surgery is suitable timing for injection. Previous radiotherapy predicts failure for this procedure. Further studies are needed to find the exact false-negative rate of this method for breast cancer.

Single-injection gamma probe-guided sentinel lymph node detection in 40 melanomatous lymphadenectomies.

The aim of the study was to evaluate single-injection gamma probe-guided sentinel lymph node (SLN) detection, applied in 40 melanomatous selective sentinel lymphadenectomies (SSLNDs). Thirty-four patients underwent preoperative lymphoscintigraphy, intraoperative SLN identification by a gamma-detecting probe and blue dye, and SLN sampling. The first 11 patients underwent formal lymphadenectomy. The following 23 patients underwent formal lymphadenectomy only when the SLN was involved with tumor. Evaluation included hematoxylin-eosin-stained slide microscopy, monoclonal antibodies to S-100 protein, and the melanoma-associated antigen HMB45. In all patients, single or multiple SLNs were identified by the gamma-detecting probe. However, only 82.5% of these specimens included blue-stained nodes. None of the non-SLN specimens were the exclusive site of metastases. Four patients had metastases in their SLN specimen without non-SLN involvement. We conclude that SSLND can be performed easily and precisely with the exclusive use of the gamma-detecting probe. A single injection is feasible, and decreases operating room contamination and patient discomfort.

Localization of monoclonal antibody CC49 in colonic metastasis from renal cell carcinoma.

We report a rare case of solitary metastasis from renal cell carcinoma which manifested as a primary colonic tumour 5 years after nephrectomy. A monoclonal antibody CC49 (anti-TAG-72 antibody), used in Radioimmunoguided Surgery, was found to localize in the tumour. Pathological examination revealed metastasis of renal cell carcinoma in the colon. Immunohistochemistry with CC49 showed moderate staining of the colonic mucosa around the metastasis with no reaction in the tumour itself. Based on this case and other published studies, we conclude that TAG-72, the antigen manifested in many adenocarcinomas, can be up-regulated and expressed in normal colonic mucosa adjacent to another tumour as a result of stimulations, such as cytokine release, in response to this tumour.

Immunoreactivity of canine mammary neoplasms with monoclonal antibody CC49.

Monoclonal antibody (MAb) CC49 binds to human tumour-associated glycoprotein termed TAG-72. CC49 is a second-generation MAb with higher affinity to TAG-72 than the original MAb B72.3. CC49 was applied to 42 samples from different canine mammary tumours, belonging to seven different histopathological types. Immunoreactivity was detected by the use of an avidin-biotin complex immunoperoxidase method. Most sections from all types of mammary neoplasm reacted with this MAb. Normal tissue did not stain or stained only weakly. The results of this study suggest CC49 has selective immunoreactivity for a variety of canine mammary tumours, which seems superior to that reported with MAb 72.3. These results support the proposal for further study of diagnostic and therapeutic uses of CC49 in the management of canine mammary tumours.

Radioimmunoguided surgery benefits for recurrent colorectal cancer.

BACKGROUND: Despite new adjuvant therapy, 50% of patients with colon cancer will have recurrent disease. This study investigated the use of a radiolabeled monoclonal antibody in locating occult tumor during surgery for recurrent colorectal cancer. METHODS: Twenty-two patients with recurrent colorectal cancer underwent surgery using the radioimmunoguided surgery (RIGS) system. All patients were subjected to abdominal and chest computed tomography (CT). Before surgery, patients were injected with the CC49 monoclonal antibody (MoAb), anti-TAG antibody labeled with 125I. Ten patients with elevated carcinoembryonic antigen (CEA) levels and no CT findings had a scintigraphy scan with an anti-CEA MoAb labeled with 99Tc. Human antimouse antibody levels of these patients were within normal limits. Surgical exploration including liver ultrasound examination was followed by survey with a gamma-detecting probe (GDP). RESULTS: There was MoAb tumor localization in 100% of the patients. CT found nine tumor sites, traditional surgical exploration 30, and the GDP 51, with 44 confirmed by pathology (hematoxylin and eosin). The RIGS system found occult tumor in 10 patients (45.4%) and resulted in major changes in surgical procedure in 11 patients. In the 10 patients who had scintigraphy scans, 10 tumor sites were identified, whereas RIGS found an additional eight sites. CONCLUSION: RIGS technology offers a substantial benefit for patients undergoing surgery for recurrent colorectal cancer and a better chance of finding recurrent tumor intraoperatively in patients who have elevated CEA levels with no other CT findings.

Intraoperative detection of occult colon cancer micrometastases using 125 I-radiolabled monoclonal antibody CC49.

BACKGROUND: The detection of locally-disseminated disease is one of the principal goals of oncologic surgery. For this study, a hand-held, gamma-detecting probe was used intraoperatively to assess the extent of colorectal carcinoma in patients previously injected with radiolabeled antibody to the TAG-72 antigen (CC49); this technique is known as Radioimmunoguided Surgery (RIGS) (Neoprobe Corporation, Dublin, OH). RIGS-positive areas (i.e. those with increased signal over background) have previously been shown to contain carcinoma in a high proportion of cases. However, some RIGS-positive areas had no tumor detectable by clinical examination or routine histopathologic analysis. This study was undertaken to determine if the presence of occult metastases might account for this disparity. METHODS: A total of 57 regional lymph nodes (LN), resected from 16 patients with primary (9) or recurrent (7) colorectal carcinoma, were studied. The patients were injected with 125I labeled CC49 murine monoclonal antibody approximately 3 weeks prior to surgery. After routine histologic evaluation, the LN were analyzed for occult metastases; paraffin sections were cut at 5 levels (50 micron apart) and were examined by histology (hematoxylin and eosin stain [H & E]) and by immunohistochemistry (IHC) with a cocktail of monoclonal antibodies to cytokeratins. RESULTS: Fifty-seven LN were included in this study; 17 were H & E-positive (i.e., contained tumor by routine histologic examination [overt tumor]), while 40 LN were H & E-negative (i.e., no evidence of tumor after routine histologic examination). Thirty-nine LN were RIGS-positive, but only 14 of these were H & E-positive. Of the 25 RIGS-positive/H & E-negative LN, 10 (40%) demonstrated the presence of occult metastases after serial section/IHC analysis. Thus, a total of 27 LN contained metastatic carcinoma (17 overt, 10 occult); routine histologic analysis was able to identify tumor in only 17 of these 27 LN (63%), while the probe signaled the presence of tumor in 24 of these LN (89%). None of the RIGS-negative/H & E-negative LN were found to have occult metastases (0/15). Specific immunoreactivity with CC49 antibody was observed in 5 of 15 RIGS-positive/H & E-negative LN in which no tumor could be identified by any method (histopathology or IHC. CC49 immunoreactivity was not observed in 15 RIGS-negative/H & E-negative LN. CONCLUSIONS: The finding of a RIGS-positive LN had a significant association with the presence of tumor cells (P < 0.05). In this study, the RIGS procedure was more sensitive than clinical or histopathologic examination in detecting the regional spread of a tumor. Furthermore, in LN that showed no evidence of tumor by routine histopathologic examination, a positive RIGS reading was significantly associated with the presence of occult LN metastases (P < 0.01). This study is the first to demonstrate the detection of histologically occult tumor by a remote imaging device. RIGS assessment is a highly sensitive method for detecting occult tumor deposits, and may guide therapeutic intervention in patients with colorectal carcinoma.

Radioimmunoguided Surgery in the Treatment and Evaluation of Rectal Cancer Patients.

Several therapeutic options are available for the treatment of rectal cancer. To determine the most appropriate method of treatment, Radioimmunoguided Surgery (RIGS) can be used as an intraoperative diagnostic tool and as an adjuvant to traditional methods for more accurate staging. RIGS employs radiolabeled monoclonal antibodies directed against tumor-associated antigens and a gamma-detection probe to discriminate between normal and abnormal tissue. Most patients with primary or recurrent rectal cancer are considered good candidates for surgery using RIGS scanning. Use of the RIGS system may result in improved patient survival through accurate assessment of extent of disease and the selection of appropriate therapy. Prospective studies are necessary to define the optimal use of this approach as an experimental and clinical tool.

Intraperitoneal hyperthermic perfusion with mitomycin C for colorectal cancer with peritoneal metastases.

BACKGROUND: Intraperitoneal (i.p.) metastases pose a special problem for surgical treatment because of their multiplicity and microscopic size. This study was designed to examine the feasibility and safety of i.p. hyperthermic perfusion (IPHP) with mitomycin C (MMC) for treating recurrent colorectal cancer. METHODS: Fifteen patients with metastatic colon cancer were treated. All patients underwent cytoreductive procedures leaving only residual i.p. metastases < 1 cm in diameter. All patients had received prior systemic chemotherapy, but their disease had progressed. Intraperitoneal chemotherapy was administered through three large catheters (28 French) using a closed system of two pumps, a heat exchanger, and two filters. After the patient's abdominal temperature reached 41 degrees C, 45-60 mg of MMC was circulated intraperitoneally for 1 h. RESULTS: The majority of patients had various anastomoses: small bowel (n = 11), large bowel (n = 5), and urologic (n = 5). No anastomotic complications occurred in any of the patients. One patient experienced severe systemic MMC toxicity, which caused cytopenia and respiratory depression. In all patients the carcinoembryonic antigen (CEA) level decreased after surgery and IPHP. Median follow-up was 10 months, and recurrence was defined as an elevation in CEA level. Disease recurred in three patients within 5 months, and disease recurred in seven other patients over the next 3 months; one patient remains clinically free of disease after 8 months. CONCLUSION: Our data suggest that IPHP is a safe palliative method of treatment for patients with peritoneal carcinomatosis. The median patient response duration of 6 months may warrant consideration of a repeat IPHP procedure at that time.

Peritoneal carcinomatosis and radioimmunoguided surgery.

The Radioimmunoguided Surgery (RIGS) system was developed, in part, to detect occult tumor in patients with recurrent colorectal cancer. Unfortunately, however, patients are sometimes found to have unresectable peritoneal metastasis. For these patients, intraperitoneal hyperthermic perfusion (IPHP) with mitomycin C (MMC) was used as a novel treatment method. Thirty-six intraperitoneal hyperthermic perfusions with MMC were given over the course of several studies. A preliminary study delineated two groups as possible candidates for this treatment: patients with pseudomyxoma peritonei and patients with peritoneal metastasis < 0.5 cm. Intraperitoneal hyperthermic perfusion (IPHP) was conducted for 1 hour after achieving an abdominal temperature of 41 degrees C. A dose of 30 mg MMC in 31 Plasmalyte was injected followed by a second 30 mg dose given at 30 minutes. Plasma pharmacokinetics of IPHP with MMC indicate an advantage in the range of 100-fold enhancement of exposure compared with delivery in plasma. The method was found to be safe when flow was observed and dosage decisions were made during perfusion according to flow. A clinical study group consisting of 15 patients underwent cytoreductive surgery followed by IPHP. The majority of them had either gastrointestinal or urologic anastomoses. There were no complications. In every patient the CEA level decreased after surgery and IPHP, with a median response of 6 months. RIGS technology aided in the selection of IPHP as a treatment choice by demonstrating the presence of an occult tumor burden in those patients whose traditional explorations were deceiving. This chapter includes technical details and suggestions for improving and modifying the use of IPHP.

Radioimmunoguided surgery in primary colorectal carcinoma: an intraoperative prognostic tool and adjuvant to traditional staging.

BACKGROUND: The prognostic value of traditional staging classification for colorectal cancer has changed little since Dukes created the first staging scheme. Some patients with known metastatic disease are long-term survivors, while other patients with local disease die early. New intraoperative cancer detection technology, the radioimmunoguided surgery (RIGS) system, is being studied as a tool to aid in prediction of patient outcome. PATIENTS AND METHODS: Thirty-one patients with primary colorectal cancer were injected with the monoclonal antibody CC49, which was radiolabeled with iodine 125 (125I). A hand-held gamma-detecting probe was used at surgery to detect the radiolabeled antibody. Patients were classified as to the presence or absence of 125I-CC49-positive residual tissue at the close of surgery. Patient survival was analyzed. RESULTS: Follow-up ranged from 30 to 54 months. Survival of 11 stage I or II patients was longer than in 20 stage III or IV patients (P = 0.019). All 14 patients cleared of RIGS-positive tissue were alive at last follow-up, while 15 of 17 RIGS-positive patients died of their disease (P < 0.0001). CONCLUSIONS: The RIGS system used during surgery provides the surgeon with immediate prognostic information on patients with colorectal cancer and supplements traditional pathologic staging.