Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States.

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

Intrachromosomal genomic instability in human sporadic colorectal cancer measured by genome-wide allelotyping and inter-(simple sequence repeat) PCR.

We have used genome-wide allelotyping with 348 polymorphic autosomal markers spaced, on average, 10 cM apart to quantitate the extent of intrachromosomal instability in 59 human sporadic colorectal carcinomas. We have compared instability measured by this method with that measured by inter-(simple sequence repeat) PCR and microsatellite instability assays. Instability quantitated by fractional allelic loss rates was found to be independent of that detected by microsatellite instability analyses but was weakly associated with that measured by inter-(simple sequence repeat) PCR. A set of seven loci were identified that were most strongly associated with elevated rates of fractional allelic loss and/or inter-(simple sequence repeat) PCR instability; these seven loci were on chromosomes 3, 8, 11, 13, 14, 18, and 20. A lesser association was seen with two loci flanking p53 on chromosome 17. Coordinate loss patterns for these loci suggest that at least two separate sets of cooperating loci exist for intrachromosomal genomic instability in human colorectal cancer.

Is there a role for curative surgery for pelvic recurrence from rectal carcinoma in the presence of hydronephrosis?

BACKGROUND: The prognosis for patients with recurrent rectal adenocarcinoma is not uniformly fatal if one can safely and selectively reoperate on a subset of patients with resectable disease. Even with careful selection, many patients undergo exploratory laparotomy and do not have resectable disease. We have reported that the presence of hydronephrosis in the setting of recurrent rectal carcinoma portends a poor outcome because of invariable association with unresectable disease. The purpose of this study was to update our experience of patients presenting with unilateral or bilateral hydronephrosis and recurrent rectal cancer. METHODS: A retrospective chart review of 142 patients with recurrent rectal cancer evaluated at our institution from January 1989 to December 1999 was performed. RESULTS: Twenty-seven of 142 patients referred for the management of recurrent rectal cancer had unilateral or bilateral hydronephrosis. Fifteen (55%) of these patients had distant metastatic disease. Twelve patients (45%) with hydronephrosis and local recurrent disease on evaluation were analyzed. Six of the 12 patients underwent exploratory laparotomy, with none found to have resectable disease. Their mean survival after diagnosis of recurrent disease was 14 months. CONCLUSIONS: Based on our results, the presence of hydronephrosis (unilateral or bilateral) in recurrent rectal adenocarcinoma portends a survival equivalent to the presence of distant metastasis. Therefore, we do not believe potential curative surgery has a role for patients with locally recurrent rectal adenocarcinoma in the presence of hydronephrosis.

Local excision of rectal carcinoma.

The purpose of this study was to identify the recurrence rate, the salvage rate after recurrence, and the overall survival after local excision of rectal adenocarcinomas. A retrospective medical chart review was performed in 31 consecutive patients with rectal adenocarcinoma who underwent local excision at Roswell Park Cancer Institute from January 1990 through December 1999. After excision nine patients were excluded from further analysis because they were found to have advanced stage on pathologic examination (T2 primary tumors with vascular invasion or T3 tumors). Eight of the nine patients underwent abdominoperineal resection as definitive therapy. In the remaining 22 patients who underwent transanal excision as definitive surgical therapy there were 13 patients with T1 tumors and nine patients with T2 tumors. Overall seven patients (32%) developed local recurrences after local excision. This included four patients with T1 and three patients with T2 primary tumors. All recurrences occurred in the seven patients who did not receive adjuvant chemoradiation. All patients underwent salvage resection of the recurrence. Four patients who underwent salvage resection of the recurrence remain without evidence of disease at a median follow-up of 19.5 months. Local excision without adjuvant therapy has an unacceptably high rate of local recurrence. Although most patients who recur locally are salvaged by radical resection the long-term results after resection remain unknown. The use of adjuvant chemoradiation appears to reduce this high recurrence rate and may eventually become a standard adjunct to local excision of rectal cancer.

Rectal cancer in hereditary nonpolyposis colorectal cancer.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% to 5% of all colorectal cancers. Rectal cancer in HNPCC is not well characterized. METHODS: A retrospective medical record review of HNPCC patients with colorectal cancer diagnosis from December 1948 to December 1999 was performed in an attempt to elucidate the natural history of rectal cancer in HNPCC. Group A consisted of patients diagnosed with rectal cancer as the index colorectal cancer. Group B consisted of patients diagnosed with rectal cancer as a metachronous colorectal cancer. RESULTS: Twenty-five of 104 patients developed rectal cancer in our HNPCC registry. There were 18 patients in group A with a median age at diagnosis of rectal cancer of 48 years (range 24 to 79) and 7 patients in group B diagnosed at a median age of 58 years (range 45 to 68). Three of 18 patients (17%) in group A developed metachronous colon cancers at a median of 203 months (range 27 to 373) from the index rectal cancer. Rectal cancer in group B was diagnosed at a median 245 months (range 51 to 564) from the index colorectal cancer diagnosis. CONCLUSIONS: Rectal cancer in HNPCC is not uncommon. The presentation of rectal carcinoma should not obviate the evaluation for HNPCC in suspected cases.

Hepatic lymphatic mapping: a pilot study for porta hepatis lymph node identification.

The status of the porta hepatis lymph nodes in patients with hepatic metastases from colorectal cancer affects their prognosis and management. Lymphatic mapping with isosulfan blue dye is well established in breast cancer and melanoma. An animal model consisting of three dogs receiving general anesthesia was utilized. Each dog underwent a laparotomy and increasing doses of isosulfan blue dye were injected into the right medial segment of the liver. Intraoperatively, the presence of blue dye in the porta hepatis region was determined and the lymph node identified. Continuous physiological monitoring was performed. Serum determination of liver function tests, amylase levels, and white blood cell count were performed preoperatively and on postoperative days 1, 2, 4, and 7. The animals were sacrificed on day 7. A portal lymph node was identified in each case and there was no perioperative morbidity or mortality. There were no significant alterations in blood pressure or heart rate in the animals. There was a dose-responsive decrease in the O2 saturation as measured by transcutaneous monitoring, but arterial blood gas analysis showed that pO2 levels remained stable. There were no significant changes in the liver function tests, amylase levels, or white blood cell counts. There was a small increase in alkaline phosphatase, which normalized by postoperative day 7. Hepatic injection of isosulfan blue dye appears to be safe and effective in identifying porta hepatis lymph nodes in the animal model and sets the basis for further study in human subjects.

Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations.

UNLABELLED: Hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur. Juvenile polyposis syndrome (JPS) results from germ-line mutations in the SMAD-4 gene (18q21.1) that encodes for an enzyme involved in transforming growth factor beta(TGF-beta) signal transduction. The increased neoplastic risk may result from SMAD-4 mutations in the stromal component, which stimulate epithelial dysplasia and progression to invasive malignancy. Peutz-Jeghers syndrome (PJS) is associated with germ-line mutations in the LKB1 gene (19p13.3) that encodes a multifunctional serine-threonine kinase. These mutations occur in the epithelial component, suggesting a direct tumor suppressor effect. Patients are at an increased risk of intestinal and extraintestinal malignancies, including breast, pancreatic, ovarian, testicular, and cervical cancer. Cowden's disease is associated with germ-line mutations in the PTEN gene (10q22-23) and an increased risk of breast and thyroid malignancies. Ruvalcaba-Myhre-Smith syndrome is less common; controversy suggests that it may represent a variant of Cowden's disease. CONCLUSIONS: Genetic alterations underlying hamartomatous polyposis syndromes are diverse. Carcinogenesis may result from either germ-line mutations in the stroma (JPS) or as a direct result of functional deletion of tumor suppressor genes (PJS). Diagnosis depends on clinical presentation and patterns of inheritance within families. Suggested surveillance guidelines for the proband and first-degree relatives are outlined.

Guidelines 2000 for colon and rectal cancer surgery.

BACKGROUND: Oncologic resection techniques affect outcome for colon cancer and rectal cancer, but standardized guidelines have not been adopted. The National Cancer Institute sponsored a panel of experts to systematically review current literature and to draft guidelines that provide uniform definitions, principles, and practices. METHODS: Methods were similar to those described by the American Society of Clinical Oncology in developing practice guidelines. Experts representing oncology and surgery met to review current literature on oncologic resection techniques for level of evidence (I-V, where I is the best evidence and V is the least compelling) and grade of recommendation (A-D, where A is based on the best evidence and D is based on the weakest evidence). Initial guidelines were drafted, reviewed, and accepted by consensus. RESULTS: For the following seven factors, the level of evidence was II, III, or IV, and the findings were generally consistent (grade B): anatomic definition of colon versus rectum, tumor-node-metastasis staging, radial margins, adjuvant R0 stage, inadvertent rectal perforation, distal and proximal rectal margins, and en bloc resection of adherent tumors. For another seven factors, the level of evidence was II, III, or IV, but findings were inconsistent (grade C): laparoscopic colectomy; colon lymphadenectomy; level of proximal vessel ligation, mesorectal excision, and extended lateral pelvic lymph node dissection (all three for rectal cancer); no-touch technique; and bowel washout. For the other four factors, there was little or no systematic empirical evidence (grade D): abdominal exploration, oophorectomy, extent of colon resection, and total length of rectum resected. CONCLUSIONS: The panel reports surgical guidelines and definitions based on the best available evidence. The availability of more standardized information in the future should allow for more grade A recommendations.

Use of vitamins, minerals, and nutritional supplements by participants in a chemoprevention trial.

BACKGROUND: The growing use of vitamins, minerals, and nutritional supplements has the potential to influence the design and interpretation of randomized controlled trials of chemopreventive agents. To the extent that these complementary agents are effective, they could limit the ability of trials to demonstrate an effect of the agents under study. METHODS: During the course of a colorectal neoplasia chemoprevention trial using aspirin in a group of colorectal carcinoma survivors, the authors obtained information on the use of vitamins, minerals, and supplements at baseline and every 6 months. The information from 622 study participants was categorized and enumerated. RESULTS: One or more supplements were used at some time by 341 (55%) subjects. Among those who took supplements, 66% took more than 1 and 13% took 5 or more. The mean number of supplements taken was 2.6 (1.7 standard deviation). Vitamins were the most commonly used (49%), followed by minerals (22%), botanicals (13%), and others (5%). Among the vitamins, the most frequently used were multivitamins (38% of subjects), vitamin C (18%), and vitamin E (22%). Calcium (16%) was the most frequent mineral. Among users, there were no differences in supplement use by age or gender. CONCLUSIONS: Supplement use was common among colorectal carcinoma survivors enrolled in a prevention trial. Investigators should record the information on supplement use so that the possible impact of the supplements on trial endpoints can be evaluated. It may be necessary to increase the size of studies if many of the subjects take potentially effective supplements.

The effect of cardiopulmonary lymphatic obstruction on heart and lung function.

Many thoracic surgical procedures involve excision or destruction of intrathoracic and mediastinal lymphatics. It is widely assumed that the mediastinal lymphatic system is surgically expendable, and that destruction of mediastinal lymphatics has no significant adverse physiological effect. Cardiac lymphatic obstruction may give rise to cardiac lymphedema and impaired cardiac function. Similarly, obstruction of pulmonary lymphatics may result in pulmonary perivascular lymphedema, endothelial injury, and pulmonary artery hypertension. This review summarizes the possible deleterious effects of intrathoracic lymphatic destruction and the benefits of pharmacological and surgical enhancement of active lymph drainage.

Early postoperative oral feeding after colectomy: an analysis of factors that may predict failure.

BACKGROUND: Previous studies have shown that early postoperative oral feeding is feasible. Traditionally patients were fed when flatus or defecation documented the return of bowel function. This study was undertaken to determine factors that may preclude early feeding. METHODS: One hundred four successive patients underwent colorectal surgery from October 1999 to January 2001. Eighty-nine patients started an oral diet either on postoperative day 1 or 2. Their clinical outcomes were recorded prospectively. Fifteen of the 104 patients were excluded for small-bowel resection (5 patients), perioperative complications (5 patients), prior radiation (3 patients), and small-bowel obstruction (2 patients). A failure in postoperative feeding consisted of nausea, vomiting, or readmission. RESULTS: The mean age of our cohort was 65 years (range, 28-87 years). There were 45 male and 44 female patients. The mean postoperative hospital stay was 6 days (range, 3-13 days). The median American Society of Anesthesiology score was II (range, I-IV). The types of resection performed were right colectomy (27 patients), low anterior resection (26 patients), sigmoid resection (11 patients), abdominoperineal resection (8 patients), formation or closure of colostomy (7 patients), posterior pelvic exenteration (4 patients), total colectomy (3 patients), left colectomy (2 patients), and transverse colectomy (1 patient). Sixty-five patients (73%) tolerated early oral feeding. Of the 24 patients that did not, 16 had nausea or emesis, and 8 required readmission for postoperative complications (small-bowel obstruction [4 patients], wound dehiscence [1 patient], abdominal pain [1 patient], and anastomotic leak [2 patients]). Univariate analysis revealed that the use of volume expanders contributed to intolerance of early feeding. On multivariate analysis, blood loss during the operation was the only factor contributing to failure of early postoperative oral feeding. CONCLUSIONS: Early oral feeding is safe and feasible for postcolectomy patients with a history of colorectal neoplasms.

Effect of pyloric drainage on the healing of esophagogastric anastomoses in rats.

BACKGROUND AND OBJECTIVES: Esophagogastric anastomotic leaks complicate 5% to 20% of esophagectomies for esophageal cancer and are responsible for approximately one-third of perioperative deaths. Poor gastric emptying is a predisposing factor for anastomotic leakage. An animal experiment was used to test the hypothesis that a pyloric drainage procedure (pyloromyotomy) would have a positive effect on esophagogastric anastomotic healing. METHODS: In 40 rats single-layer esophagogastric anastomoses were constructed with interrupted 7-0 polypropylene sutures. A pyloromyotomy was done in the experimental group (20 rats) but not in the control group (20 rats). Rats were sacrificed on the 7th postoperative day and their anastomoses were excised, mounted in a tensiometer, and distracted at 10 mm/min to measure breaking strength. After that, the hydroxyproline concentration (an indicator of wound collagen) of the anastomotic tissue was measured. RESULTS: There were no anastomotic leaks. The mean (and standard deviation) breaking strength of the esophagogastric anastomosis was 3.96 (1.14) N in the pyloromyotomy rats and 4.11 (0.75) N in the control rats (p = 0.64). The mean (and SD) hydroxyproline concentration in esophagogastric anastomotic tissue was 368.6 (31.5) nmol/mg in the pyloromyotomy rats and 376.6 (31.3) nmol/mg in the control rats (p = 0.77). CONCLUSION: Pyloric drainage (pyloromyotomy) did not have any effect on esophagogastric anastomotic wound healing in this rat model.

Absorbable mesh sling prevents radiation-induced bowel injury during "sandwich" chemoradiation for rectal cancer.

HYPOTHESIS: Absorbable mesh slings can prevent radiation-induced bowel injury when adjuvant pelvic radiotherapy is given in the early postoperative period. We hypothesized that the mesh sling technique is similarly effective during "sandwich" sequence adjuvant chemoradiation. DESIGN: Retrospective review. SETTING: Tertiary care comprehensive cancer center. PATIENTS: Nonrandomized series of 19 consecutive patients who underwent abdominoperineal resection and received postoperative sandwich sequence chemoradiation at Roswell Park Cancer Institute, Buffalo, NY, between January 1994 and September 1999. INTERVENTIONS: Twelve patients had an absorbable mesh sling placed at the completion of abdominoperineal resection. Seven patients did not have an absorbable mesh sling placed. MAIN OUTCOME MEASURES: Radiotherapy dose and gastrointestinal toxic effects. RESULTS: All 12 patients in the "mesh" group were able to receive full-dose radiotherapy with tumor bed boost (total dose, 54 Gy, 11 patients; 59.4 Gy, 1 patient). Only 3 of 7 patients in the "no mesh" group were able to receive a tumor bed boost (total dose, 46.8 Gy, 1 patient; 50.4 Gy, 3 patients; 54 Gy, 3 patients). Acute gastrointestinal toxic effects were minimal in the mesh group (grade 1, 10 patients; grade 2, 2 patients) compared with the no mesh group (grade 2, 6 patients; grade 3, 1 patients). None of the patients in the mesh group have shown evidence of late gastrointestinal toxic effects. One patient in the no mesh group required surgery for complications of chronic radiation enteritis. CONCLUSIONS: The protective effects of an absorbable mesh sling extend beyond the life expectancy of the mesh itself. Sandwich sequence chemoradiation should not preclude the use of the mesh sling technique.

Sexual dysfunction, informed consent and multimodality therapy for rectal cancer.

BACKGROUND: This study assessed the presurgical and preradiation discussion of the risk of posttherapy sexual dysfunction among patients who underwent potentially curative therapy for rectal cancer. The incidence of sexual dysfunction after treatment for rectal cancer was then determined. METHODS: A retrospective review of the medical records of 52 consecutive patients who underwent potentially curative procedures for rectal cancer within 15 cm from the anal verge was performed. RESULTS: Presurgical discussion of the risk of sexual dysfunction was not documented in the consent in 37 of 52 patients (71%). Among the 5 males who underwent local excision, none reported posttherapy sexual dysfunction. Of the 6 males who were treated by low anterior resection, only 1 had a postoperative complaint of sexual dysfunction. Five of 15 males (33%) treated with abdominoperineal resection (APR) alone reported postprocedure sexual dysfunction, whereas 6 of 8 males (75%) treated with APR and radiation reported dysfunction. Of the entire female cohort, only 1 of the 16 reported sexual dysfunction posttherapy. CONCLUSION: A discussion of the risks of posttherapy sexual dysfunction was documented for fewer than one third of the patients. Among males after APR, the use of postoperative radiation showed a trend toward an increase in sexual dysfunction. Surgery and/or radiation therapy did not impact on sexual dysfunction in females.

Safety and efficacy of arcitumomab imaging in colorectal cancer after repeated administration.

UNLABELLED: In pivotal phase III clinical trials for detecting recurrent or metastatic colorectal cancer, most patients received a single arcitumomab injection. However, the early detection of postsurgical recurrence or metastases with arcitumomab will necessitate serial studies for surveillance. We present immunogenicity, safety, and imaging data supporting the use of multiple administrations of arcitumomab. METHODS: Human antimouse antibody (HAMA) response, adverse events, clinical laboratory values, and diagnostic imaging results were evaluated in 44 patients (24 men, 20 women; age range, 2878 y) after repeated arcitumomab administration (44 second and 3 third injections). Most patients initially had Dukes' class B or C colorectal cancer and had known or occult disease recurrence and elevated serum carcinoembryonic antigen levels at the time of the repeated injection. RESULTS: At the repeated injection, in no patient did elevated HAMA titers develop, hematology and serum chemistry changes were clinically insignificant, and only 1 adverse event (eosinophilia) was judged at least possibly related to arcitumomab. Arcitumomab imaging results at the second injection were comparable with those obtained in phase III trials after a single injection of arcitumomab, having a 78% per-lesion concordance with CT in the abdomen and pelvis and a 73% sensitivity and 94% specificity based on 9 patients with cancer confirmed surgically at 11 anatomic sites and excluded at 16 sites. CONCLUSION: These data indicate that at least 2 injections of arcitumomab can be given safely to patients with colorectal cancer, without increased immunogenicity and with imaging efficacy equivalent to the first administration.

Photodynamic therapy for residual neoplasms of the perianal skin.

PURPOSE: The aim of this study was to evaluate the efficacy of photodynamic therapy in the management of residual neoplasms of the perianal skin. METHODS: This is a retrospective review. Five patients with pathologic confirmation of residual perianal neoplasms were treated with photodynamic therapy. There were three females. The mean age was 52 (range, 33-79) years. Pathology consisted of Bowen's disease in two patients, squamous-cell carcinoma in two patients, and extramammary Paget's disease in one patient. Four patients received one photodynamic therapy treatment and one patient received two treatments three months apart. RESULTS: Treatment was followed by immediate perianal erythema, subsequent blister formation in 36 to 48 hours, and sloughing of the treated area in 72 hours. With a mean follow-up of 5.2 (range, 1-8) years, there were two recurrences. One recurrence was in a patient four years after treatment for Paget's disease, and the other was in a patient nine months after treatment for Bowen's disease. The latter was managed successfully with wide local excision. Treatment-related toxicities included significant perianal pain in four patients, controlled with analgesia management. CONCLUSIONS: Photodynamic therapy can successfully be used after wide local excision for residual neoplasms of the perianal skin. Treatment can be rendered with acceptable morbidity.

p53 tumor suppressor gene mutations predict decreased survival of patients with sporadic colorectal carcinoma.

BACKGROUND: Mutations of the p53 tumor suppressor gene play an integral role in sporadic colorectal carcinogenesis but prior studies have failed to show their prognostic significance consistently. METHODS: Fifty-six consecutive sporadic colorectal tumors were analyzed for their p53 status. Polymerase chain reaction amplification with primers for exons 5-9 was conducted and these products were subjected to single strand conformation polymorphism analysis. Suspected mutations were confirmed with DNA sequencing. p53 status was entered into a colorectal clinical database and these patients then were followed prospectively. Patient status with regard to disease recurrence and survival was updated every 6 months. Survival and disease free survival were calculated according to the method of Kaplan and Meier. The association between p53 status and clinical and pathologic factors with survival and recurrence was statistically determined using univariate analysis and the Cox proportional hazards model for multivariate analysis. RESULTS: p53 mutations were detected in 28 of 56 patients (50%). The median follow-up time was 45 months (range, 3-72 months). There were 33 patients (59%) who were alive at last follow-up. Fifteen of the 23 patients who died (65%) had p53 mutations and 8 (35%) had wild-type p53. Thirteen patients developed a disease recurrence, 9 of whom (69%) had tumors with p53 mutations. Overall 4-year survival rates for patients with wild-type p53 and mutant p53 were 71% and 54%, respectively (P = 0.05). The 4-year disease free survival rates for patients with wild-type p53 and mutant p53 were 83% and 62%, respectively (P = 0.09). p53 status and stage were found to be independent significant predictors for survival (p53 negative: P = 0. 02; stage: P = 0.0002.) Stage was found to be the sole significant predictor for disease free survival (P = 0.006). CONCLUSIONS: In this group of colorectal carcinoma patients, p53 mutations were a significant negative prognostic indicator for overall survival. This finding holds prognostic and therapeutic implications for the management of colorectal carcinoma patients.