Session 4: Shaping radiotherapy for rectal cancer: should this be personalized?

Preoperative radiotherapy continues to be widely used in patients with operable rectal cancer. However, the indications and goals for such treatment are evolving. Professor Marijnen reviews the historic and current evidence base for the use of preoperative neoadjuvant radiotherapy and the future challenges in tailoring the therapy according to the patients' needs and tumour stage.

Impact of multimodal therapy in locally recurrent rectal cancer.

BACKGROUND: The practice of salvaging recurrent rectal cancer has evolved. The aim of this study was to define the evolving salvage potential over time among patients with locally recurrent disease, and to identify durable determinants of long-term success. METHODS: The study included consecutive patients with recurrent rectal cancer undergoing multimodal salvage with curative intent between 1988 and 2012. Predictors of long-term survival were defined by Cox regression analysis and compared over time. Re-recurrence and subsequent treatments were evaluated. RESULTS: After multidisciplinary evaluation of 229 patients, salvage therapy with curative intent included preoperative chemotherapy and/or radiotherapy (73·4 per cent; with 41·3 per cent undergoing repeat pelvic irradiation), surgical salvage resection with or without intraoperative irradiation (36·2 per cent), followed by postoperative adjuvant chemotherapy (38·0 per cent). Multivisceral resection was undertaken in 47·2 per cent and bone resection in 29·7 per cent. The R0 resection rate was 80·3 per cent. After a median follow-up of 56·5 months, the 5-year overall survival rate was 50 per cent in 2005-2012, markedly increased from 32 per cent in 1988-1996 (P = 0·044). Long-term success was associated with R0 resection (P = 0·017) and lack of secondary failure (P = 0·003). Some 125 patients (54·6 per cent) developed further recurrence at a median of 19·4 months after salvage surgery. Repeat operative rescue was feasible in 21 of 48 patients with local re-recurrence alone and in 17 of 77 with distant re-recurrence, with a median survival of 19·8 months after further recurrence. CONCLUSION: The long-term salvage potential for recurrent rectal cancer improved significantly over time, with the introduction of an individualized treatment algorithm of multimodal treatments and surgical salvage. Durable predictors of long-term success were R0 resection at salvage operation, avoidance of secondary failure, and feasibility of repeat rescue after re-recurrence.

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.

The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)--results of an international collaborative study.

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2-5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.

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.

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.

Colorectal cancer: how does it start? How does it metastasize?

Colorectal carcinogenesis is a multistep process with an apparently orderly progression from benign tissue to invasive malignancy and metastases. Yet at the genome level, a considerably more chaotic situation exists, with order arising through the process of natural selection in the midst of genomic instability. Major pathways for colorectal carcinogenesis begin with suppressor loss or acquisition of a mutator phenotype, but there are other pathways known and yet to be described. These pathways result in the natural selection of cells with unstable genomes leading to malignancy and metastases.

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.

The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. METHODS: We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. RESULTS: At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. CONCLUSIONS: In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

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.

Analysis of genetic and phenotypic heterogeneity in juvenile polyposis.

BACKGROUND: Juvenile polyposis syndrome (JPS) is characterised by gastrointestinal (GI) hamartomatous polyposis and an increased risk of GI malignancy. Juvenile polyps also occur in the Cowden (CS), Bannayan-Ruvalcaba-Riley (BRRS) and Gorlin (GS) syndromes. Diagnosing JPS can be problematic because it relies on exclusion of CS, BRRS, and GS. Germline mutations in the PTCH, PTEN and DPC4 (SMAD4) genes can cause GS, CS/BRRS, and JPS, respectively. AIMS: To examine the contribution of mutations in PTCH, PTEN, and DPC4 (SMAD4) to JPS. METHODS: Forty seven individuals from 15 families and nine apparently sporadic cases with JPS were screened for germline mutations in DPC4, PTEN, and PTCH. RESULTS: No patient had a mutation in PTEN or PTCH. Five different germline mutations were detected in DPC4; three of these were deletions, one a single base substitution creating a stop codon, and one a missense change. None of these patients had distinguishing clinical features. CONCLUSIONS: Mutations in PTEN and PTCH are unlikely to cause juvenile polyposis in the absence of clinical features indicative of CS, BRRS, or GS. A proportion of JPS patients harbour DPC4 mutations (21% in this study) but there remains uncharacterized genetic heterogeneity in JPS.

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.