Clinical end points for developing pharmaceuticals to manage patients with a sporadic or genetic risk of colorectal cancer.

To reduce the morbidity and mortality from colorectal cancer (CRC), current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients at risk for CRC. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with a sporadic or genetic risk of CRC. It will also discuss therapeutic end points under evaluation in current efforts to develop drugs for treating CRC risk factors.

Preoperative radiation therapy for upper rectal cancer T3,T4/Nx: selectivity essential.

This review explores the current available literature regarding the role of neoadjuvant therapy for upper locally advanced rectal cancers (≥10 cm-15 cm). Although there is a paucity of data evaluating the outcomes of preoperative chemoradiation for upper rectal cancers the authors suggest that T3N0 tumors will not likely benefit from radiation and that treatment of T4N0 should be individualized.

KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer.

INTRODUCTION: We examined two genetic markers established early in colorectal tumor development, microsatellite instability (MSI) and mutation of the KRAS proto-oncogene, to see if these genetic changes influence metastatic disease progression and survival. PATIENTS AND METHODS: MSI and KRAS mutation status were assessed in 532 primary adenocarcinomas (stage I-IV) from patients treated by colon resection. Median follow-up was 4.1 years (range 0-13.3 years) overall, 5.4 years for survivors. RESULTS: MSI and KRAS mutation were detected in 12 and 36% of cases, respectively. MSI was more common in early-stage disease (I, 15%; II, 21%; III, 10%; IV, 2%; P = 0.0001). Prevalence of KRAS mutation did not vary with stage (I, 36%; II, 34%; III, 35%; IV, 40%; P = ns). Disease-specific survival was far superior for MSI tumors than for microsatellite stability (MSS) tumors (5-year survival 92 vs. 59%, P < 0.0001). KRAS mutation was a marker of poor survival (5-year survival 55 vs. 68%, P = 0.0002). Using Cox regression analysis MSI, KRAS mutation, and stage were strong independent predictors of survival in the entire patient population. A high-mortality group with MSS/KRAS-mutant tumors was identified within the stage I and II cohort. CONCLUSIONS: MSI and KRAS mutation provide fundamental genetic signatures influencing tumor behavior across patient subsets and stages of tumor development.

Predictors of recurrence in patients with T2 and early T3, N0 adenocarcinoma of the rectum treated by surgery alone.

PURPOSE: Treatment of rectal cancer with neoadjuvant radiotherapy has been shown to reduce local recurrence and improve overall survival. The role of chemoradiotherapy in patients with T2, N0 and early T3, N0 rectal cancer, treated by radical surgery with total mesorectal excision, remains controversial. The aim of this study was to identify predictors of recurrence in this group of patients to enhance treatment selection. PATIENTS AND METHODS: One hundred patients with primary T2-3, N0 adenocarcinoma of the rectum, uniformly treated by surgery alone, were studied. The pathology slides available for 97 patients were rereviewed. Three patients with incomplete data sets were excluded. Clinical and survival data were obtained from a prospective computerized database and updated from hospital and office charts. The study end points were disease-free survival, disease-specific survival (DSS), time to pelvic recurrence (PR), and distant recurrence. RESULTS: Complete follow-up was available for all study patients. Median follow-up was 79.5 months (range, 57.7 to 105.9 months). During this time period 30 patients (31.9%) died as a result of disease and 64 patients (68.1%) remained alive and disease free. Five-year DSS was 73%. The cumulative risk for PR was 8% at 5 years and 10% at 8 years. Lymphovascular invasion, preoperative serum carcinoembryonic antigen (CEA > 5 ng/mL) level, and age older than 70 years were all associated with adverse outcome. CONCLUSION Patients with T2-3, N0 rectal cancers and either lymphovascular invasion or elevated CEA levels have reduced survival and a higher incidence of PR, and should be considered for future randomized trials.

Sacral resection for recurrent rectal cancer: analysis of morbidity and treatment results.

PURPOSE: Composite sacropelvic resection for locally advanced recurrent rectal cancer is a high-risk procedure that benefits select patients. We reviewed our recent institutional experience to evaluate case selection, morbidity, and outcomes. METHODS: Between 1987 and 2004, 29 patients underwent composite resection for recurrent locoregional rectal cancer (17 females; median age, 60 years). Clinicopathologic indicators were evaluated as indicators of survival by log-rank test and Cox proportional hazards model. RESULTS: Of 29 total patients, 27 (93 percent) received radiotherapy with their previous surgery (n = 10; 34 percent) or before sacrectomy (n = 17; 59 percent), and 12 (41 percent) received intraoperative therapy. Sacral resections were performed at S2/S3 (55 percent) or S4/S5 (45 percent) using anterior (41 percent) or combined anterior-posterior approach (59 percent), with adherence to (62 percent) or cortical invasion in (38 percent) the sacrum. A majority of those who had undergone previous abdominoperineal resection had total exenteration (9/13), whereas most patients who had undergone a previous sphincter-preserving procedure had abdominoperineal resection (12/16) and none had exenteration. Pedicle flaps (omental, 11; abdominal rectus, 7) often were used. A median of five (range, 1-33) units of blood was given intraoperatively. Transfusions were associated with previous abdominoperineal resection (P < 0.03), correlating strongly with postoperative morbidity (P < 0.02). There were 33 complications in 17 (59 percent) patients, most commonly perineal wound breakdown (9 (31 percent)) and pelvic abscess (5 (17 percent)). Median hospital stay was 18 (range, 7-56) days, significantly longer in patients with previous abdominoperineal resection (P < 0.02) or postoperative morbidity (P < 0.03). The only postoperative death was from pelvic sepsis. Resection was complete (R0) in 18 patients (62 percent), with microscopically positive margins (R1) in 10 (34 percent) and grossly positive margins (R2) in 1 (3 percent). Two-year and five-year recurrence rates were 47 and 85 percent, respectively; disease-specific survival was 63 and 20 percent, respectively. Less transfusion (P = 0.03), R0 resection (P = 0.005), lack of anterior organ involvement (P = 0.02), and absence of cortical bone invasion (P < 0.001) were associated with better survival on univariate analysis; original colorectal cancer stage was not. CONCLUSIONS: Sacrectomy for rectal cancer is a high-risk procedure that can achieve clear resection margins with low mortality in select patients. This procedure has a low cure rate but may provide local disease control with acceptable morbidity.

T1 adenocarcinoma of the rectum: transanal excision or radical surgery?

BACKGROUND: Recent studies suggest local excision may be acceptable treatment of T1 adenocarcinoma of the rectum, but there is little comparative data with radical surgery to assess outcomes and quantify risk. We performed a retrospective evaluation of patients with T1 rectal cancers treated by either transanal excision or radical resection at our institution to assess patient selection, cancer recurrence, and survival. METHODS: All patients who underwent surgery for T1 adenocarcinomas of the rectum (0-15 cm from anal verge) by either transanal excision (TAE) or radical resection (RAD) between January 1987 and January 2004 were identified from a prospective database. Data were analyzed using Fisher exact test, Kaplan-Meier method, and log-rank test. RESULTS: Three hundred nineteen consecutive patients with T1 lesions were treated by transanal excision (n = 151) or radical surgery (n = 168) over the 17-year period. RAD surgery was associated with higher tumor location in the rectum, slightly larger tumor size, a similar rate of adverse histology, and a lymph node metastasis rate of 18%. Despite these features, patients who underwent RAD surgery had fewer local recurrences, fewer distant recurrences, and significantly better recurrence-free survival (P = 0.0001). Overall and disease-specific survival was similar for RAD and TAE groups. CONCLUSION: Despite a similar risk profile in the 2 surgical groups, patients with T1 rectal cancer treated by local excision were observed to have a 3- to 5-fold higher risk of tumor recurrence compared with patients treated by radical surgery. Local excision should be reserved for low-risk cancers in patients who will accept an increased risk of tumor recurrence, prolonged surveillance, and possible need for aggressive salvage surgery. Radical resection is the more definitive surgical treatment of T1 rectal cancers.

Complications after preoperative combined modality therapy and radical resection of locally advanced rectal cancer: a 14-year experience from a specialty service.

BACKGROUND: Preoperative combined modality therapy followed by total mesorectal excision has emerged as the optimal treatment paradigm for locally advanced rectal cancer (T3 to 4, N1, or both). But its impact on postoperative complications has not been adequately evaluated. Our aims were to evaluate our comprehensive experience and identify factors predictive of complications in this patient population. STUDY DESIGN: The study group consisted of 297 consecutive patients with locally advanced rectal adenocarcinoma treated with preoperative combined modality therapy (radiation: 5,040 cGy; chemotherapy: 5-FU-based) and then operation. Major complications were defined as those requiring medical or surgical treatment. A prospectively collected database was queried to determine the incidence of postoperative complications and associated clinicopathologic factors. RESULTS: Median followup was 43.9 months (range 0.8 to 128.6 months). There were no postoperative mortalities (within 30 days of operation). But there were 145 major complications in 98 patients (33% of study population). The most common complications were small bowel obstruction (n = 32 [11%]) and wound infection (n = 31 [10%]). There were eight anastomotic leaks (4%) and nine pelvic abscesses (4%) in patients treated with low anterior resection (n = 210). Preoperative comorbidity was the only clinicopathologic factor associated with postoperative complications (p = 0.02). Postoperative complications had no significant impact on oncologic outcomes. CONCLUSIONS: Although postoperative mortalities are rare, complications requiring treatment can be anticipated in one-third of patients undergoing preoperative combined modality therapy and total mesorectal excision. A policy of selective fecal diversion after preoperative combined modality therapy and total mesorectal excision for locally advanced rectal cancer can achieve low rates of pelvic sepsis, but may lead to an increased incidence of small bowel obstruction.

Technical complications and durability of hepatic artery infusion pumps for unresectable colorectal liver metastases: an institutional experience of 544 consecutive cases.

BACKGROUND: Hepatic arterial infusion pump chemotherapy is an important component in the treatment of patients with hepatic metastases. Successful use of a hepatic arterial infusion pump requires a low technical complication rate. We evaluated the complications and longterm durability of these devices at our institution. STUDY DESIGN: Between April 1986 and March 2001, 544 patients underwent hepatic arterial infusion pump placement for treatment of unresectable colorectal liver metastases. Patient- and pump-related data were collected by chart review. Pump-related complications, duration of pump function, and overall patient survival were recorded. RESULTS: Median patient survival was 24 months after pump placement. The incidences of pump failure were 9% at 1 year and 16% at 2 years. Pump complications occurred in 120 (22%) of the patients. Complications that occurred early after operation (< 30 days) were more likely to be salvaged than those occurring late (70% versus 30%, p < 0.001). Increased pump complication rates occurred in the setting of variant arterial anatomy (28% versus 19%, p = 0.02), when the catheter was inserted into a vessel other than the gastroduodenal artery (42% versus 21%, p = 0.004), if the pump was placed during the first half of the study period (1986 to 1993, 25% versus 1994 to 2001, 18%; p = 0.05), and if the surgeon had performed fewer than 25 earlier procedures (< 25, 31% versus > or = 25, 19%; p < 0.002). CONCLUSIONS: In this large single institution experience, pump-related complications were low, the majority of early pump complications were salvaged, and pump complication rates improved as institutional experience accumulated. Longterm durability of pump function was excellent.

Clinical examination following preoperative chemoradiation for rectal cancer is not a reliable surrogate end point.

PURPOSE: Clinical assessment of rectal cancer response to preoperative combined-modality therapy (CMT) using digital rectal examination (DRE) has been proposed as a means of assessing efficacy of therapy. However, because the accuracy of this approach has not been established, we conducted a prospective analysis to determine the operating surgeon's ability to assess response using DRE. PATIENTS AND METHODS: Ninety-four prospectively accrued patients with locally advanced rectal cancer (T3/4 or N1) were evaluated with DRE and sigmoidoscopy in order to determine the following tumor characteristics: size, location, mobility, morphology, and circumference. Following preoperative CMT (50.40 Gy with fluorouracil-based chemotherapy) and under general anesthesia, the same surgeon estimated tumor response based on changes in these tumor characteristics, assessed via DRE. Percent pathologic tumor response was determined prospectively by a single pathologist using whole mount sections of the resected cancer. RESULTS: Clinical assessment using DRE underestimated pathologic response in 73 cases (78%). In addition, DRE was able to identify only 3 of 14 cases (21%) with a pathologic complete response. There were no clinical overestimates of response. None of the clinicopathologic tumor characteristics examined had a significant impact on DRE estimation of response. CONCLUSION: Clinical examination underestimates the extent of rectal cancer response to preoperative CMT. Given the inaccuracy of DRE following preoperative CMT, it should not be used as a sole means of assessing efficacy of therapy nor for selecting patients following CMT for local surgical therapies.

Rectus flap reconstruction decreases perineal wound complications after pelvic chemoradiation and surgery: a cohort study.

BACKGROUND: A major source of morbidity after abdominoperineal resection (APR) after external beam pelvic radiation is perineal wound complications, seen in up to 66% of cases. Our purpose was to determine the effect of rectus abdominus myocutaneous (RAM) flap reconstruction on perineal wound morbidity in this population. METHODS: The study group consisted of 19 patients with anorectal cancer treated with external beam pelvic radiation followed by APR and RAM flap reconstruction of the perineum. A prospectively collected database was queried to identify a control group (n = 59) with anorectal cancer treated with similar radiation doses that subsequently underwent an APR without a RAM flap during the same time period. Comparison of percentages was performed with a two-sided Fisher's exact test, and comparison of means was performed with Wilcoxon's test. RESULTS: Perineal wound complications occurred in 3 (15.8%) of the RAM flap patients and 26 (44.1%) of the control patients (P = .03). The incidence of other complications was not different between groups (42.1% vs. 42.4%; P = .8). Despite an increased number of anal squamous tumors, an increased vaginectomy rate, increased use of intraoperative radiotherapy, and an increased proportion of cases with recurrent disease, the flap group had a significantly lower rate of perineal wound complications relative to the control group. CONCLUSIONS: Perineal closure with a RAM flap significantly decreases the incidence of perineal wound complications in patients undergoing external beam pelvic radiation and APR for anorectal neoplasia. Because other complications are not increased, RAM flap closure of the perineal wound should be strongly considered in this patient population.

Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer.

OBJECTIVE: Our aims were to (1) determine the long-term oncologic outcome for patients with rectal cancer treated with preoperative combined modality therapy (CMT) followed by total mesorectal excision (TME), (2) identify factors predictive of oncologic outcome, and (3) determine the oncologic significance of the extent of pathologic tumor response. SUMMARY BACKGROUND DATA: Locally advanced (T3-4 and/or N1) rectal adenocarcinoma is commonly treated with preoperative CMT and TME. However, the long-term oncologic results of this approach and factors predictive of a durable outcome remain largely unknown. METHODS: Two hundred ninety-seven consecutive patients with locally advanced rectal adenocarcinoma at a median distance of 6 cm from the anal verge (range 0-15 cm) were treated with preoperative CMT (radiation: 5040 centi-Gray (cGy) and 5-fluorouracil (5-FU)-based chemotherapy) followed by TME from 1988 to 2002. A prospectively collected database was queried for long-term oncologic outcome and predictive clinicopathologic factors. RESULTS: With a median follow-up of 44 months, the estimated 10-year overall survival (OS) was 58% and 10 year recurrence-free survival (RFS) was 62%. On multivariate analysis, pathologic response >95%, lymphovascular invasion and/or perineural invasion (PNI), and positive lymph nodes were significantly associated with OS and RFS. Patients with a >95% pathologic response had a significantly improved OS (P = 0.003) and RFS (P = 0.002). CONCLUSIONS: Treatment of locally advanced rectal cancer with preoperative CMT followed by TME can provide for a durable 10-year OS of 58% and RFS of 62%. Patients who achieve a >95% response to preoperative CMT have an improved long-term oncologic outcome, a novel finding that deserves further study.

Surgical salvage of recurrent rectal cancer after transanal excision.

PURPOSE: This study examines surgical salvage of locally recurrent rectal cancer following transanal excision of early tumors. METHODS: Through retrospective review of a colorectal database we identified 50 patients who underwent attempted surgical salvage for local recurrence following initial transanal excision of T1 or T2 rectal cancer. Eight patients had resectable synchronous distant disease. Clinicopathologic variables were associated with extent of surgery required for salvage and outcome. RESULTS: Salvage procedures included abdominoperineal resection (31), low anterior resection (11), total pelvic exenteration (4), and transanal excision (3). One patient had unresectable disease at exploration, requiring diverting ostomy. Of the 49 patients who underwent successful salvage, 27 (55 percent) required an extended pelvic dissection with en bloc resection of one or more of the following structures: pelvic sidewall and autonomic nerves (18); coccyx or portion of sacrum (6); prostate (5); seminal vesicle (5); bladder (4); portion of the vagina (3); ureter (2); ovary (1); and uterus (1). Complete pathologic resection (R0) was accomplished in 47 of 49 patients. Of the eight patients with distant and local recurrence, two underwent synchronous resection and six had delayed metastasectomy. With a median follow-up of 33 months, 29 patients had recurred or died of disease at the time of this analysis. Five-year disease-specific survival was 53 percent. Factors predictive of survival included evidence of any mucosal recurrence on endoscopy, low presalvage carcinoembryonic antigen, and absence of poor pathologic features (lymphovascular and perineural invasion). Patients who required an extended pelvic resection had a worse survival rate. CONCLUSION: Pelvic recurrence following transanal excision of early rectal cancer is often locally advanced, requiring an extended pelvic dissection with en bloc resection of adjacent pelvic organs to achieve salvage. The long-term outcome in patients undergoing resection is less than expected, considering the early stage of their initial disease. When contemplating local excision for early rectal cancer, the risk of local recurrence, the extent and morbidity of surgery required for salvage, and the modest cure rate following salvage should be considered.

Operative salvage for locoregional recurrent colon cancer after curative resection: an analysis of 100 cases.

PURPOSE: Locoregional recurrence after resection of colon carcinoma is an uncommon and difficult clinical problem. Outcome data to guide surgical management are limited. This investigation was undertaken to review our experience with surgical resection for patients with locoregional recurrence colon cancer, determine predictors of respectability, and define prognostic factors associated with survival. PATIENTS AND METHODS: A prospective database was queried for patients who had recurrent colon cancer between January 1991 and October 2002. Patients were selected for analysis if they had either isolated resectable locoregional recurrence or concomitant resectable distant disease. Disease-specific survival analysis was performed with the Kaplan-Meier actuarial method, and factors associated with outcome were determined by the log-rank test and Cox regression. RESULTS: During this period of time, 744 patients with recurrent colon cancer were identified and 100 (13.4 percent) underwent exploration with curative intent for potentially resectable locoregional recurrence: 75 with isolated locoregional recurrence, and 25 with locoregional recurrence and resectable distant disease. The median follow-up for survivors was 27 months. Locoregional recurrence was classified into four categories: anastomotic; mesenteric/nodal; retroperitoneal; and peritoneal. Median survival for all patients was 30 months. Fifty-six patients had an R0 resection (including distant sites). Factors associated with prolonged disease-specific survival included R0 resection (P < 0.001); age <60 years (P < 0.01); early stage of primary disease (P = 0.05); and no associated distant disease (P = 0.03). Poor prognostic factors included more than one site of recurrence (P = 0.05) and involvement of the mesentery/nodal basin (P = 0.03). The ability to obtain an R0 resection was the strongest predictor of outcome, and these patients had a median survival of 66 months. CONCLUSION: Salvage surgery for locoregional recurrence colon cancer is appropriate for select patients. Complete resection is critical to long-term survival and is associated with a single site of recurrence, perianastomotic disease, low presalvage carcinembryonic antigen level, and absence of distant disease.

American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer.

PURPOSE: To address whether all medically fit patients with curatively resected stage II colon cancer should be offered adjuvant chemotherapy as part of routine clinical practice, to identify patients with poor prognosis characteristics, and to describe strategies for oncologists to use to discuss adjuvant chemotherapy in practice. METHODS: An American Society of Clinical Oncology Panel, in collaboration with the Cancer Care Ontario Practice Guideline Initiative, reviewed pertinent information from the literature through May 2003. RESULTS: A literature-based meta-analysis found no evidence of a statistically significant survival benefit of adjuvant chemotherapy for stage II patients. Recommendations The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology. CONCLUSION: Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials.

Ovarian neoplasms in patients with colorectal cancer: understanding the role of prophylactic oophorectomy.

Although the role of prophylactic oophorectomy is currently under debate and not well defined, it is of increasing and considerable relevance, especially in premenopausal women, particularly those with identifiable hereditary cancer syndromes. Patients with colorectal cancer with ovarian metastases are often symptomatic, require surgery, and have poor survival. Prophylactic oophorectomy abolishes the increased risk of primary ovarian cancer in these patients, resects synchronous metastases, and prevents development of metachronous ovarian metastases. Prophylactic oophorectomy trials, mostly conducted in postmenopausal women, have not shown survival advantage. In patients with ovarian metastases of colorectal cancer, maximal cytoreductive surgery followed by adjuvant therapy employing newer chemotherapeutic agents, whole abdominal irradiation with chemosensitization, or hyperthermic intraperitoneal chemotherapy may improve outcomes in selected patients.

Contemporary outcomes of total pelvic exenteration in the treatment of colorectal cancer.

PURPOSE: Total pelvic exenteration is performed infrequently in selected patients with locally advanced or recurrent colorectal cancer. We reviewed our contemporary experience with pelvic exenteration for colorectal cancer to identify selection criteria and prognostic factors for long-term survival. METHODS: Between 1991 and 2000, 55 patients (males, 29; median age, 62 years) undergoing total pelvic exenteration for colorectal cancer were identified from a prospective database. Clinicopathologic variables were evaluated as prognostic indicators of long-term survival by log-rank test and multivariate Cox regression. RESULTS: Indications for surgery were recurrent colorectal cancer in 71 percent and primary colorectal cancer in 29 percent. Of 39 patients with recurrent colorectal cancer, 85 percent had previous radiotherapy, and 64 percent had previous abdominoperineal resection. At the time of pelvic exenteration, 49 percent of patients received intraoperative radiation, and 20 percent required sacrectomy. Complete resection with negative margins was achieved in 73 percent. Perioperative mortality after pelvic exenteration was 5.5 percent, and complications included perineal wound infection (40 percent), pelvic abscess (20 percent), abdominal wound infection (18 percent), and cardiopulmonary events (18 percent). Median disease-specific survival for all patients was 48.9 (range, 3.2-105.6) months. Univariate analysis identified five factors associated with decreased survival: male gender, recurrent colorectal cancer, previous abdominoperineal resection, positive surgical margin, and administration of intraoperative radiation. On multivariate analysis, only previous abdominoperineal resection was an independent predictor of unfavorable outcome (P < 0.04). CONCLUSIONS: Total pelvic exenteration can be performed safely in highly selected patients with colorectal cancer and can result in significantly prolonged survival. Less satisfactory outcomes are observed in patients whose indication for pelvic exenteration is recurrent colorectal cancer after abdominoperineal resection.