George J. Chang

Improved Survival in Metastatic Colorectal Cancer Is Associated With Adoption of Hepatic Resection and Improved Chemotherapy

PURPOSE Fluorouracil/leucovorin as the sole therapy for metastatic colorectal cancer (CRC) provides an overall survival of 8 to 12 months. With an increase in surgical resections of metastatic disease and development of new chemotherapies, indirect evidence suggests that outcomes for patients are improving in the general population, although the incremental gain has not yet been quantified. METHODS We performed a retrospective review of patients newly diagnosed with metastatic CRC treated at two academic centers from 1990 through 2006. Landmark analysis evaluated the association of diagnosis year and liver resection with overall survival. Additional survival analysis of the Surveillance Epidemiology and End Results (SEER) database evaluated a similar population from 1990 through 2005. RESULTS Two thousand four hundred seventy patients with metastatic CRC at diagnosis received their primary treatment at the two institutions during this time period. Median overall survival for those patients diagnosed from 1990 to 1997 was 14.2 months, which increased to 18.0, 18.6, and 29.3 months for patients diagnosed in 1998 to 2000, 2001 to 2003, and 2004 to 2006, respectively. Likewise, 5-year overall survival increased from 9.1% in the earliest time period to 19.2% in 2001 to 2003. Improved outcomes from 1998 to 2004 were a result of an increase in hepatic resection, which was performed in 20% of the patients. Improvements from 2004 to 2006 were temporally associated with increased utilization of new chemotherapeutics. In the SEER registry, overall survival for the 49,459 identified patients also increased in the most recent time period. CONCLUSION Profound improvements in outcome in metastatic CRC seem to be associated with the sequential increase in the use of hepatic resection in selected patients (1998 to 2006) and advancements in medical therapy (2004 to 2006).

Effect of Laparoscopic-Assisted Resection vs Open Resection of Stage II or III Rectal Cancer on Pathologic Outcomes: The ACOSOG Z6051 Randomized Clinical Trial

IMPORTANCE Evidence about the efficacy of laparoscopic resection of rectal cancer is incomplete, particularly for patients with more advanced-stage disease. OBJECTIVE To determine whether laparoscopic resection is noninferior to open resection, as determined by gross pathologic and histologic evaluation of the resected proctectomy specimen. DESIGN, SETTING, AND PARTICIPANTS A multicenter, balanced, noninferiority, randomized trial enrolled patients between October 2008 and September 2013. The trial was conducted by credentialed surgeons from 35 institutions in the United States and Canada. A total of 486 patients with clinical stage II or III rectal cancer within 12 cm of the anal verge were randomized after completion of neoadjuvant therapy to laparoscopic or open resection. INTERVENTIONS Standard laparoscopic and open approaches were performed by the credentialed surgeons. MAIN OUTCOMES AND MEASURES The primary outcome assessing efficacy was a composite of circumferential radial margin greater than 1 mm, distal margin without tumor, and completeness of total mesorectal excision. A 6% noninferiority margin was chosen according to clinical relevance estimation. RESULTS Two hundred forty patients with laparoscopic resection and 222 with open resection were evaluable for analysis of the 486 enrolled. Successful resection occurred in 81.7% of laparoscopic resection cases (95% CI, 76.8%-86.6%) and 86.9% of open resection cases (95% CI, 82.5%-91.4%) and did not support noninferiority (difference, -5.3%; 1-sided 95% CI, -10.8% to ∞; P for noninferiority = .41). Patients underwent low anterior resection (76.7%) or abdominoperineal resection (23.3%). Conversion to open resection occurred in 11.3% of patients. Operative time was significantly longer for laparoscopic resection (mean, 266.2 vs 220.6 minutes; mean difference, 45.5 minutes; 95% CI, 27.7-63.4; P < .001). Length of stay (7.3 vs 7.0 days; mean difference, 0.3 days; 95% CI, -0.6 to 1.1), readmission within 30 days (3.3% vs 4.1%; difference, -0.7%; 95% CI, -4.2% to 2.7%), and severe complications (22.5% vs 22.1%; difference, 0.4%; 95% CI, -4.2% to 2.7%) did not differ significantly. Quality of the total mesorectal excision specimen in 462 operated and analyzed surgeries was complete (77%) and nearly complete (16.5%) in 93.5% of the cases. Negative circumferential radial margin was observed in 90% of the overall group (87.9% laparoscopic resection and 92.3% open resection; P = .11). Distal margin result was negative in more than 98% of patients irrespective of type of surgery (P = .91). CONCLUSIONS AND RELEVANCE Among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet the criterion for noninferiority for pathologic outcomes. Pending clinical oncologic outcomes, the findings do not support the use of laparoscopic resection in these patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00726622.

Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer

The objective of this study was to identify predictive factors for pathologic complete response and tumor downstaging after preoperative chemoradiation for rectal cancer.

Neoadjuvant treatment response as an early response indicator for patients with rectal cancer

PURPOSE Neoadjuvant chemoradiotherapy for rectal cancer is associated with improved local control and may result in complete tumor response. Associations between tumor response and disease control following radical resection should be established before tumor response is used to evaluate treatment strategies. The purpose of this study was to assess and compare oncologic outcomes associated with the degree of pathologic response after chemoradiotherapy. PATIENTS AND METHODS All patients with locally advanced (cT3-4 or cN+ by endorectal ultrasonography, computed tomography, or magnetic resonance imaging) rectal carcinoma diagnosed from 1993 to 2008 at our institution and treated with preoperative chemoradiotherapy and radical resection were identified, and their records were retrospectively reviewed. The median radiation dose was 50.4 Gy with concurrent chemotherapy. Recurrence-free survival (RFS), distant metastasis (DM), and local recurrence (LR) rates were compared among patients with complete (ypT0N0), intermediate (ypT1-2N0), or poor (ypT3-4 or N+) response by using Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression. RESULTS In all, 725 patients were classified by tumor response: complete (131; 18.1%), intermediate (210; 29.0%), and poor (384; 53.0%). Age, sex, cN stage, and tumor location were not related to tumor response. Tumor response (complete v intermediate v poor) was associated with 5-year RFS (90.5% v 78.7% v 58.5%; P < .001), 5-year DM rates (7.0% v 10.1% v 26.5%; P < .001), and 5-year LR only rates (0% v 1.4% v 4.4%; P = .002). CONCLUSION Treatment response to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection is an early surrogate marker and correlate to oncologic outcomes. These data provide guidance with response-stratified oncologic benchmarks for comparisons of novel treatment strategies.

Surgical Strategies for Synchronous Colorectal Liver Metastases in 156 Consecutive Patients: Classic, Combined or Reverse Strategy?

BACKGROUND An increasing number of patients with synchronous colorectal liver metastases (CLM) are candidates for resection. The optimal treatment sequence in these patients has not been defined. STUDY DESIGN Data on 156 consecutive patients with synchronous resectable CLM and intact primary were reviewed. Surgical strategies were defined as combined (combined resection of primary and liver), classic (primary before liver), and reverse (liver before primary) after preoperative chemotherapy. Postoperative morbidity and mortality rates and overall survival were analyzed. RESULTS One hundred forty-two patients (83%) had resection of all disease. Seventy-two patients underwent classic, 43 combined, and 27 reverse strategies. Median numbers of CLMs per patient were 1 in the combined, 3 in the classic, and 4 in the reverse strategy group (p = 0.01 classic vs reverse; p < 0.001 reverse vs combined). Postoperative mortality rates in the combined, classic, and reverse strategies were 5%, 3%, and 0%, respectively (p = NS), and postoperative cumulative morbidity rates were 47%, 51%, and 31%, respectively (p = NS). Three-year and 5-year overall survival rates were, respectively, 65% and 55% in the combined, 58% and 48% in the classic, and 79% and 39% in the reverse strategy (NS). On multivariate analysis, liver tumor size >3 cm (hazard ratio [HR] 2.72, 95% CI 1.52 to 4.88) and cumulative postoperative morbidity (HR 1.8, 95% CI 1.03 to 3.19) were independently associated with overall survival after surgery. CONCLUSIONS The classic, combined, or reverse surgical strategies in patients with synchronous presentation of CLM are associated with similar outcomes. The reverse strategy can be considered as an alternative option in patients with advanced CLM and an asymptomatic primary.

Surgical treatment of high-grade anal squamous intraepithelial lesions: A prospective study

AbstractPURPOSE: The prevalence of anal squamous intraepithelial lesions is high among human immunodeficiency virus-positive homosexual males and, to a lesser extent, among human immunodeficiency virus-negative homosexual males. Furthermore, the incidence of high-grade squamous intraepithelial lesions, the putative precursor lesion to invasive cancer, is also high. We report the first prospective study of high-resolution anoscopy-directed surgical treatment of high-grade squamous intraepithelial lesions. METHODS: A prospective study of patients undergoing surgical treatment of high-grade squamous intraepithelial lesions (excision/cauterization of lesions visualized with high-resolution anoscopy) was performed. Follow-up anoscopy with biopsy and Papanicolaou smear was performed every three to six months. RESULTS: Patients diagnosed with high-grade squamous intraepithelial lesions during the course of their participation in a prospective cohort study of anal squamous intraepithelial lesions were identified. From this group, 37 patients who were treated surgically between 1995 and 1999 were studied. Of these, 29 had tested positive for human immunodeficiency virus and 8 were negative for the virus. Mean patient age was 45 ± 8 years. Mean duration of follow-up was 32.3 ± 20.6 months in the human immunodeficiency virus-negative group and 28.6 ± 12.9 months in the human immunodeficiency virus-positive group. No human immunodeficiency virus-negative patient developed recurrent high-grade squamous intraepithelial lesions. Twenty-three of 29 human immunodeficiency virus-positive patients had persistent or recurrent high-grade squamous intraepithelial lesions (P = 0.003; mean time to recurrence, 12 months). Six patients underwent reoperation for high-grade squamous intraepithelial lesions (4 recurred by 6 months). No patients developed incontinence, stenosis, postoperative infection, or significant bleeding after surgical treatment. CONCLUSIONS: Surgical intervention directed by high-resolution anoscopy is safe and eliminates high-grade squamous intraepithelial lesions in human immunodeficiency virus-negative patients. The high persistence or recurrence rate in human immunodeficiency virus-positive patients suggests that multiple staged procedures and continued surveillance may be necessary.

Preoperative Bevacizumab Does Not Significantly Increase Postoperative Complication Rates in Patients Undergoing Hepatic Surgery for Colorectal Cancer Liver Metastases

PURPOSE Although bevacizumab (BV) increases survival rates when used with chemotherapy (CTX) in patients who have metastatic colorectal cancer (CRC), an increase in wound complications has been observed in patients who undergo surgery while receiving BV. We therefore evaluated whether neoadjuvant BV is associated with an increase in postoperative complications in patients undergoing surgery for CRC liver metastases. PATIENTS AND METHODS Two subgroups of patients who received neoadjuvant CTX + BV (n = 81) or CTX alone (n = 44) were identified from a database of patients who underwent surgery for CRC liver metastases. Univariate and multivariate logistic regression models were used to evaluate the association of patient and tumor characteristics, neoadjuvant therapy, and operative factors with postoperative complications. RESULTS Postoperative complications developed in 40 patients (49%) who received CTX + BV and 19 patients (43%) who received CTX. The median time from BV discontinuation to surgery was 58 days (range, 31 to 117 days). No significant associations were identified between BV use and timing of BV discontinuation and postoperative complications. On multivariate analysis, lower serum albumin and concomitant surgical procedures were associated with an increased risk of developing any complication (P = .035 and .023, respectively), and lower serum albumin was associated with hepatobiliary complications (P = .016). CONCLUSION Neither the use of BV nor timing of BV administration was associated with an increase in complication rates. These data suggest that the combination of BV with neoadjuvant CTX in patients who have CRC liver metastases does not increase surgical complications. To determine the optimal timing of surgery in patients receiving neoadjuvant BV, confirmatory prospective studies are required.

Increasing Disparities in the Age-Related Incidences of Colon and Rectal Cancers in the United States, 1975-2010

IMPORTANCE The overall incidence of colorectal cancer (CRC) has been decreasing since 1998 but there has been an apparent increase in the incidence of CRC in young adults. OBJECTIVE To evaluate age-related disparities in secular trends in CRC incidence in the United States. DESIGN, SETTING, AND PATIENTS A retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) CRC registry. Age at diagnosis was analyzed in 15-year intervals starting at the age of 20 years. SEER*Stat was used to obtain the annual cancer incidence rates, annual percentage change, and corresponding P values for the secular trends. Data were obtained from the National Cancer Institutes SEER registry for all patients diagnosed as having colon or rectal cancer from January 1, 1975, through December 31, 2010 (N = 393 241). MAIN OUTCOME AND MEASURE Difference in CRC incidence by age. RESULTS The overall age-adjusted CRC incidence rate decreased by 0.92% (95% CI, -1.14 to -0.70) between 1975 and 2010. There has been a steady decline in the incidence of CRC in patients age 50 years or older, but the opposite trend has been observed for young adults. For patients 20 to 34 years, the incidence rates of localized, regional, and distant colon and rectal cancers have increased. An increasing incidence rate was also observed for patients with rectal cancer aged 35 to 49 years. Based on current trends, in 2030, the incidence rates for colon and rectal cancers will increase by 90.0% and 124.2%, respectively, for patients 20 to 34 years and by 27.7% and 46.0%, respectively, for patients 35 to 49 years. CONCLUSIONS AND RELEVANCE There has been a significant increase in the incidence of CRC diagnosed in young adults, with a decline in older patients. Further studies are needed to determine the cause for these trends and identify potential preventive and early detection strategies.

Population-Based Study of Contralateral Prophylactic Mastectomy and Survival Outcomes of Breast Cancer Patients

BACKGROUND Despite increased demand for contralateral prophylactic mastectomy (CPM), the survival benefit of this procedure remains uncertain. METHODS We used the Surveillance, Epidemiology, and End Results database to identify 107 106 women with breast cancer who had undergone mastectomy for treatment between 1998 and 2003 and a subset of 8902 women who also underwent CPM during the same period. Associations between predictor variables and the likelihood of undergoing CPM were evaluated by use of chi(2) analyses. Risk-stratified (estrogen receptor [ER] status, stage, and age) adjusted survival analyses were performed by using Cox regression. Statistical tests were two-sided. RESULTS In a univariate analysis, CPM was associated with improved disease-specific survival (hazard ratio [HR] of death = 0.63, 95% confidence interval [CI] = 0.57 to 0.69; P < .001). Risk-stratified analysis showed that this association was because of a reduction in breast cancer-specific mortality in women aged 18-49 years with stages I-II ER-negative cancer (HR of death = 0.68, 95% CI = 0.53 to 0.88; P = .004). Five year-adjusted breast cancer survival for this group was improved with CPM vs without (88.5% vs 83.7%, difference = 4.8%). Although rates of contralateral breast cancer among young women with stages I-II disease undergoing CPM were independent of ER status, women with ER-positive tumors in the absence of prophylactic mastectomy also had a lower overall risk for contralateral breast cancer than women with ER-negative tumors (0.46% vs 0.90%, difference = 0.44%; P < .001). CONCLUSIONS CPM is associated with a small improvement in 5-year breast cancer-specific survival mainly in young women with early-stage ER-negative breast cancer. This effect is related to a higher baseline risk of contralateral breast cancer.

Phase II Trial of Neoadjuvant Bevacizumab, Capecitabine, and Radiotherapy for Locally Advanced Rectal Cancer

PURPOSE We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer. METHODS Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m(2) orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later. RESULTS Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5-32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences. CONCLUSIONS The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study.