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Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings.The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition.This was a retrospective study.The study was conducted at a tertiary-referral institution.Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort.Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data.We measured detection of pathogenic germline variants.A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7).This study was limited by its small sample size and advanced-stage patients.Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at http://links.lww.com/DCR/A906.

Squamous cell carcinoma (SCC) of the rectum is a rare disease with

Background Conditional survival estimates account for time survived since diagnosis to provide prognostic information for long-term cancer survivors. For rectal cancer, stage-related treatment (eg, neoadjuvant radiotherapy) affects pathologic stage and therefore stage-associated survival estimates. Objectives The aim of this study is to estimate conditional survival for patients who have rectal cancer and to develop an interactive calculator to use for individualized patient counseling. Patients Patients with rectal adenocarcinoma were identified by using the Surveillance Epidemiology and End Results registry (1988-2002, N = 22,610). Design Cox regression models were developed to determine adjusted survival estimates (years 1-10) and used to calculate 5-year adjusted conditional survival. Models were built separately for no radiotherapy, preoperative radiotherapy, postoperative radiotherapy, and patients with stage IV disease. Covariates included age, sex, race, tumor grade, and type of surgery. An Internet-based conditional survival calculator was developed. Results Radiotherapy was given to 42.6% of patients (14.1% preoperative, 28.4% postoperative). Significant improvements in 5-year conditional survival were observed for all stages, with the exception of stage I because of the initial high survival probability at diagnosis. Patients with advanced stage had the greatest improvements in conditional survival, with 5-year absolute increases of 33% (stage IIIC) and 54% (IV). Other factors associated with conditional survival included sequence of radiotherapy and surgery, age, race, and tumor grade. The Internet-based conditional survival calculator can be accessed at www.mdanderson.org/rectalcalculator. Limitations The data source used does not include information on chemotherapy treatment, change in staging after neoadjuvant treatment, or patient comorbidities. Conclusion Conditional survival estimates improve over 5 years in patients who have rectal cancer; the greatest improvements are observed among patients with advanced stage disease. The conditional survival calculator is an individualized decision support tool that informs patients, who must make non-treatment-related life decisions, and their clinicians planning follow-up and surveillance.

Local excision, alone or in combination with chemoradiation, is increasingly considered for rectal cancer. Higher risks of disease recurrence have been demonstrated after local excision.The aim of this study was to examine the outcomes of current-era multimodality salvage for recurrent rectal cancer after local excision.This was a single-institutional retrospective study.This study was conducted at a tertiary-referral cancer center between 1993 and 2011.Forty-six patients with recurrent rectal cancer after initial local excision were included.Multimodality salvage treatment was performed as appropriate.The primary outcomes measured were the pattern of disease recurrence, salvage treatments, and resultant overall and re-recurrence-free survival.After the initial local excision, recurrent disease was diagnosed after a median interval of 1.9 years: local/regionally in 67%, distantly in 18%, and both in 15%. Four patients (9%) had recurrence that was unsalvageable, 2 (4%) declined treatment, and 40 (87%) underwent surgical salvage. Preoperative chemoradiation was given in 30 (75%) patients. The R0 resection rate was 80%, requiring multivisceral resection (33%), total pelvic exenteration (5%), and metastasectomy (25%). The rate of sphincter preservation was 33%, and perioperative morbidity was 50%. The first site of failure after salvage was distant in 38% and was local only in 10%. The 5-year overall and 3-year re-recurrence-free survival were 63% and 43%. Pathologic stage at initial local excision, receipt of neoadjuvant chemoradiation before local excision, recurrence pattern after local excision, pathologic stage at salvage, and R0 resection at salvage influenced re-recurrence-free survival.This study was limited by the referral and selection biases inherent in a small study cohort.Failure after local excision for rectal cancer may not be salvageable. When feasible, multimodality treatment, including multivisceral resection, pelvic irradiation, and chemotherapy, was associated with potentially lasting treatment-related morbidities and only modest success in long-term disease control. These findings should be compared with the expected stage-specific outcomes of standard proctectomy for early-stage rectal cancer, when local excision is being considered.

Adenocarcinoma of the anal canal is a rare malignancy with limited data regarding treatment and outcomes. The purpose of this study is to evaluate disease control and survival outcomes in patients with adenocarcinoma of the anal canal.A retrospective consecutive cohort study of all patients in whom adenocarcinoma of the anal canal was diagnosed between 1983 and 2004 was performed. Tumor, patient, and treatment characteristics were categorized. Overall survival and recurrence outcomes were evaluated by use of the Kaplan-Meier method and the log-rank test. Cox proportional hazards regression analysis was performed to evaluate covariate adjusted effects.Thirty-four patients were identified; six underwent palliative treatment (Stage IV, n = 4; poor performance, n = 2). Median follow-up for the remaining 28 patients was 37 months (interquartile range, 22-62 months). Thirteen patients (46%) were treated with local excision followed by radiotherapy or chemoradiotherapy. Fifteen patients (54%) underwent radical surgery and preoperative or postoperative chemoradiotherapy. Median disease-free survival was 13 months after local excision and 32 months after radical surgery (P = 0.055). Overall survival at five years was 43% for patients treated with local excision and 63% for patients treated with radical surgery (P = 0.3). Tumor grade was predictive of overall survival (P = 0.04) and recurrence (P = 0.046). On multivariate analysis, the type of surgical treatment was an important predictor of overall survival (P = 0.045) and disease-free survival (P = 0.004).Combined modality treatment with radical surgical resection improves survival among patients with adenocarcinoma of the anal canal, but a high risk for distant failure emphasizes the need for effective adjuvant therapeutic regimens.

BACKGROUND: Perineal wound complications after chemoradiotherapy and abdominoperineal resection (APR) for anorectal cancer occur in up to 60% of patients, including perineal abscess and wound dehiscence. Vertical rectus abdominis myocutaneous (VRAM) flaps have been used in an attempt to reduce these complications by obliterating the noncollapsible dead space with vascularized tissue and closing the perineal skin defect with nonirradiated flap skin. Many surgeons are reluctant to use VRAM flaps unless primary closure is not possible. STUDY DESIGN: All patients who underwent chemoradiotherapy and APR during a 12-year period at the University of Texas MD Anderson Cancer Center were retrospectively reviewed. Patient, tumor, and treatment characteristics and surgical complications and outcomes were compared between patients who underwent VRAM flap reconstruction of wounds that could have been closed primarily (flap group, n = 35) and those who had primary closure of the perineal wound (control group, n = 76). RESULTS: Overall, there were no significant differences in the incidence of perineal wound complications between the groups; the flap group had a significantly lower incidence of perineal abscess (9% versus 37%, p = 0.002), major perineal wound dehiscence (9% versus 30%, p = 0.014), and drainage procedures required for perineal/pelvic fluid collections (3% versus 25%, p = 0.003) than the control group had. Despite flap harvest and the need for donor site closure in the flap group, there was no significant difference in abdominal wall complications between groups during the study's mean patient followup of 3.8 years. CONCLUSIONS: VRAM flap reconstruction of irradiated APR defects reduces major perineal wound complications without increasing early abdominal wall complications. Strong consideration should be given to immediate VRAM flap reconstruction after chemoradiation and APR.

implant placements and the remaining 3,721 procedures (32.4%) were revision procedures. Of the primary placements, there were 6,705 (86.3%) inflatable penile prostheses and 1,060 (13.7%) malleable penile prostheses placed. There were no differences in type of implant placed based on age or race. There were no differences between type of surgery or numbers of surgeries per patient between races. As age increased there were fewer implant placements and more revision surgeries, as well as more implant removals without replacement (see chart below). CONCLUSIONS: In contrast to previously studied populations, age and race do not appear to play a role in the selection of malleable penile prostheses compared to inflatable penile prostheses in the veteran population. As veterans age, they are more likely to undergo revision surgery and more likely to have implants removed without replacement. Further studies are warranted to determine preoperative risk factors for eventual revision surgery.

Objectives: To identify predictive factors for locoregional recurrence (LR), distant metastasis (DM), and overall survival (OS) in patients treated with chemoradiation and surgery for rectal cancer. Methods: Between 1989 and 2001, 470 patients with rectal cancer were treated with preoperative (89%) or postoperative (11%) chemoradiation and mesorectal excision. Median radiation dose was 45 Gy; 97% received concurrent infusional 5-fluorouracil, and 65% received adjuvant chemotherapy. Median follow-up interval was 5.7 years. Results: The 5-year rates of freedom from LR, freedom from DM, and OS were 90%, 79%, and 80%, respectively. On univariate analysis, significant predictors of LR were female sex, clinical T stage, pathologic T and N stages, and positive radial margin. Significant univariate predictors of DM were circumferential extent of tumor, tumor immobility, lymphovascular invasion, perineural involvement, and pathologic T and N stages. Significant univariate predictors of lower OS were age, circumferential extent of tumor, shorter distance from anal verge, tumor size, tumor immobility, anal canal involvement, lymphovascular invasion, perineural involvement, positive radial margin, and pathologic T and N stages. On Cox multivariate analysis, female sex and pathologic T and N stages independently predicted for LR; pathologic T and N stages independently predicted for DM; and age, circumferential extent of tumor, positive radial margin, and pathologic T and N stages independently predicted for lower OS. Conclusions: Pathologic T and N stages significantly predicted for all 3 end points (LR, DM and OS) on multivariate analysis. Investigations of more aggressive adjuvant chemotherapy appear warranted for pathologic stage T3/T4 or N1/2 rectal cancer.

COX-2 activation may mediate capecitabine induced toxicities, eg, hand-foot syndrome (HFS) and colorectal cancer progression, both of which may be improved by concurrent celecoxib.From October 2000 to December 2003, 66 patients with metastatic colorectal cancer received concurrent capecitabine at 1000 mg/m/d b.i.d. and celecoxib at 200 mg b.i.d. (XCEL). Twenty-four patients were chemo-naive, 42 patients were second-line; while 34 had XCEL with radiation.The median duration of XCEL was 7.2 months (range, 1.5-38 months). Ninety percent of Grade 2/3 HFS (17%) occurred after 6 months and incidence of grade 3/4 diarrheas was 8%. The overall response rate was 38% (95% confidence interval [CI], 26-51%), with 11 patients (17%) achieving complete responses and 2 patients (3%) with near complete responses. Six patients (9%) become resectable after sustaining treatment response. The median progression-free survival (PFS) and overall survival (OS) was 8.3 months (95% CI, 7.0-11.0 months) and 22 months (95% CI, 17.8-31.5 months), respectively. Improved median PFS of 14.5 months (P = 0.0001) and OS of 31.5 months (P = 0.005) were noted in patients with normal lactate dehydrogenase (LDH) levels (n = 37) than patients with high levels of LDH (n = 29).XCEL integrating radiation may improve response rate and survival and reduce toxicities, notably HFS for patients with metastatic colorectal cancer, leading to a randomized phase III study.

Few biologic markers have been studied as prognostic factors in recurrent rectal carcinoma patients. We sought to determine the influence of clinical, pathologic, and biologic (p53, bcl-2, and ki-67) variables on survival after curative resection of locally recurrent rectal cancer. Retrospective review of patients with locally recurrent rectal cancer who received surgery with curative intent. From 1988 to 1998, 134 patients with locally recurrent rectal cancer underwent operative exploration. Curative resection was performed in 85 patients. Median follow-up was 43 (range, 1.3–149) months. On multivariate analysis, negative predictors of overall survival included an elevated carcinoembryonic antigen level (P = 0.02; hazard ratio 2.41; 95 percent confidence interval, 1.19–4.89) and an R1 resection margin (P = 0.01; hazard ratio, 2.81; 95 percent confidence interval, 1.27–6.21). In 26 patients for whom biologic variables were available, p53, bcl-2, and ki-67 did not significantly impact disease-specific survival or overall survival. Five-year disease-specific survival, overall survival, and pelvic control rates were 46, 36, and 51 percent respectively. Of the 50 patients who relapsed, time to second local recurrence was longer than time to development of metastasis (median, 16.5 vs. 9 months). Median survival for patients with metastatic recurrence was 26.l vs. 41.5 months for those with a subsequent local recurrence alone. Approximately two-thirds of patients with locally recurrent rectal cancer can be resected for cure. Preoperative carcinoembryonic antigen and an R0 resection margin were the only significant predictors of overall survival. p53, bcl-2, and ki-67 did not impact survival outcomes.

PURPOSE: An increased incidence of multiple (synchronous and metachronous) colorectal carcinomas has been reported in hereditary nonpolyposis colorectal cancer. This review was undertaken to determine the clinical implications of multiple colorectal carcinomas in hereditary nonpolyposis colorectal cancer. METHODS: A retrospective review of the records of patients in the hereditary nonpolyposis colorectal cancer registry at Roswell Park Cancer Institute who had either synchronous or metachronous colorectal carcinomas was conducted. RESULTS: Twenty-five of 93 patients with documented pathology were found to have multiple colorectal carcinomas. The mean age at diagnosis of the index colorectal carcinoma was 46.7 (range, 28–65) years. There were 7 (7.5 percent) patients with synchronous colorectal carcinomas and 20 (21.5 percent) patients with metachronous colorectal carcinomas. Two of the seven (28.6 percent) patients with synchronous colorectal carcinomas developed a metachronous colorectal carcinoma. In the patients with metachronous colorectal carcinomas, 29 metachronous events were noted: colon (23) and rectum (6). The mean and median time interval for metachronous colorectal carcinomas were 10.9 and 11.8 (range, 1.5–43.8) years, respectively. The mean times to first, second, and third events were 11.7 (range, 1.5–43.5), 7.9 (range, 2.7–18.7), and 12.3 (range, 11.8–12.7) years, respectively. The majority of patients with metachronous colorectal carcinomas did not have stage progression at the diagnosis of the metachronous colorectal carcinomas: 13 patients had lower or same stage at first event, 4 had lower or same stage at second event, and 2 patients had lower stage at third event. Three of 20 patients with metachronous colorectal carcinomas died of their disease. CONCLUSION: Multiple colorectal cancers are common in hereditary nonpolyposis colorectal cancer. Even though stage progression may not be evident at diagnosis of metachronous colorectal cancer, some of these patients will nevertheless die of their disease.

Squamous cell carcinoma of the anal canal serves as a paradigm for the successful application of multimodality treatment of solid tumors. Since 1974, multimodality treatment with combined radiation and chemotherapy has become the standard. The compelling advantage of sphincter preservation and the substantial survival benefit compared with surgery alone prompted investigators to adopt chemoradiation treatment. Several questions regarding the optimal radiation dose and chemotherapy in initial as well as salvage therapy remain, and only recently have results of several prospective randomized studies become available to address some of these unresolved issues. We reviewed the clinical aspects and historical treatment results of anal canal and perianal epidermoid cancers in light of the results of these modern trials. Current management strategies are redefined, and future directions of clinical studies are outlined.

ObjectiveThe authors analyzed the incidence of rectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) after an abdominal colectomy.Summary Background DataThe treatment of choice for a newly diagnosed patient with HNPCC with colon cancer is an abdominal colectomy. The in

CONCLUSIONS: There is a substantial unmet desire for greater involvement in provider choice among gastrointestinal cancer patients. Participants in this study attached particular importance to surgery-specific information. Improving involvement and information provision will require a coordinated approach in both primary and secondary care. Greater involvement in decision-making may increase satisfaction and contribute to a greater sense of control among these patients.

Rectal involvement by locally advanced adenocarcinoma of the prostate is theoretically prevented by the barrier effect of Denonvilliers’ fascia. Vesicorectal and urethrorectal fistulas have not been reported in the absence of prior radiation or surgery. We report a case of vesicorectal fistula resulting from local invasion of hormone refractory prostate cancer. CASE REPORT A 79-year-old man presented with a urinary tract infection, microscopic hematuria and prostate specific antigen (PSA) 13.7 ng./ml. He had a history of alcohol abuse, malnutrition and transurethral resection of the prostate performed 8 years earlier for histologically confirmed benign prostatic hyperplasia. He denied any history of pneumaturia, fecaluria, diarrhea or urinary tract infection. Rectal examination revealed an irregular, diffusely firm prostate. Cystourethroscopy demonstrated a 3 3 2 cm. sessile, necrotic tumor at the bladder neck overlying the base of the prostate and no other lesions in the bladder. Transrectal ultrasound showed a large hypoechoic lesion extending into the bladder neck and biopsies were positive for Gleason score 8 adenocarcinoma (fig. 1, A). Radionuclide bone scan revealed metastatic spread to the right hemipelvis. Although androgen ablation was recommended, the patient was lost to followup for 6 months, at which time he presented with grossly infected urine and PSA 19.8 ng./ml. After the initial 3-month injection of goserelin acetate, PSA decreased to 3.4 ng./ml. but increased to 6.9 ng./ml. at 6 months. Two months later the patient complained of a 6-week history of watery diarrhea, 9 kg. weight loss, dysuria, frequency and pneumaturia. PSA was 14.0 ng./ml. Rectal examination revealed an irregular mass compromising but not occluding the rectal lumen. Sigmoidoscopy confirmed erosion into the rectum anteriorly 2 to 4 cm. above the anal verge with no other abnormalities in the sigmoid colon. Sigmoidoscopic biopsy demonstrated PSA positive, cytokeratin 7 and cytokeratin 20 negative adenocarcinoma consistent with prostatic origin (fig. 1, B). Computerized tomography showed intravesical air and contrast material tracking between the bladder and rectum through the prostate/bladder neck mass with no evidence of colonic diverticulas or solid masses (fig. 2). Due to the poor medical condition the patient was treated conservatively with enteric nutrition. He died of cachexia 18 months after diagnosis.

The medical records of 11 patients with recurrent unresectable adenocarcinoma of the rectum who had intrathecal phenol block for the management of intractable pain were reviewed. There were seven patients with pelvic and four with combined pelvic and perineal recurrences. Five patients had sacral involvement by tumor. Six patients had received prior irradiation. Three patients had good, three had fair and five patients had poor results after phenol rhizotomy. Patients with good results had relief for a median of three months. The over-all survival rate after phenol injection was three months. Phenol rhizotomy is indicated for the relief of intractable pain secondary to recurrent unresectable carcinoma of the rectum in carefully selected patients.