The value of post-operative chemotherapy after chemoradiotherapy in patients with high-risk locally advanced rectal cancer-results from the RAPIDO trial.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial. PATIENTS AND METHODS: Patients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT- group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT ≥75% group) were compared with patients who did not receive pCT (pCT-/- group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression. RESULTS: In total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT- and pCT-/- groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT-), and 0.5 and 0.8 (pCT ≥75% versus pCT-/-). However, all 95% confidence intervals included 1. CONCLUSIONS: These data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant.

Conversion therapy in patients with colorectal liver metastases.

BACKGROUND: The occurrence of colorectal liver metastases (CRLM) impairs prognosis, yet long-term survival can be achieved by enabling liver resection. This study aims to describe factors associated with conversion therapy leading to liver surgery and treatment outcome. METHODS: A retrospective cohort study was conducted including all patients with CRLM discussed at multidisciplinary team conference at Karolinska University Hospital, Stockholm, Sweden, from 2013 to 2018. Factors associated with conversion therapy and outcome following conversion therapy were analysed with logistic regression and survival analyses. RESULTS: Out of 1023 patients with CRLM, 100 patients (10%) received conversion chemotherapy, out of whom 31 patients (31%) subsequently underwent liver resection. Patients in whom conversion chemotherapy resulted in liver resection were younger (median age 61 vs. 66 years, p = .024), less likely to have a KRAS/NRAS-mutated primary tumours (25% vs. 53%, p = .039) and more likely to have received anti-EGFR agents (32% vs. 4%, p = .001) than patients progressing during conversion chemotherapy. The median OS for patients treated with conversion chemotherapy leading to liver resection was 24 months, compared to 14 months for patients progressing during conversion chemotherapy, p < .001. The OS for patients progressing during conversion chemotherapy was similar to patients given palliative chemotherapy, approximately 13 months. CONCLUSION: Conversion therapy offers a survival benefit in selected patients. Despite treatment advances, the majority of patients undergoing conversion chemotherapy never become eligible for curative treatment.

Pelvic local recurrence from colorectal cancer: surgical challenge with changing preconditions.

AIM: Although the rate of local recurrence (LR) after colorectal cancer surgery has decreased, it still poses major surgical and oncological challenges. The aims of this study, based on an audit from a tertiary referral centre, was to evaluate determinants associated with outcomes after surgery for pelvic LR and how these have changed over time. METHOD: Retrospective analysis of all resections for pelvic LR of colorectal cancer performed at the Karolinska University Hospital from January 2003 until August 2009 (period 1) and from September 2009 until November 2013 (period 2) . RESULTS: Ninety-five patients with pelvic LR were operated on with a curative intent. An R0 resection was achieved in 77% and an R1 resection in 23%. Lateral compartments were invaded in 48% and this proportion increased in resections performed in period 2 (37% vs 60%, P = 0.05). R1 resections were associated with a higher risk of local re-recurrence than R0 resections (64% vs 16%; OR = 8.90, 95% CI: 2.71-29.78). Lateral recurrences were associated with a lower R0-resection rate than nonlateral recurrences (63% vs 90%; OR = 0.20, 95% CI: 0.05-0.64) and a higher risk of treatment failure in terms of local re-recurrence or distant metastases, or death, as first event (hazard ratio [HR] = 1.75, 95% CI: 1.06-2.75). However, in a multivariate analysis only R1 resections remained a significant prognostic factor for treatment failure (HR = 2.37, 95% CI: 1.32-4.27). CONCLUSION: The proportion of lateral pelvic recurrences has increased over time. In comparison with non-lateral LRs, lateral LRs are more difficult to resect radically and are associated with worse overall and disease-free survival. However, with radical surgery many patients with pelvic locally recurrent colorectal cancer may be offered curative treatment.

Risk factors for anastomotic leakage following ileosigmoid or ileorectal anastomosis.

AIM: Reconstruction with an ileosigmoidal anastomosis (ISA) or ileorectal anastomosis (IRA) is a surgical option after a subtotal colectomy. Anastomotic leakage (AL) is a problematic complication and high rates have been reported, but there is limited understanding of the risk factors involved. The aim of this study was to assess the established and potential predictors of AL following ISA and IRA. METHOD: This was a retrospective cohort study including all patients who had undergone ISA or IRA at three Swedish referral centres for colorectal surgery between January 2007 and March 2015. Data regarding clinical characteristics, treatment and outcome were collected from medical records. Univariate and multivariate logistic regression models were used to determine the association between patient and treatment related factors and the cumulative incidence of AL. RESULTS: In total, 227 patients were included. Overall, AL was detected amongst 30 patients (13.2%). Amongst patients undergoing colectomy with synchronous ISA or IRA (one-stage procedure), AL occurred in 23 out of 120 (19.2%) compared with seven out of 107 (6.5%) after stoma reversal with ISA or IRA (two-stage procedure) (P = 0.004). In addition, the multivariate analyses revealed a statistically significantly lower odds ratio for AL following a two-stage procedure (OR 0.10, 95% CI 0.03-0.41, P = 0.001). CONCLUSIONS: This study confirms high rates of AL following ISA and IRA. In particular, a synchronous procedure with colectomy and ISA/IRA carries a high risk of AL.

Colectomy prior to diagnosis of primary sclerosing cholangitis is associated with improved prognosis in a nationwide cohort study of 2594 PSC-IBD patients.

BACKGROUND: Despite the close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the association between colectomy and the prognosis of PSC remains controversial. AIM: To explore whether colectomy prior to PSC-diagnosis is associated with transplant-free survival. METHODS: A nationwide cohort study in Sweden including all patients aged 18 to 69 years in whom both PSC and IBD was diagnosed between 1987 and 2014 was undertaken. Each patient was followed from date of both PSC and IBD diagnoses until liver transplantation or death, or 31 December 2014. Patients with colon in situ, and colectomy prior to PSC-diagnosis were compared. Survival analyses were performed using the Kaplan-Meier method and multivariable Cox regression models. RESULTS: Of the 2594 PSC-IBD patients, 205 patients were treated with colectomy before PSC-diagnosis. During follow-up, liver transplantations were performed in 327 patients and 509 died. The risk of liver transplantation or death was lower in patients treated with colectomy prior to PSC-diagnosis (HR 0.71, 95% CI 0.53-0.95) than in patients with colon in situ. Male gender, longer time between IBD and PSC-diagnosis and older age were all associated with an increased risk of liver transplantation or death. Colectomy after PSC-diagnosis was however not associated with an increased risk of liver transplantation or death during long-term follow-up. CONCLUSIONS: In PSC-IBD patients, colectomy prior to PSC-diagnosis is associated with a decreased risk of liver transplantation or death.

Screening vs. non-screening detected colorectal cancer: Differences in pre-therapeutic work up and treatment.

Objectives To compare preoperative staging, multidisciplinary team-assessment, and treatment in patients with screening detected and non-screening detected colorectal cancer. Methods Data on patient and tumour characteristics, staging, multidisciplinary team-assessment and treatment in patients with screening and non-screening detected colorectal cancer from 2008 to 2012 were collected from the Stockholm-Gotland screening register and the Swedish Colorectal Cancer Registry. Results The screening group had a higher proportion of stage I disease (41 vs. 15%; p < 0.001), a more complete staging of primary tumour and metastases and were more frequently multidisciplinary team-assessed than the non-screening group ( p < 0.001). In both groups, patients with endoscopically resected cancers were less completely staged and multidisciplinary team-assessed than patients with surgically resected cancers ( p < 0.001). No statistically significant differences were observed between the screening and non-screening groups in the use of neoadjuvant treatment in rectal cancer (68 vs.76%), surgical treatment with local excision techniques in stage I rectal cancer (6 vs. 9%) or adjuvant chemotherapy in stages II and III disease (46 vs. 52%). Emergency interventions for colorectal cancer occurred in 4% of screening participants vs. 11% of non-compliers. Conclusions Screening detected cancer patients were staged and multidisciplinary team assessed more extensively than patients with non-screening detected cancers. Staging and multidisciplinary team assessment prior to endoscopic resection was less complete compared with surgical resection. Extensive surgical and (neo)adjuvant treatment was given in stage I disease. Participation in screening reduced the risk of emergency surgery for colorectal cancer.

Impact of pre-treatment patient-related selection parameters on outcome in rectal cancer.

BACKGROUND: Preoperative radiotherapy (RT) for rectal cancer reduces local recurrence rates and possibly also mortality. Patient-related parameters such as age and comorbidity have a major impact on selection to preoperative RT. The aim of this study was to investigate how this selection influences the outcome in rectal cancer regardless of dose or fractionation of RT. METHODS: Data from the Swedish Colorectal Cancer Registry and the Swedish National Patient Register on all patients without distant metastasis who underwent elective trans-abdominal surgery for rectal cancer 2000-2010 in the Stockholm-Gotland region was retrieved. Factors influencing survival and recurrence were identified by Cox regression analyses. RESULTS: There were 2300 patients included. Among these 70.3% received preoperative RT. Three-year overall survival (OS), disease-free survival (DFS) and local recurrence rate were 80.2, 68.6 and 4.7%, respectively. All outcome measures were significantly improved over time. In a multivariable analysis in patients with comorbidity (Charlson comorbidity index score ≥1), OS were significantly better following preoperative RT than after surgery alone (HR 0.65, 95% CI 0.49-0.87). OS among patients with advanced age (≥80 years), was not influenced by preoperative RT. CONCLUSION: OS among patients with comorbidity was better following preoperative RT than after surgery alone while no differences were seen among the elderly. This indicates that the selection process may be optimised for the patients with advanced age but comorbidity should be used cautiously for exclusion of patients from preoperative RT.

Probability, rate and timing of reconstructive surgery following colectomy for inflammatory bowel disease in Sweden: a population-based cohort study.

AIM: Many patients with inflammatory bowel disease (IBD) need colectomy, but the rate of reconstructive surgery with restoration of intestinal continuity is unknown. The aim of this study was to investigate the probability, rate and timing of reconstructive surgery after colectomy in patients with IBD in a population-based setting. METHOD: The study cohort included all patients with IBD in Sweden who underwent colectomy from 2000 to 2009. Each patient was followed from admission for colectomy to admission for reconstructive surgery, date of death, migration or 31 December 2010. Kaplan-Meier survival curves and multivariable Poisson regression models were used to describe the probability, rate and timing of reconstructive surgery. RESULTS: Out of 2818 IBD patients treated with colectomy, 61.0% were male and 78.9% had ulcerative colitis. No reconstructive surgery had been performed in 1595 (56.6%) patients by the end of follow-up. Of the remaining 1223 patients, 526 underwent primary reconstructive surgery and 697 had a secondary reconstruction following a median interval of 357 days from primary surgery in the form of colectomy. The probability of reconstructive surgery was dependent on age (55.6% and 18.1% at ages 15-29 and ≥ 59 years, respectively), and the chance of reconstructive surgery was higher in hospitals that performed more than 13 colectomies for IBD per year [incidence rate ratio and 95% confidence interval 1.27 (1.09-1.49)]. CONCLUSION: Fewer than half of the patients having a colectomy for IBD underwent subsequent reconstructive surgery. Older age and low hospital volume were risk factors for no reconstructive surgery.

Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up.

Squamous cell carcinoma of the anus (SCCA) is a rare cancer but its incidence is increasing throughout the world, and is particularly high in the human immunodeficiency virus positive (HIV+) population. A multidisciplinary approach is mandatory (involving radiation therapists, medical oncologists, surgeons, radiologists and pathologists). SCCA usually spreads in a loco-regional manner within and outside the anal canal. Lymph node involvement at diagnosis is observed in 30%-40% of cases while systemic spread is uncommon with distant extrapelvic metastases recorded in 5%-8% at onset, and rates of metastatic progression after primary treatment between 10 and 20%. SCCA is strongly associated with human papilloma virus (HPV, types 16-18) infection. The primary aim of treatment is to achieve cure with loco-regional control and preservation of anal function, with the best possible quality of life. Treatment dramatically differs from adenocarcinomas of the lower rectum. Combinations of 5FU-based chemoradiation and other cytotoxic agents (mitomycin C) have been established as the standard of care, leading to complete tumour regression in 80%-90% of patients with locoregional failures in the region of 15%. There is an accepted role for surgical salvage. Assessment and treatment should be carried out in specialised centres treating a high number of patients as early as possible in the clinical diagnosis. To date, the limited evidence from only 6 randomised trials [1,2,3,4,5,6,7], the rarity of the cancer, and the different behaviour/natural history depending on the predominant site of origin, (the anal margin, anal canal or above the dentate line) provide scanty direction for any individual oncologist. Here we aim to provide guidelines which can assist medical, radiation and surgical oncologists in the practical management of this unusual cancer.

Preoperative treatment selection in rectal cancer: a population-based cohort study.

BACKGROUND: Preoperative radiotherapy and chemoradiotherapy for rectal cancer reduce local recurrence rates but is also associated with side effects. Thus, it is important to identify patients in whom the benefits exceed the risks. This study assessed the pretherapeutic parameters influencing the selection to preoperative treatment. METHODS: Data on all patients in the Stockholm-Gotland area, Sweden, who underwent elective trans-abdominal surgery for rectal cancer in 2000-2010, was retrieved from the Regional Cancer Registry and the Swedish National Patient Register. Clinical variables were analysed in relation to selected preoperative therapy. Odds Ratios were derived from univariable and multivariable logistic regression models. RESULTS: In total 2619 patients were included. Of these 1789 (68.3%) received preoperative radiotherapy or chemoradiotherapy. Over time, use of preoperative therapy increased (p < 0.001). In a multivariable model, age (≥ 80 years) and comorbidity (Charlson Comorbidity Index score ≥ 2) were strongly correlated to omittance of preoperative treatment (OR: 0.05; 95% CI: 0.04-0.07 and 0.29; 95% CI: 0.21-0.39) but there was no difference between genders. Pre-treatment tumour stage was a strong predictor for selection to preoperative (chemo-) radiotherapy. However, 8.2% of patients with intermediate or advanced tumours were selected to no preoperative treatment while 55.0% of patients with early tumours were selected to preoperative therapy. CONCLUSIONS: The use of preoperative (chemo-) radiotherapy increased over time. Suboptimal adherence to guidelines appears to exist leading to a risk of overtreatment and to a small extent also undertreatment. More robust selection criteria, also including age and comorbidity should be developed.

Mortality after total colectomy in 3084 patients with inflammatory bowel disease: a population-based cohort study.

BACKGROUND: A high post-operative mortality has been reported following colectomy in patients with inflammatory bowel disease (IBD), especially in some patient groups. AIMS: To investigate the 40-day mortality following colectomy in patients with IBD. The secondary aim was to assess whether colectomised IBD patients have an increased mortality compared to the general population. METHODS: This is a population-based register study of all patients with IBD in Sweden who underwent total colectomy in 2000-2010. The cohort was identified using international classification codes for ulcerative colitis (UC) and Crohn's disease (CD). Patients registered with both UC and CD before colectomy (UCCD) were analysed separately. Each patient was followed-up to the date of death, migration or 31st of December 2010, whichever came first. Kaplan-Meier survival curves, Cox proportional hazards models and relative mortality rates were used to describe mortality. RESULTS: In the cohort of 3084 patients, 2424 were diagnosed with UC, 326 with CD and 334 with UCCD. The 40-day, 1-year and 3-year mortality was 1.3%, 3.1% and 6.0%, respectively. The highest 40-day mortality was seen in patients ≥59 years of age (4.4%). Colectomy at the primary hospitalisation for IBD did not significantly increase the risk of post-operative mortality, nor did hospital volume. The relative survival after 3 years was 0.99, 0.98, 0.97 and 0.90 in those <30, 30-43, 44-58 and ≥59 years old, respectively. CONCLUSION: The 40-day mortality following total colectomy in IBD patients in Sweden is low, except in patients ≥59 years old.

Laparoscopic extralevator abdominal perineal excision of the rectum: the best of both worlds.

We report a combined laparoscopic and open technique for extralevator abdominal perineal excision of the rectum. The key steps are a laparoscopic rectal dissection limited distally by the coccyx. The open, prone, perineal dissection affords excellent views and allows a cylindrical specimen to be obtained. The resulting perineal defect is closed by a biological mesh. Extralevator abdominal perineal excision of the rectum offers a superior oncological specimen with reduced circumferential resection margin involvement compared to traditional techniques. Combined with a laparoscopic approach, this also has the potential to improve postoperative recovery and reduce morbidity.

Tumour budding correlates with local recurrence of rectal cancer.

AIM: Predictive tools for local recurrence (LR) of rectal cancer are needed. This study assessed the predictive value of tumour budding detected by MNF-116 and laminin-5 γ2 chain (Ln-5 γ2). METHOD: In a case-control study, the surgical specimens of 48 patients with LR after from primary resection of rectal carcinoma and 82 control patients matched for gender and preoperative radiation from a population of 1180 patients operated with total mesorectal excision were studied. The presence of budding was examined using immunohistochemistry with Ln-5 γ2 and pan-cytokeratin staining with MNF-116. RESULTS: Tumour budding counts ranged from 0 to 106 buds (mean 43, median 38) for all patients. Significantly more tumours with more than 35 buds were seen in the LR than in the control group (67 vs 44%; P = 0.02). The spread of budding was also more extensive in the LR than in the control group (63 vs 49%, P = 0.03). In a multivariate analysis with tumour, node, metastasis stage, MNF-116-stained budding was an independent predictor of local failure (P = 0.02). The budding frequency was higher in irradiated tumours in comparison with tumours that had not received irradiation (mean 53 vs 38, P = 0.03). For Ln-5 γ2, more tumours with ≥ 10 buds were seen in the group with LR than among the control patients, but this difference was not statistically significant (73 vs 57%; P = 0.09). No additive value was found in the multivariate logistic regression model when Ln-5 γ2-stained budding frequency was added to MNF-116 and tumour, node, metastasis stage. The agreement between budding frequency determined by MNF-116 and Ln-5 γ2 was moderate, with a κ-coefficient of 0.34 (0.16-0.51). CONCLUSION: Tumour budding determined by MNF-116 staining may serve as a predictive marker for LR in rectal cancer.

Factors influencing local failure in rectal cancer: analysis of 2315 patients from a population-based series.

PURPOSE: This study aimed to identify risk factors for local failure in an effort to optimize treatment for rectal cancer. METHODS: A total of 154 patients with local failure after abdominal resection were identified from a population-based consecutive series of 2315 patients who underwent operations for rectal cancer in the Stockholm region between January 1995 and December 2004. Surgeons trained in total mesorectal excision performed the surgery, and preoperative radiotherapy was given according to defined protocols. Data from the 9 hospitals in the region, prospectively registered in a database, were reviewed with regard to tumor location and stage, radiation therapy, surgical treatment, and follow-up. RESULTS: In a multivariable analysis, independent risk factors for local failure were distal tumor location and advanced tumor and nodal stage, omission of preoperative radiation, residual disease, and hospitals with lower caseload. Low anterior resection and total mesorectal excision were deployed more often in centers with low failure rates. Discriminators for radiation therapy were patients with male gender, less advanced age, and tumors situated <6 cm from the anal verge. CONCLUSION: The variability of patient outcome according to local failure depends on tumor stage, nodal stage, and location. Omission of radiation therapy and surgical performance are important additional risk factors to consider when optimizing treatment for rectal cancer.

Importance of clear resection margins in anorectal malignant melanoma.

BACKGROUND: Anorectal melanoma is rare and surgery is the recommended primary treatment. There has been some debate whether abdominoperineal resection (APR) or local excision is most appropriate. The aim of this study was to provide a population-based analysis of symptoms, treatment and outcome. METHODS: From the Swedish National Cancer Registry, 251 patients with anorectal melanoma were identified from 1960 to 1999. Medical reports were collected and reviewed retrospectively. R0 resection was defined by clear macroscopic margins and a pathology report showing a margin greater than 10 mm. Survival was compared with the log rank test, and Cox multivariable analysis was performed. RESULTS: APR and local excision was performed in 66 and 86 patients respectively. Median survival after surgery was 14 months, with no statistically significant difference between the two groups. Seventy-two patients in whom an R0 resection was achieved, irrespective of approach, had a significantly better overall 5-year survival rate than patients with involved margins (19 versus 6 per cent; P < 0.001). Multivariable analysis showed resection status and tumour stage to be independent prognostic variables. CONCLUSION: Both APR and LE seem appropriate for anorectal melanoma provided clear margins can be achieved; prognosis is poor regardless of surgical approach.