An International Expert-Based Consensus on the Definition of a Clinical Near-Complete Response After Neoadjuvant (Chemo)radiotherapy for Rectal Cancer.

BACKGROUND: A variety of definitions for a clinical near-complete response after neoadjuvant (chemo) radiotherapy for rectal cancer are currently used. This variety leads to inconsistency in clinical practice, long-term outcome, and trial enrollment. OBJECTIVE: The aim of this study was to reach expert-based consensus on the definition of a clinical near-complete response after (chemo) radiotherapy. DESIGN: A modified Delphi process, including a systematic review, 3 surveys, and 2 meetings, was performed with an international expert panel consisting of 7 surgeons and 4 radiologists. The surveys consisted of individual features, statements, and feature combinations (endoscopy, T2-weighted MRI, and diffusion-weighted MRI). SETTING: The modified Delphi process was performed in an online setting; all 3 surveys were completed online by the expert panel, and both meetings were hosted online. MAIN OUTCOME MEASURES: The main outcome was to reach consensus (80% or more agreement). RESULTS: The expert panel reached consensus on a 3-tier categorization of the near-complete response category based on the likelihood of the response to evolve into a clinical complete response after a longer waiting interval. The panelists agreed that a near-complete response is a temporary entity only to be used in the first 6 months after (chemo)radiotherapy. Furthermore, consensus was reached that the lymph node status should be considered when deciding on a near-complete response and that biopsies are not always needed when a near-complete response is found. No consensus was reached on whether primary staging characteristics have to be taken into account when deciding on a near-complete response. LIMITATIONS: This 3-tier subcategorization is expert-based; therefore, there is no supporting evidence for this subcategorization. Also, it is unclear whether this subcategorization can be generalized into clinical practice. CONCLUSIONS: Consensus was reached on the use of a 3-tier categorization of a near-complete response, which can be helpful in daily practice as guidance for treatment and to inform patients with a near-complete response on the likelihood of successful organ preservation. See Video Abstract. UN CONSENSO INTERNACIONAL BASADO EN EXPERTOS ACERCA DE LA DEFINICIN DE UNA RESPUESTA CLNICA CASI COMPLETA DESPUS DE QUIMIORADIOTERAPIA NEOADYUVANTE CONTRA EL CNCER DE RECTO: ANTECEDENTES:Actualmente, se utilizan una variedad de definiciones para una respuesta clínica casi completa después de quimioradioterapia neoadyuvante contra el cáncer de recto. Esta variedad resulta en inconsistencia en la práctica clínica, los resultados a largo plazo y la inscripción en ensayos.OBJETIVO:El objetivo de este estudio fue llegar a un consenso de expertos sobre la definición de una respuesta clínica casi completa después de quimioradioterapia.DISEÑO:Se realizó un proceso Delphi modificado que incluyó una revisión sistemática, 3 encuestas y 2 reuniones con un panel internacional de expertos compuesto por siete cirujanos y 4 radiólogos. Las encuestas consistieron en características individuales, declaraciones y combinaciones de características (endoscopía, T2W-MRI y DWI).AJUSTE:El proceso Delphi modificado se realizó en un entorno en línea; el panel de expertos completó las tres encuestas en línea y ambas reuniones se realizaron en línea.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue llegar a un consenso (≥80% de acuerdo).RESULTADOS:El panel de expertos llegó a un consenso sobre una categorización de tres niveles de la categoría de respuesta casi completa basada en la probabilidad de que la respuesta evolucione hacia una respuesta clínica completa después de un intervalo de espera más largo. Los panelistas coincidieron en que una respuesta casi completa es una entidad temporal que sólo debe utilizarse en los primeros 6 meses después de la quimioradioterapia. Además, se llegó a un consenso en que se debe considerar el estado de los nódulos linfáticos al decidir sobre una respuesta casi completa y que no siempre se necesitan biopsias cuando se encuentra una respuesta casi completa. No se llegó a un consenso sobre si se deben tener en cuenta las características primarias de estadificación al decidir una respuesta casi completa.LIMITACIONES:Esta subcategorización de 3 niveles está basada en expertos; por lo tanto, no hay evidencia que respalde esta subcategorización. Además, no está claro si esta subcategorización puede generalizarse a la práctica clínica.CONCLUSIONES:Se alcanzó consenso sobre el uso de una categorización de 3 niveles de una respuesta casi completa que puede ser útil en la práctica diaria como guía para el tratamiento y para informar a los pacientes con una respuesta casi completa sobre la probabilidad de una preservación exitosa del órgano. (Traducción - Dr. Aurian Garcia Gonzalez).

Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression.

Signaling proteins driving the proliferation of stem and progenitor cells are often encoded by proto-oncogenes. EphB receptors represent a rare exception; they promote cell proliferation in the intestinal epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth. We show that cell migration and proliferation are controlled independently by the receptor EphB2. EphB2 regulated cell positioning is kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas EphB2 tyrosine kinase activity regulates cell proliferation through an Abl-cyclin D1 pathway. Cyclin D1 regulation becomes uncoupled from EphB signaling during the progression from adenoma to colon carcinoma in humans, allowing continued proliferation with invasive growth. The dissociation of EphB2 signaling pathways enables the selective inhibition of the mitogenic effect without affecting the tumor suppressor function and identifies a pharmacological strategy to suppress adenoma growth.

Postoperative complications and emergency surgeries in colorectal cancer patients <50 years-a national cohort study.

AIM: The incidence of colorectal cancer (CRC) in Sweden is increasing in individuals <50 years. This study aimed to examine differences in postoperative 30-day complications and rate of emergency surgeries in CRC patients <50 years at diagnosis compared to older age groups since population-based research on this topic is scarce. METHOD: This population-based study included data from the Swedish Colorectal Cancer Registry for patients undergoing CRC resection between 2010 and 2018. Bivariate analysis and logistic regression were used to analyse the relationship between age groups (<50, 50-79 and ≥80 years) and probability of postoperative 30-day complications adjusted for gender, tumour localization, neoadjuvant (chemo)radiotherapy and American Society of Anesthesiologists score. RESULTS: In total 33 320 patients were included. Patients <50 years had a lower American Society of Anesthesiologists score, more advanced tumours and received more neoadjuvant treatment. Emergency surgeries were less common in the youngest age group (P < 0.001) as well as overall postoperative 30-day complications: ORadj 0.84 (95% CI 0.74-0.96) compared to those ≥80 years. Surgical complications were more common in age groups <50 and 50-79 years (16.5% and 16.9% respectively) compared to patients ≥80 years (14.1%) (P < 0.001). Anastomotic leakage and intra-abdominal infections were more frequent in patients <50 years (5.7% and 3.5% respectively) compared to age groups 50-79 years (5.1% and 2.8% respectively) and ≥80 years (3.5% and 2.1% respectively) (P < 0.001). Wound infections were more common in the two youngest age groups compared to patients ≥80 years (5.3% vs. 3.7% respectively) (P < 0.001). CONCLUSION: Colorectal cancer patients <50 years and 50-79 years had a higher proportion of surgical complications regarding anastomotic leakage, intra-abdominal infections and wound infections but lower overall postoperative complications. The incidence of surgical emergencies was highest amongst patients ≥80 years. Postoperative diagnostic workup in symptomatic individuals <50 years is warranted.

Sex differences in metastatic surgery following diagnosis of synchronous metastatic colorectal cancer.

The aim was to investigate gender differences in the likelihood to receive metastatic surgery, and to compare overall survival between men and women, among patients with synchronous metastatic colorectal cancer (mCRC) in a population-based setting. All Swedish adult patients diagnosed with synchronous mCRC in 2007-2016 were identified using the nationwide colorectal cancer database (CRCBaSe). Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression, comparing the odds of receiving treatment. The Kaplan-Meier method was used to calculate survival proportions and Cox regression models to estimate hazard ratios (HRs) and 95% CIs of all-cause mortality rates. All multivariable models were adjusted for age, ASA score, Charlson comorbidity index, year of diagnosis, location of primary tumor and single or multiple metastatic locations. A total of 12 201 patients met the study criteria. Women received 23% less metastatic surgery for mCRC (adjusted OR = 0.77, CI:0.69-0.86) and experienced a slightly higher mortality following diagnosis (adjusted HR = 1.09, CI:1.05-1.14). In analyses restricted to patients who received metastatic surgery, no significant differences in mortality were found. In conclusion, this population-based study showed that women less often received metastatic surgery of mCRC and experienced slightly higher all-cause mortality compared with men. The differences persisted despite adjustments of patient and cancer characteristics. Gender differences in receiving treatment are unacceptable if the underlying explanation cannot be motivated. Further studies are needed to understand if the differences are based on sex (i.e., biology) or gender (including clinically unmotivated differences in treatment approach).

Watch and wait after neoadjuvant treatment in rectal cancer: comparison of outcomes in patients with and without a complete response at first reassessment in the International Watch & Wait Database (IWWD).

BACKGROUND: In rectal cancer, watch and wait for patients with a cCR after neoadjuvant treatment has an established evidence base. However, there is a lack of consensus on the definition and management of a near-cCR. This study aimed to compare outcomes in patients who achieved a cCR at first reassessment versus later reassessment. METHODS: This registry study included patients from the International Watch & Wait Database. Patients were categorized as having a cCR at first reassessment or at later reassessment (that is near-cCR at first reassessment) based on MRI and endoscopy. Organ preservation, distant metastasis-free survival, and overall survival rates were calculated. Subgroup analyses were done for near-cCR groups based on the response evaluation according to modality. RESULTS: A total of 1010 patients were identified. At first reassessment, 608 patients had a cCR; 402 had a cCR at later reassessment. Median follow-up was 2.6 years for patients with a cCR at first reassessment and 2.9 years for those with a cCR at later reassessment. The 2-year organ preservation rate was 77.8 (95 per cent c.i. 74.2 to 81.5) and 79.3 (75.1 to 83.7) per cent respectively (P = 0.499). Similarly, no differences were found between groups in distant metastasis-free survival or overall survival rate. Subgroup analyses showed a higher organ preservation rate in the group with a near-cCR categorized exclusively by MRI. CONCLUSION: Oncological outcomes for patients with a cCR at later reassessment are no worse than those of patients with a cCR at first reassessment.

CRCBaSe: a Swedish register-based resource for colorectal adenocarcinoma research.

OBJECTIVES: To facilitate high-quality register-based research on colorectal cancer (CRC) in Sweden by constructing a database consisting of CRC patients, matched comparators, and relatives. MATERIAL AND METHODS: Patients with adenocarcinoma in the colon and/or rectum were identified in the Swedish Colorectal Cancer Register, a nationwide quality-of-care register. For each patient, six comparators from the general population were matched on birth year, sex, year of CRC diagnosis, and county. Comparators were free from CRC at the time of matching, but could later become cases. For both patients and comparators, first-degree relatives (parents, siblings, and children) were identified. Information from nationwide population-based registers was retrieved and linked to each individual in the database using the personal identification number unique to all Swedish residents. RESULTS: A total of 76,831 CRC patients diagnosed between 1995 and 2016 were identified (51% colon, 49% rectal; before 2007 only rectal cancer patients were included). Among all patients, 37% were stage I-II, 22% stage III, and 22% stage IV. The median follow-up time was 11.9 years (inter-quartile range, IQR: 8.6-15.3). Together with comparators and relatives, the database contains 2,413,139 individuals with information on demographics, dates and causes of death, in- and outpatient healthcare records, cancer diagnoses, prescribed and dispensed drugs, childbirths (among women), and social security information (such as sick leave and early retirement). CONCLUSION: The Colorectal Cancer Database Sweden (CRCBaSe) is a large and unique register-based data research platform, which opens up for clinically important, large epidemiological studies with innovative design in the field of colorectal adenocarcinoma.

Locally recurrent rectal cancer: oncological outcomes with different treatment strategies in two tertiary referral units.

BACKGROUND: The optimal treatment for patients with locally recurrent rectal cancer (LRRC) is controversial. The aim of this study was to investigate different treatment strategies in two leading tertiary referral hospitals in Europe. METHODS: All patients who underwent curative surgery for LRRC between January 2003 and December 2017 in Catharina Hospital, Eindhoven, the Netherlands (CHE), or Karolinska University Hospital, Stockholm, Sweden (KAR), were studied retrospectively. Available MRIs were reviewed to obtain a uniform staging for optimal comparison of both cohorts. The main outcomes studied were overall survival (OS), local re-recurrence-free survival (LRFS), and metastasis-free survival (MFS). RESULTS: In total, 377 patients were included, of whom 126 and 251 patients came from KAR and CHE respectively. At 5 years, the LRFS rate was 62.3 per cent in KAR versus 42.3 per cent in CHE (P = 0.017), whereas OS and MFS were similar. A clear surgical resection margin (R0) was the strongest prognostic factor for survival, with a hazard ratio of 2.23 (95 per cent c.i. 1.74 to 2.86; P < 0.001), 3.96 (2.87 to 5.47; P < 0.001), and 2.00 (1.48 to 2.69; P < 0.001) for OS, LRFS, and MFS respectively. KAR performed more extensive operations, resulting in more R0 resections than in CHE (76.2 versus 61.4 per cent; P = 0.004), whereas CHE relied more on neoadjuvant treatment and intraoperative radiotherapy, to reduce the morbidity of multivisceral resections (P < 0.001). CONCLUSION: In radiotherapy-naive patients, neoadjuvant full-course chemoradiation confers the best oncological outcome. However, neoadjuvant therapy does not diminish the need for extended radical surgery to increase R0 resection rates.

Hospital factors and metastatic surgery in colorectal cancer patients, a population-based cohort study.

BACKGROUND: Only a limited proportion of patients with metastatic colorectal cancer (mCRC) receives metastatic surgery (including local ablative therapy). The aim was to investigate whether hospital volume and hospital level were associated with the chance of metastatic surgery. METHODS: This national cohort retrieved from the CRCBaSe linkage included all Swedish adult patients diagnosed with synchronous mCRC in 2009-2016. The association between annual hospital volume of incident mCRC patients and the chance of metastatic surgery, and survival, were assessed using logistic regression and Cox regression models, respectively. Hospital level (university/non-university) was evaluated as a secondary exposure in a similar manner. Both uni- and multivariable (adjusted for sex, age, Charlson comorbidity index, year of diagnosis, cancer characteristics and socioeconomic factors) models were fitted. RESULTS: A total of 1,674 (17%) out of 9,968 mCRC patients had metastatic surgery. High hospital volume was not associated with increased odds of metastatic surgery after including hospital level in the model, whereas hospital level was (odds ratio (OR) (95% confidence interval (CI)): 1.94 (1.68-2.24)). All-cause mortality was lower in university versus non-university hospitals (hazard ratio (95% CI): 0.83 (0.78-0.88)). CONCLUSIONS: Patients with mCRC initially cared for by a university hospital experienced a greater chance to receive metastatic surgery and had superior overall survival. High hospital volume in itself was not associated with a greater chance to receive metastatic surgery nor a greater survival probability. Additional efforts should be imposed to provide more equal care for mCRC patients across Swedish hospitals.

Circulating tumor DNA (ctDNA) in adjuvant therapy of early stage colon cancer: current status and future perspectives.

BACKGROUND: This article reviews the current knowledge on circulating tumor DNA (ctDNA) in early stage colon cancer and ongoing trials on ctDNA-guided treatment in the adjuvant setting. METHODS: A literature search of Pubmed was performed to identify studies on ctDNA in early stage colon cancer and neoadjuvant or adjuvant treatment. For ongoing trials, we searched clinicaltrials.gov and the Australian New Zealand Clinical Trials Registry (ANZCTR). RESULTS: Several studies show that ctDNA is a strong predictor for recurrence and survival after surgery and adjuvant chemotherapy. The specificity of this marker is extremely high, and the sensitivity is increasing with the development of technology. Recurrences can be detected very early and the analysis can potentially be used to guide neoadjuvant and adjuvant treatment. Ongoing and planned studies are now looking into escalation and de-escalation of therapy according to ctDNA-status after surgery. CONCLUSION: Serial measurement of ctDNA shows great promise as a marker for both prognosis and response to treatment in early colon cancer. Future studies will show whether we can use this analysis for tailoring treatment for patients in the adjuvant and neoadjuvant setting. With improved technology, ctDNA has the potential of becoming a 'game-changer' in the treatment of early stage colon cancers.

Impact of Androgens on Sexual Function in Women With Rectal Cancer - A Prospective Cohort Study.

BACKGROUND: Women treated for rectal cancer are at risk of sexual dysfunction and impaired ovarian androgen production. AIM: To investigate a possible association between serum levels of endogenous androgens and sexual function in women with rectal cancer. METHODS: Women diagnosed with stage I-III rectal cancer were consecutively included and prospectively followed with the Female Sexual Function Index (FSFI) questionnaire from baseline to 2 years postoperatively and blood samples for hormone analyses, baseline to 1 year. Androgens were measured with liquid chromatography-mass spectrometry and electrochemiluminescence. The associations between the 4 measured androgens (testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulphate) and sexual function were assessed with generalized least squares random effects regression analysis in sexually active women. OUTCOMES: The primary outcome measure was the mean change observed in the FSFI total score when the serum androgen levels changed with one unit. Secondary outcomes were the corresponding mean changes in the FSFI domain scores: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain/discomfort. RESULTS: In the 99 participants, the median FSFI total score decreased from 21.9 (range 2.0 - 36.0) to 16.4 (3.5 - 34.5) and 11.5 (2.0 to 34.8) at 1 and 2-years follow-up. After adjustment for age, partner, psychological well-being, preoperative (chemo)radiotherapy, and surgery, total testosterone and androstenedione were significantly associated with FSFI total score (ß-coefficients 3.45 (95% CI 0.92 - 5.97) and 1.39 (0.46 - 2.33) respectively). Testosterone was significantly associated with the FSFI-domains lubrication and orgasm, free testosterone with lubrication, androstenedione with all domains except desire and satisfaction, and dehydroepiandrosterone sulphate with none of the domains. STRENGTHS AND LIMITATIONS: This is the first study investigating whether androgen levels are of importance for the impaired sexual function seen in women following rectal cancer treatment. The prospective design allows for repeated measures and the use of the FSFI for comparisons across studies. No laboratory data were collected at the 2-year follow-up, and the missing data could have further clarified the studied associations. CONCLUSION AND CLINICAL IMPLICATION: Testosterone and androstenedione were associated with sexual function in female rectal cancer patients. The results are of interest for future intervention studies and contribute to the understanding of sexual problems, which is an essential component of the rehabilitation process in pelvic cancer survivors. Svanström Röjvall A, Buchli C, Flöter Rådestad A, et al. Impact of Androgens on Sexual Function in Women With Rectal Cancer - A Prospective Cohort Study. J Sex Med 2021;18:1374-1382.

Oncological outcomes after complete mesocolic excision in right-sided colon cancer: a population-based study.

AIM: Complete mesocolic excision (CME) has been proposed as the preferred surgical technique for resection of colon cancer. This prospective cohort study evaluates the effect of CME surgery on colon cancer mortality after right-sided hemicolectomy on a population level. METHODS: Data from the Swedish Colorectal Cancer Registry and the Cause of Death Registry on all patients treated with elective right-sided hemicolectomy for colon cancer Stages I-III in the Stockholm County 2008-2012 were analysed. Adherence to principles of CME surgery was determined by structured analysis of anonymized surgical reports regarding the presence of five essential features. The exposure to CME was graded as group 0 (not exposed to CME), group 1 (intermediate) and group 2 (exposed to CME). RESULTS: In total, 1171 patients were analysed with 234 (20.0%) patients in CME group 0, 453 (38.7%) patients in CME group 1 and 484 (41.3%) in CME group 2. The 5-year colon cancer mortality was 20.2% in CME group 0, 13.9% in CME group 1 and 13.1% in CME group 2 (P = 0.026). The adjusted hazard ratio for colon cancer mortality was 0.61 (95% CI 0.42-0.91; P = 0.014) for CME group 1 and 0.52 (95% CI 0.35-0.77; P = 0.001) for CME group 2. DISCUSSION: The presence of predefined CME features in surgical reports was related to a graded benefit on cancer-specific mortality after right-sided hemicolectomy for colon cancer Stages I-III.

Incidence of wound dehiscence after colorectal cancer surgery: results from a national population-based register for colorectal cancer.

BACKGROUND: Patient-related risk factors for wound dehiscence after colorectal surgery remain obscure. METHODS: All open abdominal procedures for colorectal cancer registered in the Swedish Colorectal Cancer Registry (SCRCR, 5) 2007-2013 were identified. Potential risk factors for wound dehiscence were identified by cross-matching between the SCRCR and the National Patient Register (NPR). The endpoint in this study was reoperation for wound dehiscence registered in either the SCRCR or NPR and patients not reoperated were considered controls. RESULTS: A total of 30,050 patients were included in the study. In a multivariable regression analysis, age > 70 years, male gender, BMI > 30, history of chronic obstructive pulmonary disease, history of generalised inflammatory disease, and duration of surgery less than 180 min were independently and significantly associated with increased risk for wound dehiscence. A history of diabetes, chronic renal disease, liver cirrhosis, and distant metastases was not associated with wound dehiscence. The hazard ratio for postoperative death was 1.24 for patients who underwent reoperation for wound dehiscence compared with that for controls. DISCUSSION: Patients reoperated for wound dehiscence face a significantly higher postoperative mortality than those without. Risk factors include male gender, age > 70 years, obesity, history of chronic obstructive pulmonary disease, and history of generalised inflammatory disease. Patients at high risk for developing wound dehiscence may, if identified preoperatively, benefit from active prevention measures implemented in routine surgical practice.

Treatment and survival of rectal cancer patients over the age of 80 years: a EURECCA international comparison.

BACKGROUND: The optimal treatment strategy for older rectal cancer patients remains unclear. The current study aimed to compare treatment and survival of rectal cancer patients aged 80+. METHODS: Patients of ≥80 years diagnosed with rectal cancer between 2001 and 2010 were included. Population-based cohorts from Belgium (BE), Denmark (DK), the Netherlands (NL), Norway (NO) and Sweden (SE) were compared side by side for neighbouring countries on treatment strategy and 5-year relative survival (RS), adjusted for sex and age. Analyses were performed separately for stage I-III patients and stage IV patients. RESULTS: Overall, 19 634 rectal cancer patients were included. For stage I-III patients, 5-year RS varied from 61.7% in BE to 72.3% in SE. Proportion of preoperative radiotherapy ranged between 7.9% in NO and 28.9% in SE. For stage IV patients, 5-year RS differed from 2.8% in NL to 5.6% in BE. Rate of patients undergoing surgery varied from 22.2% in DK to 40.8% in NO. CONCLUSIONS: Substantial variation was observed in the 5-year relative survival between European countries for rectal cancer patients aged 80+, next to a wide variation in treatment, especially in the use of preoperative radiotherapy in stage I-III patients and in the rate of patients undergoing surgery in stage IV patients.

Risk of Acute Testicular Failure After Preoperative Radiotherapy for Rectal Cancer: A Prospective Cohort Study.

OBJECTIVE: The aim of this study was to assess the acute effect of preoperative RT for rectal cancer on endocrine testicular function. BACKGROUND: Preoperative radiotherapy (RT) enhances local control and cancer-specific survival in patients treated for rectal cancer. In case series, a negative acute effect on Leydig cell function has been reported. METHODS: This prospective cohort study included 168 males with rectal or prostate cancer stage I-III. Males treated with preoperative RT and surgery for rectal cancer formed the exposed group (n = 93). Males treated with surgery alone were assigned to the unexposed group (n = 75). The androgen levels were assessed at baseline and after preoperative RT. The exposure was quantified with the treatment planning system to estimate the cumulative testicular dose (TD). The risk of low T (serum T < below 8 nmol/L) was the primary endpoint. Secondary endpoints were serum testosterone (T), bioavailable T, luteinizing hormone (LH), and the LH-T ratio. RESULTS: The baseline levels of androgens were not related to exposure status or type of cancer. The proportion of low T increased from 14.6% at baseline to 35.4% after RT, relative risk 2.41 (95% CI 1.57 to 3.71, P < 0.001). Preoperative RT resulted in a significant decrease of serum and bioavailable T and a significant increase of LH and LH-T ratio. The decline in serum and bioavailable T was related to the TD. CONCLUSIONS: Preoperative RT for rectal cancer results in dose-dependent primary testicular failure increasing the risk of hypogonadism at the time of surgery by 2.4 times (number needed to harm = 5).

Treatment and Survival of Patients with Colon Cancer Aged 80 Years and Older: A EURECCA International Comparison.

BACKGROUND: Colon cancer in older patients represents a major public health issue. As older patients are hardly included in clinical trials, the optimal treatment of these patients remains unclear. The present international EURECCA comparison explores possible associations between treatment and survival outcomes in elderly colon cancer patients. SUBJECTS, MATERIALS, AND METHODS: National data from Belgium, Denmark, The Netherlands, Norway, and Sweden were obtained, as well as a multicenter surgery cohort from Germany. Patients aged 80 years and older, diagnosed with colon cancer between 2001 and 2010, were included. The study interval was divided into two periods: 2001-2006 and 2007-2010. The proportion of surgical treatment and chemotherapy within a country and its relation to relative survival were calculated for each time frame. RESULTS: Overall, 50,761 patients were included. At least 94% of patients with stage II and III colon cancer underwent surgical removal of the tumor. For stage II-IV, the proportion of chemotherapy after surgery was highest in Belgium and lowest in The Netherlands and Norway. For stage III, it varied from 24.8% in Belgium and 3.9% in Norway. For stage III, a better adjusted relative survival between 2007 and 2010 was observed in Sweden (adjusted relative excess risk [RER] 0.64, 95% confidence interval [CI]: 0.54-0.76) and Norway (adjusted RER 0.81, 95% CI: 0.69-0.96) compared with Belgium. CONCLUSION: There is substantial variation in the rate of treatment and survival between countries for patients with colon cancer aged 80 years or older. Despite higher prescription of adjuvant chemotherapy, poorer survival outcomes were observed in Belgium. No clear linear pattern between the proportion of chemotherapy and better adjusted relative survival was observed. IMPLICATIONS FOR PRACTICE: With the increasing growth of the older population, clinicians will be treating an increasing number of older patients diagnosed with colon cancer. No clear linear pattern between adjuvant chemotherapy and better adjusted relative survival was observed. Future studies should also include data on surgical quality.

Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial.

BACKGROUND: Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. METHODS: In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 × 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 × 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1·7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813. FINDINGS: Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33·4 months (range 18·2-62·2) in the short-course radiotherapy group and 19·3 months (8·5-39·5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33·3 months (range 17·8-114·3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1·44 [95% CI 0·41-5·11]; long-course radiotherapy with delay 2·24 [0·71-7·10]; p=0·48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (<1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 [50%] of 129 patients in the short-course radiotherapy group; 48 [38%] of 128 patients in the short-course radiotherapy with delay group; 50 [39%] of 128 patients in the long-course radiotherapy with delay group; odds ratio [OR] vs short-course radiotherapy: short-course radiotherapy with delay 0·59 [95% CI 0·36-0·97], long-course radiotherapy with delay 0·63 [0·38-1·04], p=0·075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0·61 [95% CI 0·45-0·83] p=0·001). INTERPRETATION: Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery. FUNDING: Swedish Research Council, Swedish Cancer Society, Stockholm Cancer Society, and the Regional Agreement on Medical Training and Clinical Research in Stockholm.

Preoperative anaemia and perioperative red blood cell transfusion as prognostic factors for recurrence and mortality in colorectal cancer-a Swedish cohort study.

PURPOSE: The hypothesis in this study was that anaemia prior to surgery and perioperative red blood cell transfusion increases the risk for recurrence and overall mortality in patients with stages I-III colorectal cancer after abdominal resection with curative intent. METHODS: This is a Swedish single centre retrospective cohort study. Data on 496 consecutive radical abdominal resections stages I-III colorectal cancer performed at the Karolinska University Hospital 2007-2010 were extracted from the Swedish Colorectal Cancer Registry. Data were linked to local laboratory and transfusion databases to identify preoperative anaemia and perioperative transfusion. Disease recurrence was validated by scrutiny of patient records. A total of 496 stages I-III colorectal cancer patients were included in the analysis. Multivariate Cox regression analysis adjusted for tumour and patient characteristics were performed to assess risk for recurrence and overall mortality. RESULTS: Anaemia prior to surgery was associated with increased risk for overall mortality (HR 2.1, 95% CI 1.4-3.2). There was no association between anaemia and risk for recurrence (HR 1.6, 95% CI 0.97-2.6). Transfusion was not associated with increased risk of recurrence (HR 0.7, 95% CI 0.4-1.3) or overall mortality (HR 1.04, 95% CI 0.7-1.6). CONCLUSIONS: Anaemia prior to colorectal cancer surgery was associated with increased risk for overall mortality while a no increased risk was seen for recurrence. Previous findings indicating an association between blood transfusion and increased risk for recurrence could not be confirmed.

Anthropometry-based Obesity Phenotypes and Risk of Colorectal Adenocarcinoma: A Large Prospective Cohort Study in Norway.

BACKGROUND: It is unclear whether obesity phenotypes measured by different anthropometric indices are associated with a risk of colorectal adenocarcinoma by anatomical location. METHODS: We compiled harmonized population-based cohort studies (Cohort of Norway, CONOR) with 143,477 participants that were conducted between 1994 and 2010. General, abdominal, and gluteofemoral obesity were assessed by body mass index (BMI, kg/m(2)), waist circumference (cm), and hip circumference (cm). Other measures examined were waist to hip ratio, waist to height ratio, and body adiposity index. We performed Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of obesity relative to a risk of colorectal adenocarcinoma. RESULTS: In total, 2,044 incident cases of colorectal adenocarcinoma were identified. We observed a positive association between waist circumference (high versus low) and adenocarcinoma in the proximal colon (HR = 1.9, 95% CI = 1.5, 2.5) and distal colon (HR = 1.7, 95% CI = 1.3, 2.3) when adjusted for BMI. The association with waist circumference was especially strong in men. BMI was not associated with adenocarcinoma in the colon or rectum after adjusting for waist circumference. We found no association between hip circumference and colorectal adenocarcinoma. When adjusted for BMI plus waist circumference, body adiposity index was negatively associated with adenocarcinoma in the proximal or distal colon. CONCLUSION: Abdominal obesity, but not general or gluteofemoral obesity, was associated with an increased risk of adenocarcinoma in the proximal and the distal colon, especially in men. Muscularity may be negatively associated with risk of colon adenocarcinoma.

Assessment of testicular dose during preoperative radiotherapy for rectal cancer.

BACKGROUND: Radiotherapy (RT) for rectal cancer can have adverse effects on testicular function resulting in azoospermia and low testosterone levels. Variability of testicular dose (TD) due to differences in position of testes has been assessed with scrotal dosimeters and resulted in substantial variability of delivered TD. The aim of this study was to estimate planned and delivered TD using a treatment planning system (TPS). METHODS: In 101 men treated with RT for rectal cancer the cumulative mean TD (mTD) was calculated by TPS based on plan-computed tomography (CT) to evaluate the effect of different predictors on planned TD. The delivered TD was estimated by TPS based on repeated cone-beam CTs in 32 of 101 men to assess within-person variability of planned and delivered TD in a longitudinal analysis. RESULTS: The median planned mTD for short course RT was 0.57 Gy (range 0.06-14.37 Gy) and 0.81 Gy (range 0.36-10.80 Gy) for long course RT. The median planned mTD was similar to the median delivered mTD in the 32 men analysed over the entire course of RT (p=0.84). The mTD did not change significantly over time of planning and delivering RT. The variation in proximity between testes and planning target volume (PTV) was related to within-person variability of mTD in men on the 50th and 75th percentile of mTD and as expected the absolute difference between planned and delivered mTD increased with higher mTD. CONCLUSION: Testicular doses calculated based on plan-CT are an accurate estimation of delivered TD based on repeated cone beam (CB)CT. The within-person variability of TD is related to variation in proximity between testes and PTV in men with moderate to high TD.

Metabolic predispositions and increased risk of colorectal adenocarcinoma by anatomical location: a large population-based cohort study in Norway.

Whether different definitions of metabolic syndrome (MetS) are differently associated with colorectal adenocarcinoma (CA) by anatomical location is unclear. A population-based cohort study, the Cohort of Norway (CONOR) Study, was conducted in Norway from 1995 to 2010. Anthropometric measurements, blood samples, and lifestyle data were collected at recruitment. CAs were identified through linkage to the Norwegian Cancer Register. A composite index of MetS as defined by the International Diabetes Federation (IDF) or/and the National Cholesterol Education Program's Adult Treatment Panel III (ATP III) and single components of MetS, including anthropometric factors, blood pressure, lipids, triglycerides, and glucose, were analyzed. Cox proportional hazards regression was performed to estimate hazard ratios and 95% confidence intervals. Significant associations between single MetS components and CA, except for reduced high-density lipoprotein cholesterol and nonfasting glucose levels, were observed. MetS defined by 2 criteria separately showed a similar association with CA in general, and MetS defined by both the IDF and ATP III showed consistent results. Stronger associations were observed in the proximal colon among men (IDF: hazard ratio (HR) = 1.51, 95% confidence interval (CI): 1.24, 1.84; ATP III: HR = 1.40, 95% CI: 1.15, 1.70) and in the rectum among women (IDF: HR = 1.42, 95% CI: 1.07, 1.89; ATP III: HR = 1.43, 95% CI: 1.08, 1.90).