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Colorectal cancer (CRC) is the third most common diagnosis and second deadliest malignancy for both sexes combined. CRC has both strong environmental associations and genetic risk factors. The incidence of new cases and mortality has been steadily declining for the past years, except for younger adults (younger than 50 years), possibly related to an increase in cancer screening and better therapy modalities. Approximately 5% of all CRC are attributed to two inherited syndromes, Familial Adenomatous Polyposis, and Lynch syndrome. The change of the normal colonic epithelium to a precancerous lesion and ultimately an invasive carcinoma requires an accumulation of genetic mutations either somatic (acquired) and/or germline (inherited) in an approximately 10 to 15-year period. [1][2][3]Chromosomal instability, mismatch repair, and CpG hypermethylation are the major pathways to CRC. The most important prognostic colon cancer indicator is the pathological stage at presentation. All new CRC cases should be universally screen for DNA mismatch repair/microsatellite status, and RAS/BRAF mutational testing when considering for prognostic and predictive of chemotherapy efficacy. In almost all patients, a diagnostic or screening colonoscopy is required for tissue biopsy pathological confirmation of colon carcinoma. Baseline computed tomography (CT) of the chest, abdomen, and pelvis with contrast and carcinoembryonic antigen (CEA) are the preferred cost-effective, colon-cancer staging studies done before surgical resection. Surgical resection is the main treatment modality for localized early-stage colon cancer. Adjuvant therapy could augment the chance of cure on high-risk patients with colon cancer. Oligo-metastatic, liver and lung, and local-recurrence patients with colon cancer are potential curable candidates with multimodality therapies. Palliative systemic therapy is reserved for non-surgical colon cancer candidates aiming to improve quality of life and prolong life expectancy.[4][5][6]
Colon cancer (Cca) could present as sporadic (70%), familial clustering (20%) and inherited syndromes (10%). Sporadic Cca average age diagnosis is older than 50 years and mostly linked to environmental factors, different from a minority of patients with a true inherited pattern that carries a higher risk at a younger age (younger than 50 years), and the remaining 20% are familial clustering in the absence of identifiable inherited syndrome. The most common inherited CRC syndromes are familial adenomatous polyposis (FAP) and Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]). [7][8]Approximately 5% of all CRC cancers are attributed to these two inherited syndromes, but as many as 10% to 15% of unselected CRC patients will carry high-risk mutation not related to FAP or HNPCC.
Personal or family history of CRC, adenomatous polyps and polyps with villous or tubulovillous dysplasia indicate a high risk for synchronous and metachronous CRC primary cancer up to 3% to 5% at 5 years or even longer after resection requiring a closer screening interval. Inflammatory bowel disease (IBD), mainly ulcerative colitis, has a well-known association with Cca, with an estimated incidence 0.5% per year between 10 and 20 years after the time of IBD diagnosis and 1% per year after that reaching a 30% risk probability by the fourth decade of patients with pancolitis. Crohn's disease may increase Cca risk, particularly if present in the ileocolic region.
Childhood cancer survivors who received abdominal radiation (greater than 30 Gy) are at risk of CRC, and screening is recommended 10 years later or at age 35. Other illnesses that increase the risk higher of CRC are diabetes mellitus/insulin resistance, uncontrolled acromegaly disease, and long-term immunosuppressed renal transplant.
Epidemiologic study results indicate strong environmental and lifestyle associations for CRC. Modest weak increased CRC risks are seen with obesity, red/processed meat, tobacco, alcohol, androgen deprivation therapy, and cholecystectomy among others. On the other hand, large population studies with variable strength evidence have found CRC protective factors such as physical activity, diet (fruits and vegetables, fiber, resistant starch, fish), vitamin supplements (folate, folic acid, pyridoxine B6, calcium, vitamin D, magnesium), garlic and coffee, and drugs [aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), hormonal replacement therapy in postmenopausal, statins, bisphosphonate and angiotensin inhibitors].
Interestingly, a randomized controlled clinical trial found that 600 mg of aspirin in Lynch syndrome had a protective effect against colorectal adenomas and cancer with substantially reduced cancer incidence after 55.7 months with an HR of 0.56 [95% confidence interval (CI); 0.32, 0.99; p = 0.05].
CRC affects approximately 135,439 estimated new patients with a corresponding 95,520 (70%) due to Cca in the United States every year. Among all cancers sites, it is the second leading cause of death in the United States, with an estimated 50,260 deaths, when colon and rectum are combined. The CRC incidence rate has been declining 3% per year since 2004 although increasing by 2% per year among screened young adults (younger than 50 years). [9][10][11]The prior reflects an uptake on screening patterns and removal of precancerous lesions. CRC incidence varies worldwide with higher rates in developed countries than in unindustrialized countries. Low socioeconomic status has an increased risk of CRC associated with poor risk behavior and access to medical care. White American lifetime average incidence of CRC is 5% but is higher in men (greater than 20%) than in woman and African Americans (greater than 25%) than non-Hispanic whites. Findings from epidemiologic studies indicate a gradual anatomic distribution of Cca, shifting from the left-distal colon toward the right sided or proximal end, once more related to more effective left-sided screening modalities. From 1975 to 2014, there has been a 51% decrease in the mortality of CRC in the United States, attributed to early detection and improvement of treatment modalities. National Cancer Institute estimates that 65% of all treated patients for Cca will be alive at the 5-year mark.
The transformation of the normal colonic epithelium to a precancerous lesion (adenoma) and ultimately to invasive carcinoma requires an accumulation of genetic mutations either somatic (acquired) and/or germline (inherited). The theory of colonic carcinogenesis features a clonal mutation evolution that gives a cell survival-immortality advantage and allows to develop more mutations providing other cancer hallmarks as proliferation, invasion, metastasis, and others.[12][13] Clinical evidence has shown that CRCs frequently arise from adenomatous polyps that typically acquire dysplastic changes in a 10 to 15-year period before developing invasive carcinoma, and the early detection-removal of polyps will reduce the incidence of CRC. New evidence has exposed that hamartomatous and serrated polyps could lead to CRC. There are three major molecular pathways linked to CRC, chromosomal instability, mismatch repair, and hypermethylation. The chromosomal instability pathway is a gain of mutations unbalancing oncogene and tumor suppressors equilibrium as seen with mutations in the adenomatous polyposis coli (APC), a hallmark of FAP. Cells with deficiency of DNA mismatch repair (dMMR), commonly MLH1 or MSH2, accumulate errors within the genome that further will be repeated causing high levels of microsatellite instability (MSI-H), a hallmark of Lynch syndrome. CpG hypermethylation of DNA could activate or silence the expression of certain genes, BRAF and MLH1 respectively. Sporadic oncogenes somatic mutations (RAS, SRC, MYC) have been implicated in CRC, being RAS the most clinical relevance. RAS mutations variants (HRAS, KRAS, NRAS) are found in 50% of CRC sporadic cases, currently being exploited on CRC screening by stool-DNA testing, the absence of epidermal growth factor receptors (EGFR) targeted therapy response and potential direct targeted agents. In the other hand, tumor suppressors genes require bi-allelic loss ("two-hit model") and are described in loss of APC 5q21 gene (80% sporadic), TP53 17p gene (50-70% sporadic), and DCC/SMAD2-4 18q gene (73% sporadic). Specific MMR gene mutations could occur in hMSH2, hMLH1, hPMS1 and hPMS2, hMSH6, and hMLH3; each one of them that interact with MLH1 and approximately found in 15% of all sporadic CRC causing a Lynch-like syndrome with MSI-H calling for universal testing. MUTYH defects have a recessive inheritance pattern at a time requiring bi-allelic second hit or in conjunction with APC gene mutation. Cyclooxygenase (COX-2) and peroxisome proliferator–activating receptor (PPAR) genes have been implicated in CRC tumorigenesis currently under investigation for chemo-protection.
The majority of all CRC are carcinomas, and more than 90% of those are adenocarcinomas and others not frequently seen (adenosquamous, spindle, squamous and undifferentiated). CRC adenocarcinoma can be further differentiated in cribriform comedo-type, medullary, micropapillary, serrated, mucinous and signet-ring cell. Adenocarcinomas are categorized by the percentage of gland formation into well (more than 95%), moderately (more than 50%) and poorly (less than 49%) differentiated, but further divided in two-tier low-grade (well-moderate)/high-grade (poor) with prognostic significance. Mucinous or signet ring cells classification describe that more than half of the stain cells posses that particular characteristic. Differential clinicopathological diagnosis is neuroendocrine, hamartomas, mesenchymal, and lymphomas. Cytokeratin 20 (CK20) and caudal-type homeobox 2 (CDX2) immunohistochemistry (IHC) can accurately identify CRC adenocarcinoma origin, except medullary carcinoma with MSI-H expressing other markers such calretinin, CK7, SABT2, and CDH17.
The tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 2017 is the preferred staging system for CRC. Worth noticing, peritoneal carcinomatosis (M1c) and nodal micrometastases (cluster greater than 0.2 mm) are included as poor prognostic factors. Other prognostic indicators that the classification continues to exclude are extramural deposits, lymphovascular invasion (LVI), perineural invasion (PNI), poor histological grade, diagnostic serum CEA, MSI-H and RAS/BRAF mutation status. The most important prognostic indicator is the pathological stage at presentation supported by data from the SEER observed overall survival (OS) at 5-years rates for colon in stage I includes 74%; stage IIA, 66%; stage IIB, 58%; stage IIC, 37%; stage IIIA, 73%; stage IIIB, 46%; stage IIIC, 28%; and stage IV, 5%.
Complete surgical resection (R0) with all negative circumferential resection margins (CRM) is an important goal to avoid local-distant recurrence (38% CRM+ versus 10% CRM-) and furthermore increase survival. Lymph node involvement is the strongest outcome predictor and the total number resected directly influence prognosis on Stage II (node-negative) and Stage III (node-positive) disease. The current guideline recommends a minimum of 12 nodes surgical resection. Lymph node ratio from the INT-0089 trial showed a 5-year overall survival (OS) of 80% with less than 0.05 LNR versus 50% more than 0.4 ratio. LVI, PNI, poor histological grade, T4, bowel perforation and insufficient node sampling (<12) are consider a high-risk feature of stage II Cca according to the American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO), supporting the use of adjuvant chemotherapy.
The NCCN and the College of American pathologists among other associations recommend universal MMR/MSI status (15% to 20% sporadic CRC), BRAF p.V600 E (less than 10% sporadic CRC) and RAS mutational (12% to 75% sporadic CRC) testing for prognostic and predictive of chemotherapy efficacy. hMLH1 and hMSH2 IHC provides a high sensitive (92.3%), and specific (100%) method, and positive (96.7%)/negative (100%) predictive value method for screening for MMR/MSI status. MSI-H is synonymous with dMMR, and MSI-Stable will refer to proficient MMR state. The prevalence of MSI-H in CRC is about 15% in stage II, 8% in stage III, and 4% to 5% in stage IV. BRAF gene mutation testing is indicated after a negative MLH1 IHC indicating MLH1 gene down-regulation through somatic methylation.
Recently, six independent classification systems coalesced into four consensus molecular subtypes (CMSs) with distinguishing features:
CMSs classification had a prognostic value, CMS1 good, CMS4 poor and CMS2/3 intermediate.
Most all CRC will present by diagnostic colonoscopy for suspicious signs and symptoms (80%), asymptomatic, routine screening (11%), or incidental finding at an acute abdomen emergent admission (7%). Patients diagnosed with routine cancer screening are frequently earlier stage compared to advanced disease of incidental surgical findings. Diagnostic colonoscopy's triggers are blood per rectum (37%), abdominal pain (34%) and anemia (23%). Most common indications of emergency surgery are an obstruction (57%), peritonitis (25%) and perforation (18%). Tumor location on clinical presentation can be separated on left-sided with more changes in bowel habits and hematochezia, and right-sided with obscured anemia impacting on late stage at diagnosis. Late presentation with metastatic disease at diagnosis will depend on the symptoms at the organ-affected by the route of spread; to the liver via the portal system, to lungs via the inferior vena cava, to supraclavicular adenopathy via lymphatic or to neighbor structures by contiguous invasion. The provider should perform a thorough physical examination for signs of ascites, hepatomegaly, and lymphadenopathy. A comprehensive family history is of great relevance to identify familial clusters and inherent patterns that would alter surveillance and therapy on the high-risk patient.
Initial evaluation may involve barium enema or CT colonography, but ultimately a colonoscopy is required for tissue biopsy.[14][15][16] Colonoscopy sensitivity is about 94.7% (95% CI 90% to 97%) and may miss from 2% to 6% of cases, mostly right-sided, pending on preparation quality and hands experience. Flexible sigmoidoscopy is no replacement for a complete diagnostic colonoscopy, still is a screening modality that reduces CRC mortality. The Federal Drug Administration (FDA) has approved PILLCAM 2 for those non-obstructed patients with incomplete colonoscopy, and not for routine screening. CRC screening modalities and recommendations for average or high-risk patients are discussed in a different StatPearls chapter. Routine laboratory workup with complete blood count, iron studies, basic metabolic panel, liver function test and coagulation tests are not diagnostic but often useful. CEA greater than 5 ng/mL has a poor prognostic value when present, but lacks diagnostic sensitivity 46% (95% CI 0.45 to 0.47) and has limited specificity 89% (95% CI 0.88 to 0.92). Pre-operative CEA is indicated on all newly diagnosed Cca, normalization after surgical resection is expected and serial assays to be monitored on follow up visits.
Baseline CT of the chest, abdomen, and pelvis with IV and oral contrast is the preferred cost-effective staging imaging study before Cca surgical resection. CT abdomen and pelvis provides a moderate strength initial assessment of accurately staging T (50%) and N (73%) but rather provide immediate higher sensitivity for distant metastasis (87%). CT chest remains controversial, as 9% will show indeterminate lesions, of that 11% represented metastatic lesions. MRI and CT triple phase imaging have improved the detection of liver metastasis. Positron emission tomography (PET) is not routinely indicated on the preoperative staging of Cca. Biopsy of the suspicious metastatic site should be performed to confirm the diagnosis.
Surgical resection is the main treatment modality for localized non-metastatic stage Cca at any age with acceptable performance status and optimized comorbidities. Endoscopic resection (ER) is reserved for selected favorable-risk and early-stage colon carcinomas found in a polyp (cT0-1). Neoadjuvant therapy is not standard of care for Cca and reserved for advanced disease surgical conversion intend. Adjuvant therapy is recommended for all Cca stage III (node-positive) and individualized by stage II with high-risk features. Surgery in conjunction with peri-chemotherapy may provide a curative option on oligo-metastatic lung and liver disease. [17][18][6]Palliative systemic chemotherapy is offered to non-surgical candidates with unresectable locally advanced disease or high metastatic burden to improved quality of life and prolongs life expectancy. Individualized local-recurrent disease patients may achieve cure with further multimodality therapy. Rectal cancer treatment modalities are discussed in a different StatPearls chapter.
Endoscopic Resection
Local excisions by endoscopy should achieve complete tumor resection and adjacent tissue in one block. ER is reserved for patients agreeable to a close, aggressive surveillance afterward, a surgical resection for high-risk disease and/or non-surgical candidates. ER procedures are to be an offer by an experienced physician at the center of excellence. Invasion of muscularis propia (T2), poor histological grade, LVI, PNI, at the stalk or flat/depressed sessile polyp are considered ER, Cca, high-risk features and further need surgical resection. Cca polyp techniques include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) with high success rate 90.3% (95% CI 88.2% to 92.5%) and a low recurrence 13.8% (95% CI 12.9% to 14.7%), being an invasive cancer in 0.3% (95% CI 0.1% to 0.4%) on favorable risk patients. Major complications are perforation and bleeding with 6.5% and 1.5% respectively and extremely low-mortality 0.8% (95% CI 0.01% to 0.15%). Regardless of the procedure, all lesions should be tattooed to allow site identification on further required steps.
Surgical Resection
The main goal for invasive Cca is the complete resection of the tumor and potential lymphovascular spread by a goal of a minimal negative proximal and distal margin of 5 cm for colon cancer, and minimal proximal margin of 5 cm and distal of 2 cm for rectal carcinoma. Circumferential/radial margin should be greater than 1 mm. The essentials of oncologic resection involve central vascular ligation of the feeding main artery and complete mesocolic resection of the involved colonic section. Oncologic resection requires removal of 12 or more lymph nodes. The initial step for colectomy is accessing the retroperitoneum and elevating the mesentery of the colon contained within the fascia of Toltd. In laparoscopic procedures, this dissection is started medial to lateral fashion, but in open procedures, this dissection is done lateral to medial way. A secondary aim is the restoration of the bowel continuity, either by one-stage primary anastomosis or two-stage approach with temporary diversion. Conventional open colectomy or laparoscopic colectomy is the preferred surgical modality. High-volume, experienced surgeons should perform the laparoscopic approach. Experience with robotic surgery is under further investigation. Potential palliative surgical procedures for unresectable Cca tumors include resection with primary anastomosis, diverting colostomy, and internal bypass procedures.
Tumors of the appendix, cecum, ascending colon, and hepatic flexure requires right colectomy with ligation of the right colic artery at its origin. The right branch of the middle colic artery and ileocolic artery are also ligated. This procedure is completed with ill -mid-transverse colon anastomosis. Transverse colon cancers require extended right colectomy due to the ease of the procedure when compared to extended left colectomy. Extended right colectomy also involves the ligation of the middle colic artery at its origin in addition to steps involving right colectomy. This procedure is completed with ileac-descending colon anastomosis.
Patients with a distal transverse colon, splenic flexure, and descending colon cancers require left colectomy. This procedure involves the ligation of the inferior mesenteric artery at its origin, as well as ligation of the inferior mesenteric vein at the inferior border of the pancreas. The left branch of the middle colic artery is also ligated. This procedure if completed with transverse colon sigmoid or rectal anastomosis. Patients with sigmoid colon cancers undergo extended left colectomy with colorectal anastomosis.
Patients with synchronous colon cancers (two or more foci) involving the intra-abdominal colon, with distal malignant distal colonic obstruction, with Lynch (HNPCC), and with attenuated FAP should undergo total abdominal colectomy; including cecum, ascending, transverse, descending and sigmoid colons. Therefore this procedure involves ligation of ileocolic, right and middle colic, and inferior mesenteric arteries. This procedure is completed with ileorectal anastomosis.
Meta-analysis of randomized clinical trials (including COLOR trial, CLASSIC trial, and COST trial) indicates that laparoscopic-assisted colectomy surgery for Cca provides the same outcomes for 5-year overall survival (OS) (69% versus 68%) and disease-free survival (DFS) (76% versus 75%) as open laparotomy. Reported conversion rates from laparoscopic to open remains at 20% as described in the United States Intergroup Clinical Outcomes of Surgical Therapy (COST) trial. Positive margins have been retrospectively found in 5.3% of Cca resection with a worse OS (hazard ratio [HR] 3.39, 95% CI 2.41 to 4.77). Sentinel lymph node biopsy is not considered a standard of care and consensus guidelines recommend 12 lymph nodes or more with improved 5-year OS at 90% regardless open or laparoscopic approach. Locoregional recurrence can occur up to 12% of Cca resection and is classified into four categories: anastomotic; mesenteric/nodal; retroperitoneal; and peritoneal. Poor prognostic factors include more than one site of recurrence and involvement of the mesentery/nodal basin whereas the ability to obtain an R0 resection was the strongest predictor of outcome, and these patients had a median survival of 66 months.[19]
Surgery alone can be curative for patients with stage I disease. For stage III disease (node-positive), the 5-year survival rate is 20% to 50% with surgical resection alone thus adjuvant therapy is recommended. For patients with stage II disease, the 5-year survival fluctuates between 50% and 65%. Factors other than the stage adversely affect the outcome. These include old age, male gender, performances status, pMMR/MSI-S status, LVI, PNI, pre-operative CEA level greater than 5, poor histological grade, mucinous or signet ring features, the extent of local invasion T4, bowel perforation/obstruction, and insufficient node sampling less than 12. Mutations in KRAS and BRAF have not shown to be a negative prognostic impact in the adjuvant setting. Adjuvant therapy for stage II with high-risk features should be individualized.[20][2][3][21][22]
Adjuvant Therapy
There is no role for adjuvant chemotherapy for patients with Cca stage I. Low-risk stage II Cca patients can opt for surveillance without adjuvant therapy, individualized discussion with medical oncology or enrolled in a clinical trial. Current ASCO, NCCN and ESMO guidelines strongly recommend adjuvant therapy for selected stage II with high-risk/pMMR/MSI-S disease and all stage III (node-positive). For adjuvant therapy Cca, 3-year DFS is an acceptable surrogate marker for 5-year OS recognized by the FDA based on the results of the Adjuvant Colon Cancer End Points study group (ACCENT trial). Guides advocate delivering adjuvant chemotherapy within 6 to 8 weeks of surgical resection pending on patient health recovery. A meta-analysis demonstrated that a 4-week beyond the time to adjuvant chemotherapy was associated with a significant decrease in both overall survivals (HR, 1.14; 95% CI, 1.10-1.17) and disease-free survival (HR, 1.14; 95% CI, 1.10-1.18). An oxaliplatin-based combination is preferred over monotherapy either by FU/LV (MOSAIC trial, NSABP C-07 trial) or capecitabine (XELOXA trial). The standard recommended length of adjuvant therapy is six months and a potentially non-inferiority three months is under current investigation by the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial for low-risk patients or oxaliplatin dose-limiting neurotoxicity. The recommendation is to use full weight-based chemotherapy dosing particularly on those with the intention to cure.[23][24][25]
Adjuvant fluorouracil-based chemotherapy became a standard of care in stage III Cca in the early 1990s by the first randomized clinical trial, the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01, to achieve a significant improvement in DFS and OS. Evidence from a subsequent NSABP C-03 trial demonstrated that fluorouracil (5-FU) combined with leucovorin (LV) provided a superior DFS and OS at three years with six months of adjuvant therapy over NSABP C-01 lomustine, vincristine, and 5-FU. For more than a decade, 5-FU/LV remained the standard in adjuvant therapy until oxaliplatin, irinotecan, and capecitabine (oral FU pro-drug) based combinations were utilized for the treatment of advanced CRC.
Oxaliplatin was approved as part of adjuvant treatment for stage III Cca after the 2004 MOSAIC trial. Investigators randomly assigned patients who had undergone curative colon resection for stage II (40%) or III (60%) to receive FU/LV alone (LV 200 mg/m as a 2-hour infusion, followed by bolus FU 400 mg/m, and then a 22-hour infusion of FU 600 mg/m, every 2 weeks) or with oxaliplatin (FU/LV plus 85 mg/m day 1 every 14 days, a regimen termed FOLFOX4) for 6 months. Adding oxaliplatin (FOLFOX4) significantly improved 5-year DFS rates to 73.3% versus 67.4% FU/LV group, [(HR)= 0.80; 95% CI, 0.68 to 0.93; P = .003] and 6-year OS rates were 78.5% and 76.0% in the FOLFOX4 and FU/LV groups, respectively (HR = 0.84; 95% CI, 0.71 to 1.00; P = .046). Stratified, 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR = 0.80; 95% CI, 0.65 to 0.97; P = .023) but no significant difference in OS was seen in the stage II population. A 10-year OS long-term follow up results corroborated before mentioned trend results. Neuropathy was seen 92% of FOLFOX4 patients, being 13% severe grade and almost all reversible. The United States oncologists had made further modifications to the regimen including FOLFOX6 (single day regimen) and FOLFOX7 (no FU bolus). In a retrospective review of unselected patients with stage II disease, the 5-year DFS benefit for FOLFOX compared with FU/LV alone was no statistically significant (84% versus 80%, HR for recurrence 0.84, p = 0.26), but it significantly exceeded 5% for patients (82% versus 77%) on stage II tumors with high-risk clinical features (poor histological grade, T4, perforation/obstruction, less than 10 lymph nodes sampling, PNI, and LVI).
In 2011, two other trials confirmed the value of oxaliplatin-based regimen as a component of adjuvant chemotherapy for stages II and III colon cancer above FU/LV monotherapy. The NSABP C-07 phase III clinical trial evaluated the impact on DFS of adding oxaliplatin to bolus weekly FU combined with LV as surgical adjuvant therapy for stage II (29%) and III (71%) Cca patients. After intent of curative resection, patients were randomly assigned to either FU (500 mg/m2 IV) bolus weekly for 6 weeks plus LV (500 mg/m2 IV) weekly for 6 weeks during each 8-week cycle for three cycles (FU/LV), or the same FU/LV regimen with oxaliplatin (85 mg/m2 IV) administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). In the NSABP C-07 trial, the 8-year OS was similar between treatment groups (HR, 0.88; 95% CI, 0.75 to 1.02; .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; .002). The effect of oxaliplatin on OS did not differ by stage of disease (II versus III = 0.38 for OS; 0.37 for DFS) but did vary by age (less than 70 versus greater than 70 0.39) with a similar trend for DFS (p = 0.073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was seen in older patients. FLOX regimen was associated with higher hospitalization for diarrhea (5.5% versus 3%), and a total of 1.2% of patients died of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens.
The XELOXA trial, a multicenter, randomized trial compared capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant therapy for patients with stage III Cca. Patients were randomly assigned to XELOX (O: 130 mg/m(2) on day 1 plus X: 1000 mg/m(2) twice daily on days 1 to 14 every 3 weeks for 24 weeks) or the standard bolus FU/LV adjuvant regimen. XELOX improved DFS and OS compared with bolus FU/LV in patients with resected stage III Cca after a median follow-up of almost 7 years (DFS 63% versus 56%, HR, 0.80; 95% CI; 0.69; 0.93; p = 0.0045 and OS 73% versus 67%, HR, 0.83; 95% CI, 0.70 to 0.99; P = .04). XELOX was associated with more neurotoxicity, hand-foot syndrome, and thrombocytopenia. Patients on capecitabine are recommended not to take proton pump inhibitor due to poor absorption of higher gastric pH. Another trial established that six months of oral capecitabine monotherapy is a safe and equally effective alternative to conventional FU/LV for stage III colon cancer.
There is a role for adjuvant chemotherapy for selected patients with stage II high-risk disease. The largest study of Stage II Cca, the UK QUick And Simple And Reliable (QUASAR) trial randomly assigned non-stratified patients (e.g., high-risk and low-risk) to have FU/LV with or without levamisole (later removed) as adjuvant chemotherapy following surgical resection. The relative risk (RR) of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70 to 0.95; p=0.008) and for recurrence RR 0.78 (0.67-0.91; p=0.001) after ten years follow-up. Although the absolute improvement in survival with FU/LV was 3.6%, the quality of the trial has been question due to a poor median of 6 lymph node dissection (greater than 60% with less than 12 lymph nodes), a group of patients received radiation therapy (14%) or portal infusion chemotherapy (6%), which does not meet current standards. The ACCENT retrospective analysis has demonstrated a trend toward an improved of 10-year DFS and OS for stage II with chemotherapy compared to observation regardless of the risk feature with high-risk disease (51% versus 35%). The identification of high-risk prognostic factors might help distinguish patients at higher risk of relapse which will more likely benefit from adjuvant therapy. Datasets confirmed that patients with stage II Cca without high-risk features and MSI-H/dMMR have an excellent prognosis and do not need to be treated with adjuvant chemotherapy, but remains uncertain for those with high-risk disease.
Irinotecan-based regimens are effective in palliative therapy for advanced CRC, but for unknown reasons, none of the three major phase III trials (CALGB89803, PETACC-3, ACCORD) using combination regimens of irinotecan plus FU/LV has demonstrated to be significantly superior in 3-year DFS when compared with FU/LV alone. The role of novel targeted agents, bevacizumab (antibody against VEGF) and cetuximab (antibody against EGFR), have been investigated in the adjuvant setting in large phase III trials. Three major trials have failed to demonstrate any benefit of adjuvant bevacizumab with FOLFOX (NSABP C-08), XELOX (AVANT) or Capecitabine (QUASAR2). Cetuximab was also tested as a component of adjuvant therapy in stage III Cca added to FOLFOX backbone, unfortunately, failed to improve outcome even on preselected KRAS wild-type tumor, and was detrimental to KRAS-mutated patients. Cetuximab lack of efficacy was later confirmed in the PETACC-8 trial on patients with RAS and BRAF wild-type stage III Cca.
Based on prior clinical trial results, the standard adjuvant chemotherapy for stage III Cca is an oxaliplatin-containing regimen (FOLFOX, XELOX, FLOX) administered for six months. Capecitabine or FU/LV monotherapy should be reserved for patients who are not considered optimal candidates for oxaliplatin (e.g., pre-existing neuropathy). Stage III Cca patient with MSI-high/deficient-MMR tumors are intrinsically resistant to adjuvant FU monotherapy, requiring the addition of oxaliplatin to overcome the resistance and impact outcomes. Patients with Stage II Cca and any high-risk combination should discuss risk and benefit of adjuvant therapy. Retrospective analysis from trials did not document a significant improvement with the addition of oxaliplatin to 5-FU/LV for patients over age 70, and only younger patients had a statistically significant benefit regarding DFS, OS, and time to tumor recurrence. At this point in time, irinotecan-based and targeted therapies have no indication in the adjuvant therapy of Cca outside of investigational trials. There is no conclusive evidence to recommend standard RT alone or combined CRT in the adjuvant setting. There are two web-based validated tools to calculate the relative risk of disease recurrence and mortality based on clinicopathological features and potential adjuvant benefit (an ACCENT by the Mayo Clinic and Adjuvant! Online). Furthermore, gene profiling by Oncotype DX Colon, ColDX or ColoPrint are currently available in clinical practice to assist in risk assessment but has no valid predictive value t, thus not recommended by clinical practice guidelines.
Neoadjuvant Therapy
The role of pre-operative chemotherapy for patients with Cca is currently on a phase III FOxTROT trial (NCT00647530) after promising results of their pilot study. The Foxtrot collaborative group randomized locally advanced resectable (T3 greater than 5 mm invasion beyond muscularis propia and T4) candidates to 3 preoperative cycles of FOLFOX (O; 85 mg/m(2), LV; 175 mg, FU; 400 mg/m(2) bolus, then 2400 mg/m(2) by 46 hour infusion), surgery and nine additional cycles or surgery and 12 adjuvant cycles. Findings favored neo-adjuvant therapy with a tumor regression (31% versus 2%), node-positive (1% versus 20%) and negative margins (4% versus 20%) resulting in a significant downstaging (p=0.04).
Systemic Therapy
More than half of all CRC patients will develop metastasis and the majority to the liver (80% to 90%). The prognosis for advanced non-resectable and metastatic CRC patients with best supportive care is poor by a mOS 5 to 6 months, except for a subset of patients with oligo-metastatic hepatic or pulmonary patient that are potentially curable with peri-operative chemotherapy. The goals of systemic therapy for advanced non-resectable and metastatic CRC of therapy are palliation of symptoms, improvement of the quality of life and prolong survival. Systemic therapy for cancers of the colon and rectum are addressed jointly by clinical research and practice. In the 1990s, FU/LV monotherapy was the standard first-line therapy with an approximately mOS 12 months. It was until the early 2000s that the addition of oxaliplatin and irinotecan to the backbone of FU/LV resulted in an improvement of mOS to nearly 24 months. The introduction of biologic agents monoclonal antibodies (MAbs) targeting vascular endothelial growth factors (VGFRs) and epidermal growth factors receptor (EGFR) further enhanced the efficacy of systemic medical therapy with mOS reaching 36 months and when exposed to multiple lines of therapy an impressive 20% 5-year OS even at a metastatic stage.
Current availability of nine different antineoplastic classes and more than a dozen drug options fluoropyrimidines (FU), capecitabine (CAP), S-1, tegafur plus uracil (UFT), irinotecan, oxaliplatin, anti-EGFRs (cetuximab, panitumumab), anti-VEGFRs (bevacizumab, ramucirumab), recombinant fusion protein (aflibercept), tyrosine kinase inhibitors (regorafenib), antimetabolites (TAS-102), immunotherapy (nivolumab, pembrolizumab) for mCRC has resulted in an abundance of therapeutic possibilities with different combinations and sequences not yet established. The most appropriate treatment regimen is conceivably the one that generates the highest overall response rate (ORR), greatest impact to metastases for surgical conversion and/or ultimately offers the longest PFS and OS, balanced with a favorable toxicity profile. Predictive biomarker (RAS/BRAF type and MMR/MSI status), primary location (tumor and metastasis), patient (performance status and comorbidities) and therapy goals (palliate or conversion) can help guide treatment decisions for specific patient subpopulations.
For otherwise healthy candidates, the standard first-line treatment approach is to start with a FOLFOX, CAPOX or FOLFIRI regimen plus anti-EGFR (cetuximab or panitumumab) when the tumor is RAS/BRAF wild-type and left-sided or anti-VGFR (bevacizumab) when the tumor is RAS/BRAF mutated or right-sided. At progression of disease or unacceptable toxicity switch to the opposite second-line regimen with either continuation of prior anti-VGFR or new biological agent regardless of the tumor location. ASCO, ESMO, and NCCN recommend comprehensive testing of KRAS, NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), 4 (codons 117 and 146) and BRAF V600E for anti-EGFR candidates based the results of the Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) trial and other major meta-analyses. Biological agents additions to chemotherapy backbone have significantly improved ORR, DFS, and OS in the first and second-line setting. Cetuximab and panitumumab have comparable efficacy in first, second line addition and even single agent salvage therapy, but may share cross-resistance limiting use after progression of anti-EGFRs. Bevacizumab can be continued beyond progression of first-line to second-line therapy (e.g., RAS/BRAF-mutated) but not in conjunction with the new anti-EGFRs candidate (e.g., RAS/BRAF wild-type and left sided). For patients who progressed anti-VEGF bevacizumab may consider aflibercept or ramucirumab addition to backbone chemotherapy regimen.
Sequential single agents remains a valid option for mCRC patients compared to combination treatments demonstrated in the United Kingdom Medical Research Council's FOCUS (Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing) and the Dutch Colorectal Group CAIRO (capecitabine, irinotecan, oxaliplatin) trials, although biological agents were not used on both trials, and most of all patients did not receive all three drugs. Multiple phase III trials have confirmed similar ORR, PFS, and OS between FOLFOX and FOLFIRI regimens, even with added anti-VEGFs or anti-EGFRs. In clinical practice, the choice between FOLFOX and FOLFIRI is based on treatment toxicity profile. CAPOX combination is a statistically non-inferior substitute to FOLFOX regimen in PFS and OS with tolerable toxicity profile; conversely, XELIRI had shown higher intolerable rates of gastrointestinal toxicities. Maintenance therapy with low dose capecitabine-bevacizumab after the first-line FOLFOX-bevacizumab good response is an accepted treatment option based on CAIRO3 trial results. Complete discontinuation of chemotherapy may be detrimental and remains controversial, but intermittent therapy has not resulted in significant reduced OS but the rather better quality of life.
FOLFOXIRI with or without bevacizumab is reserved for conversion approach in potential resectable liver/lung metastasis on selected excellent performance status patients. Patients not fit for triple or doublet therapies, consensus-based guidelines recommend FU/LV IV or capecitabine PO monotherapy. For patients after FOLFOX, CAPOX, FOLFIRI, anti-VEGFs and anti-EGFRs agent progression that remains eligible for further chemotherapy may consider regorafenib or TAS-102 salvage therapy, or alternative, immunotherapy is approved for MSI-H/dMMR tumors. Novel targeted agents may be available through clinical trials at different lines of therapies failure.
Recommended treatment monitoring consists of close observation of signs/symptoms of adverse reaction (before each treatment cycle and as needed), frequent checking on blood work parameters (before each treatment cycle and as indicated), CEA levels serial assays (every 1 to 3 months) and radiographic evaluation by Response Evaluation Criteria In Solid Tumors (RECIST) (every 2 to 3 months) by a multidisciplinary team. Patients should frequently be screen for somatic symptoms and psychosocial distress.
Selected Landmark Clinical Trials
Cytotoxic Chemotherapy
Fluorouracil-Leucovorin (FU/LV): An updated-meta analysis compared to FU-alone resulted in higher ORR (21% versus 11%) and 1-year OS (47% versus 37%) favoring FU/LV. The two most commonly used regimens in the United States include the Mayo regimen (bolus FU: 425 mg/m2 and LV: 20 mg/m2 on days 1 to 5 every 4 to 5 weeks) and the Roswell Park regimen (Bolus FU: 500 mg/m2 and LV: 500 mg/m2 administered weekly for 6 out of 8 weeks). Further improved by the de Gramont regimen (LV: 200 mg/m2 as a 2-hour infusion followed by bolus FU: 400 mg/m2 and 22-hour infusion FU: 600 mg/m2 for 2 consecutive days every 2 weeks) with significantly better ORR (33% vs 14%), PFS (7 versus 5 months) and OS (15.5 versus 14.2 months) with significantly less grade 3/4 toxicities (23.9% vs 11.1%) compared to the Mayo regimen.
Capecitabine (CAP): A phase III clinical trial by Hoff PM et al. prospectively randomly assigned patients to oral CAP (1250 mg/m2 twice daily for 14 days every 21 days) or FU/LV (the Mayo regimen) resulting in non-inferior ORR (24.8% versus 15.5%), time to progression (TTP 4.3 versus 4.7 months) and mOS (12.5 versus 13.3 months), respectively. Common side effects of CAP included diarrhea (overlapping toxicities with irinotecan), hyperbilirubinemia and hand-foot syndrome. CAP has never been directly compared with infusional FU/LV (de Gramont regimen), CAPOX versus infusional FOLFOX has shown to be of similar efficacy in the treatment of advanced CRC, as shown by the phase TREE-1 trial and AIO trial. In the United States clinical practice, dose-reducing CAP by about 20% (1000 mg/m2) alone or in combination regimens does not appear to decrease the treatment efficacy, but it greatly improves the side effect profile of the treatment. Other alternative oral fluoropyrimidines not approved in the United States include S1-derived three different agents tegafur-uracil, gimeracil and oteracil, and raltitrexed.
Irinotecan (IRI): In a landmark phase II clinical trial, patients with FU-refractory mCRC were randomly assigned either single-agent IRI (300 mg/m2 every 3 weeks) or BSC, showed a significant 1-year OS (36% versus 14%) with improved quality of life (performance status, weight loss, and pain-free), respectively. Following this, three key trials were conducted to test the role of IRI versus FU/LV in the front-line setting. A three-arm trial compared three treatment regimens: the Roswell Park regimen, IRI plus FU/LV weekly bolus regimen (IFL or Saltz regimen); and IRI alone.
The results of the trial significantly favored IFL with an ORR (39% versus 21%) and mOS (14.8 versus 12.6 months). In Europe, three pivotal phase III trials compared the FU/LV regimens to FOLFIRI regimens (the Douillard regimen-IRI: 180 mg/m2 on day 1, FU: 400 mg/m2 bolus followed by 600 mg/m2 over 22 hours, both on days 1 and 2, and LV: 200 mg/m2 on days 1 and 2). The Douillard FOLFIRI regimen trial demonstrated a significant ORR (49% versus 31%), TTP (6.7 versus 4.4 months) and extended mOS (17.4 versus 14.1 months). Higher side effects of irinotecan-group were diarrhea, myelosuppression, and alopecia. Of note, IRI combinations require an adequate biliary function for its active glucuronide metabolite, SN-38, be excreted. Approximately 10% of United States patients are homozygous for the UGT1A1*28 allele polymorphism increasing SN-38 bioavailability and therefore recommended starting with a lower dose of irinotecan.
Oxaliplatin (OXA): OXA has very limited activity in CRC as a single agent thus not recommended unless synergist with fluoropyrimidines. In phase III trial, FU/LV (de Gramont regimen) was compared with or without OXA (OXA: 85 mg/m2 on day 1 over 2 hours FOLFOX4 regimen) as first-line therapy for patients with mCRC. FOLFOX4 regimen had significantly higher ORR (51% versus 22%), PFS (9 versus 6 months) but comparable mOS (16.2 versus 14.7 months) with more grade 3/4 neutropenia, diarrhea, and neurotoxicity. Because no overall survival benefit was achieved in these first-line trials, the FDA did not approve OXA for CRC until years later for second-line therapy that showed prolonged PFS and increased ORR compared with FU/LV for patients who experienced disease progression while receiving first-line IRI-regimens. The most important side effect and dose-limiting toxicity of OXA is neurotoxicity. It may present as an acute and reversible, cold-triggered sensory neuropathy, or a chronic dose-limiting cumulative sensory neurotoxicity.
Irinotecan versus Oxaliplatin-based regimens: After encouraging results of previous trials conducted in the United States and Europe using OXA and IRI, the North Central Cancer Treatment Group (NCCTG)/Intergroup trial N9741 performed a pivotal and practice-changing trial comparing FOLFOX4, the standard combination IFL and new IROX combination (OXA:85 mg/m plus IRI 200 mg/m, both on day 1 every 3 weeks). The N9741 results demonstrated the superiority of FOLFOX compared with IFL and IROX as first-line therapy for mCRC with ORR (45% versus 31% versus 36%), PFS (8.7 versus 6.9 versus 6.7 months) and mOS (19.5 versus 15 versus 17.3 months), respectively. The toxicity profile likewise favored FOLFOX, except for neurotoxicity. FOLFOX emerged as new standard first-line therapy with rapid and widespread adaptation in the United States.
VEGF Inhibitors
Bevacizumab (BEV): In randomized placebo-controlled phase III trial, IFL plus BEV (5 mg/kg every 2 weeks) was assessed in first-line therapy for mCRC. For the first time, the addition of an anti-VEGF inhibitor was validated as an efficacious antineoplastic treatment by significantly improving ORR (45% versus 35%), PFS (10.6 versus 6.2 months), and mOS (20.3 versus 15.6 months). This trial was the first phase III validation of an antiangiogenic agent as an effective treatment option in human malignancy. Subsequently, FOLFOX-BEV also showed to improve mOS in first-line (TREE-2 trial 23.7 versus 18.2 months) and second-line (ECOG 3200 trial 12.9 versus 10.8 months) settings. The AVEX phase III trial selected patients age 70 or older, who were not deemed to be candidates for OXA or IRI-based chemotherapy first-line regimens, to receive CAP regimen alone or with BEV (7.5 mg/kg intravenously on day 1 given every 3 weeks). The study showed a significantly longer mPFS (9.1 versus 5.1 months) and a remarkable improvement in mOS (20.7 versus 16.8 months) for CAP-BEV than with CAP alone, respectively. Prolonged VEGF inhibition with BEV beyond the first-line progression was evaluated by the European TML (ML18147) phase III trial, which randomly assigned to progression within three months to either continue second-line with or without BEV. The mOS, primary endpoint of the study, favored BEV-chemotherapy based continuation 11.2 months versus 9.8 months chemotherapy alone. This effect was confirmed in PFS (5.7 versus 4.1 months) but not in ORR (4% versus 5%). The toxicity profile observed with BEV consists of hypertension, bleeding, gastrointestinal perforations, impaired wound healing and arterial-venous thrombotic events.
Aflibercept (AFL): AFL was evaluated in the second-line setting among patients who had all progressed OXA-based with or without BEV first-line chemotherapy by the placebo-controlled phase III VELOUR trial. Patients randomly selected to receive FOLFIRI with AFL (4 mg/kg IV every 2 weeks) had a significant improvement in ORR (19.8% versus 11.1%), PFS (6.9 versus 4.7 months and mOS (13.5 versus 12.1 months).
The aflibercept arm toxicity profile had an intensified rate of grade 3/4 diarrhea, mucositis, neutropenia, infection, and fatigue plus hypertension, proteinuria, hemorrhage, and arterial-venous thromboembolic events, usually seen in FOLFIRI-BEV second-line.
Ramucirumab (RAM): In a double-blind placebo-controlled phase III RAISE trial, the addition FOLFIRI-RAM (8mg/IV every two weeks) as second-line therapy for patients progressing with a FOLFOX-BEV improved PFS (5.7 versus 4.5 months) and mOS (13.3 versus 11.7 months). Grade 3/4 neutropenia, hypertension, diarrhea and fatigue was worse on the combination arm.
Anti-EGFR Monoclonal Antibodies
Cetuximab (CET): CET monotherapy (400 mg/m2 followed by a weekly infusion of 250 mg/m2) for patients who had experienced disease progression on prior FU, OXA and IRI-based therapy had an improved ORR (40% vs. 11%) and mOS (6.1 versus 4.6 months) compared to BSC. The EPIC and BOND trials proved PFS and ORR superiority of IRI-CET over IRI-alone on patients with prior IRI failure, without significantly improving survival. A large multicenter randomized phase III CRYSTAL trial, FOLFIRI with or without cetuximab in treatment naïve CRC patients, confirmed that selected KRAS wild-type patients have a significantly higher ORR, PFS, and mOS (23.5 versus 20 months). The benefit of FOLFOX-CET remains uncertain with three trials (OPUS, CALBG 80203, CALBG 80405) showing modest significant ORR and PFS improvements but no mOS benefit, and three other trials (MRC COIN, NORDIC VII, New EPOC) with no resulted benefit. CET arm had higher-grade diarrhea, magnesium-wasting syndrome, infusion reaction and ocular-skin toxicity, last correlated to response rate.
Panitumumab (PAN): Single-agent PAN (6 mg/kg every 2 weeks) was compared to BSC in a large international phase III trial in chemotherapy-refractory mCRC patients. PAN had an ORR (37% similar to CET) and modest prolonged mPFS (8 versus 7.3 weeks), but mOS was not increased likely because crossed over from BSC to the PAN arm. The ASPECCT phase III trial compared head-to-head PAN versus CET monotherapies on chemotherapy-refractory patients and showed non-inferior mOS (10 months) with similar expected toxicity profile. FOLFOX4-PAN benefit in first-line setting was seen in phase III PRIME trial with mPFS improvement (9.6 versus 8 months) and trend for mOS (23.0 versus 19.7 months) not significant at 55 weeks follows up.
VEGF Inhibitors Versus Anti-EGFR Monoclonal Antibodies
The FIRE-3 trial recruited treatment naïve mCRC KRAS exon2 wild-type patients and randomly assigned to receive FOLFIRI_CET or FOLFIRI-BEV. The primary endpoint of the trial, objective response rate analyzed by intention-to-treat analysis, was not reached (CET 62% versus BEV 58%, p = 0.18). Although no difference in PFS was noted (CET 10 versus BEV 10.3 months), the mOS was significantly longer in the FOLFIRI-CET arm (CET 28.7 versus BEV 25.0 months; HR, 0.77; p = 0.017). An updated analysis, which accounted for additional mutations in KRAS exon 3 and 4, as well as NRAS mutations exon 2 and 3, demonstrated a longer mOS survival of 33.1 months for FOLFIRI-CET. In contrast, the U.S. Intergroup study, CALGB/South-west Oncology Group (SWOG) 80405 trial that compared FOLFOX or FOLFIRI (dealer's choice) with CET compared with BEV as first-line therapy had no difference in mOS (30 versus 29.9 months, respectively), not even whit expanded RAS-mutated analysis. The preliminary retrospective analysis suggests that patients treated with CET for KRAS wild-type left-sided tumors mOS are significantly higher than right-sided counterpart by 33.3 versus 19.4 months, respectively. Combination therapy with VEGF inhibitors and anti-EGFRs monoclonal antibody have failed even detrimental in multiple trials (BOND-2, PACCE, CAIRO-2), thus not recommended.
Salvage Therapy for Refractory Disease
Regorafenib (REG): REG (160mg PO daily for three weeks of 4 weeks cycle) efficacy was investigated in a placebo-controlled, multicenter international, randomized, phase III CORRECT trial after progression of multiple therapies. REG compared with placebo had ORR (41% versus 15%), PFS (1.9 versus 1.7 months) and modest mOS benefit (6.4 versus 5.0 months) but significant (p = 0.0052). The observed toxicity profile with regorafenib was hand-foot skin reaction, fatigue, hypertension, diarrhea, and rash, with a 1.6% fatal hepatic failure. The CONCUR trial later confirmed REG benefit.
Trifluridine-tipiracil (TAS-102): the international, double-blind, placebo-controlled randomized-controlled, phase III RECOURSE study of patients with refractory showed that TAS-102 (35 mg/m2 orally twice daily on days 1 through 5 and 8 to 12 of each 28-day cycle) improved ORR (44% versus 16%), DFS and mOS (7.1 versus 5.3 months); The most adverse event was neutropenia (38%), febrile neutropenia (4%) and one treatment-related death.
Immune Checkpoint Inhibitors
Pembrolizumab (PEM): In a phase II study, PEM (10 mg/kg every 14 days) was given to 11 heavily pretreated patients with dMMR mCRC with a remarkable ORR of 71% and PFS rate of 67%. An expanded cohort of 54 patients, PEM showed OOR of 50% and an 89% disease control rate with the durable response for more than a year, not seen in pMMR CRC.
Nivolumab (NIV): In CheckMate-142, NIV (3mg/kg every 2 weeks) was given to 74 dMMR CRC patients resulted in 31% objective response, 69% disease control, and median duration response not reached at 12 months.
an interprofessional team including physician/nursing staff, nutritionist/dietitian, palliative service, social worker and case manager should be invited to participate and contribute in all new CRC diagnosis, treatment, and survivorship patient care. Screening for colorectal cancer is essential to identify premalignant lesions which have been shown to reduce the mortality of this disease but currently is underutilized.
Extended third-generation, blood-relative, family history pedigree from CRC patients can identify those at risk of an unrecognized hereditary syndrome and further offer early and aggressive screening on survivor's own risk and family members.
For all CRC patients during and after completion of treatment, a discussion on lifestyle changes, including to follow a healthy diet, obtain and maintain ideal body weight, establish an active exercise routine, minimize alcohol consumption and quitting smoking, should be encouraged.[26][27]
CRC patients should be regularly screened for early identification of symptoms of psychosocial stress and offer early preventive interventions that would improve the quality of life and reduce suffering.
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text:
The Path To Finding Better Experts
Guidelines for Choosing a Sports Massage Therapist in Jackson TN
Thermography is a comprehensive health assessment carried out to both men and women that includes their neck, head, torso, legs and arms. After thermography has been carried out, someone receives a detailed health report about their health. The results that you receive, helps you to know the kind of medication that you need for you to be fit.
It is important for any sports person to make sure that you receive some checkup most of the time to make sure you are safe for the sports activity that might take place all the time. Areas of interest for a sports person should include their hips, knees, shoulders, ankles and any other area that might experience some muscular inflammation.
Sports people should make sure they receive some massage for them to be fit during their sports moments. Visiting the massage place can help a sports person overcome the sports injuries that one encounters as they go on with their daily activities.
However, choosing the best sports massage place at Jackson TN is not an easy thing. There are a lot of things that one needs to consider to make sure you are choosing the right place to be visiting. Not all massage places will offer you the right sports massage. You need to make sure that you get the right place where you will be able to receive the right massage therapy.
The following are important factors for one to consider to make sure that you are able to choose the right massage place in Jackson TN.
It would be good for one to make sure that the place where you choose to have your sports massage has the right person who has the skills and training in offering sports massage. Not all therapists are able to offer the best sports massage. Therapists have specialized in offering different types of massages. Therapists have specialized in different types of massage that they offer. Hence, you need to make sure you have made the right decision to ensure you are safe with the therapist whom you choose to offer you sports massage.
You should make sure you know if the place that you are visiting have the right tools required. The best place to receive your massage is the one that has been equipped with the right tools that you can use to make sure you are safe. A place that does not have the right tools is not the best for anyone to visit because you will not receive the right services that you need to be free.

subset: commoncrawl


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The address of the new house we are building is on Tipperlinn Road in the Morningside district of Edinburgh. Our clients told us that Tipperlinn in the 18th century had been a little village on the outskirts of the city situated roughly on the grounds now occupied by the Royal Edinburgh Hospital on Tipperlinn Road. We did a little bit of research (googled) and put together here the few facts that we learnt. First of all the name itself; Tipperlinn is from the Gaelic and it means 'the well beside the waterfall' The village was tiny, consisting of twelve, two storey houses. The village produced fine linen and the well was used in the dying process. The village was said to be picturesque enjo
Following the site clearance it was time to start the heavy work. We carefully took down the 4m high garden wall that formed the corner of Tipperlinn Road and Stable Lane. This became the access onto the site for all lorry deliveries, excavation vehicles cement lorries etc. But it also meant that we couldn't carry out any of the groundworks in this area for the time being. We began by levelling the site with our own digger and driver. The excess earth was taken away in lorry loads, 16 tons at a time by Lothian Lift & Shift. Ultimately we would remove about 170 tons of earth. With the site mostly levelled, we still needed to allow vehicle access onto the site, we dug and cast the foundation o
The first survey of the site. Estimates at this stage suggested we would need to move about 120 tons of earth off the site during the groundworks. In fact we moved quite a bit more than that. Initially the plan was to make a lorry entrance off the front street by taking down the wall at its lowest point near the pedestrian gate. After some consideration we decided to make the entrance on the corner between Tipperlinn Road and Stable Lane, mainly for safety considerations. We were going to have to underpin the wall on Stable Lane because the site excavations might go down 5 metres. Since the wall was already badly leaning and had previously been reinforced by adding two buttresses, we decided
Inscape was chosen as the preferred contractor and after a short period of negotiation between ourselves and the client's quantity surveyors, which allows the client to be confident that the estimated costs are fair, the contracts were signed and the site was handed over to us. Building contracts are often awarded after the job is put out to a 'competitive tender'. Here several building companies all offer their 'best' price and the clients/architects choose one, maybe the cheapest maybe not. Inscape often tenders for work in a competitive process but in this case the form was by a 'negotiated tender'. Here the client or architect nominates a preferred contractor, possibly based on previous
While the clients still occupied the original house we were asked to install what would become the new drainage connection for the house that was about to be built. The drain would run across the remainder of the original house's garden and then track around that house to a large disconnecting manhole at the front of the property. Drainage is such a great part - and the guts of any new build. This work was done ahead of the build and before the original house was sold so there would be no disruption to the new occupants. At the same time a temporary wooden fence was built across the garden to separate the new site from the existing arden. So, with everything in place the old house could be s
We thought it might be interesting to create a blog post on the web site charting the construction of a new house we are building that has been designed by Richard Murphy Architects. The house is in the Morningside area of Edinburgh. The idea is to take the project from start to completion updating regularly and detailing the whole building process. In this case the project started on site in January 2017 so initially the blog needs to catch up. The new house is largely concealed from the street behind an existing traditional stone wall which had to be partially demolished to allow the construction work and then rebuilt to match the original. The house is of a single storey construction buil


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Definitions for "Humvee"
The replacement for the old jeep. Humvees are cool.
High-Mobility Multipurpose Wheeled Vehicles. The vehicle has replaced the jeep in the 1980's. It's modular design allows it to be used as a patrol vehicle, ambulance, anti-aircraft weapons platform and many other variants. 19
a combat vehicle used exclusively by the military


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England v West Indies: Simmons challenges batsmen to rescue Windies after Broad heroics
Phil Simmons has challenged his West Indies batsmen to come to the rescue, calling for a "big hundred" after Stuart Broad put England on course to regain the Wisden Trophy at Old Trafford.
The magnificent Broad (6-31) took four wickets in the morning session on day three of the decisive third Test as England bowled the tourists out for 197.
Rory Burns (90), Dom Sibley (56) and Joe Root (68 not out) then piled on the runs before England declared on 226-2, setting the Windies 399 to win.
Broad, who struck a rapid half-century on Saturday, removed John Campbell and nightwatchman Kemar Roach late in the day on Sunday to take his tally of Test scalps to 499 and leave Jason Holder's side deep in the mire on 10-2.
Rain looks set to hold England up in their victory charge on Monday, but head coach Simmons wants to see the Windies put up a fight whenever they are able to take to the field over the final two days.
STUMPS:— Windies Cricket (@windiescricket) July 26, 2020
Brathwaite 2* Hope 4*
Broad 2/8
Target 399#Rally #WIReady #ENGvWI #MenInMaroon pic.twitter.com/uDNouBIzZD
He said: "We haven't had any centuries in this series, so I'm always going to be putting pressure on them to go out there and get it.
"The wicket is still a good wicket to bat on, so they have to set themselves targets of getting a big hundred.
"Tomorrow is only the fourth day, so we have a lot of time to bat, we've got to show that determination to get big scores."
West Indies wicketkeeper Shane Dowrich took a nasty blow to the face when trying to take a short ball from Shannon Gabriel and was replaced by Joshua Da Silva, but Simmons revealed there was no serious damage done.
He said of Dowrich's injury: "I think he was lucky it came off the glove first. He has a little cut on the inside of the lip, but no damage to the teeth.
"It's just a cut and it's been sealed up by the doctor. I guess now all he has is a big headache."


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Know before you go
This area may have travel restrictions related to COVID-19.
Feline House in Rome
- apartment80 m²
- Sleeps: 5
- Bedrooms: 2
- Bathrooms: 1
- Min. Stay: 4 nights
- Internet
- Air Conditioning
- Pets Welcome
- Satellite or Cable
- Children Welcome
- Parking
- No Smoking
- Heater
- Bathrooms: 1
- Bathroom 1Bath (no shower)
Safety features
- Deadbolt lock
- First-aid kit
- Smoke detector
- Carbon-monoxide detector
- Exterior lighting
Location Type
- city centre
- town
- Telephone
- Air conditioning
- Heating
- Linens provided
- Washing machine
- Parking available
- Internet
- Towels available
- Iron & board
- Hair dryer
- Living Room
- Fridge
- Hob
- Oven
- Coffee maker
- Toaster
- Pantry items
- Dishes & utensils
- Kitchen
- Seating for 5 people
- Dining area
- Dining
- Television
- Satellite/Cable
- Stereo
- Books
Cancellation Policy
- 100% refund if you cancel at least 14 days before check-in.
- 50% refund (minus the service fee) if you cancel at least 7 days before check-in.
- No refund if you cancel less than 7 days before check-in.
Damage and Incidentals
You will be responsible for any damage to the rental property that is caused by you or your party during your stay.
House Rules
Children allowed
Pets allowed
No events
No smoking
Max guests: 5
- Tassa di soggiorno municipale di euro 3,50 a persona per notte , solo i bambini al disotto dei 10 anni non pagano.
From Termini station take bus No. 64 or 40 and get off at Chiesa Nuova, Corso Vittorio.
or Taxi Service
La Scala restaurant in Via della Scala - after Porta Settimiano
regional cuisine and pizza
Luisa Antonucci
- Languages:
- english, italian
About Luisa Antonucci
After many years of living in the midst of the Tuscan countryside, from time to time I crave museums, movies and good shops. Even though distance-wise I am closer to Florence, I prefer heading to Rome for my citybreaks. I like Rome because is my home town. Here I attended the Art College; that's why I love any kind of Art. I love Rome for its nightlife, no risk of finding restaurants closed at 10 pm. My favourit interests are: tea, wine, cinema, my pets, gardens, books, museums and Rome.
Luisa Antonucci purchased this apartment in 1986


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This incredibly rare 1995 BMW 850CSi could be yours
Back in the mid-90s one of the ultimate BMW cars was the 850CSi. This was a very good looking car for the era and notably had a big V12 engine under its hood. The car in the images here is an extremely rare example boasting only 39,900 miles on the odometer.
A classic V12-powered BMW with low miles in this exceptional clean condition is rare enough on its own. What sets this car apart from any other is that it also has a six-speed manual transmission and is painted in an exterior color called Daytona Violet, a beautiful purple.
This car is said to be the only 850CSi in the United States produced in that color. It also has a special interior ordered with the BMW Individual option that is in the same Daytona Violet with Lotus White. The car said to be the only E31 BMW in the entire world with this color combination.
The vehicle rolls on M System II 17-inch wheels and has Yew wood trim on the interior. This car was the flagship BMW model in the 90s, and it's 5.6-liter V12 produces 372 horsepower and 402 pound-feet of torque. Those numbers don't sound like much for modern cars but was impressive in the day.
Another famous footmark for this engine is that it became the mill used in the iconic McLaren F1. Other features of the car including a factory mobile phone, on-board computer, six-disc CD changer, heated and power-adjustable front seats, limited-slip differential, and speed-variable steering. Bids for this rare car up to $64,000 as of writing. Fans of rare BMW cars will want to pay attention to this one as they don't get any rarer than this.


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Dear Friends,
i am starting my 2.cycle soon and i have decided to stack Boldenone (EQ), Test Cypionate and oral Winstrol.
I would like to ask all you experience users for comments and critiques.
Main goal of this cycle is performance ( improving speed, explosiveness, strength, endurance ) but also gaining few kilos of lean quality muscles and loose some body fat.
I will keep you updated about the resluts
Basic info:
Age: 24
Height: 6'7 (200cm)
Weight: 210 lbs (95kg)
My 1.cycle:
4weeks 20mg of Dianabol ED + 30mg of Winstrol ED
Goal was strenght and mass , and i was very happy with the results and most of it maintained one year after the cycle.
Upcoming cycle:
10 weeks
400mg of Boldenone / week
400mg of Test Cypionate / week
30mg of Winstrol EOD
I will get injections 2x week ( 200mg of each mixed together )
Breakfast: 0,5L fat free yogurt + 100g Sport Muesli + 1 scoop Whey protein (25g of protein )
Mid-snack: Muesli bar + apple + some almond and nuts
Lunch: 200g of grilled Chicken Filet, Veggies, Some Rice
Mid-snack: 100g of Tuna, 2 full grain toast with some low fat cheese
Dinner: 200g grilled Chicken or other meat, Vegies + many Carbs ( rice, pasta …)
Before sleep: 1,5% fat yogurt
2-3 workouts daily: track&field + basketball ED, Weight room EOD
Pre workout: 10g Glutamine, 10g Creatine, 10g BCAA
Post workout: 2scoops Whey Protein + 10g Glutamine, 10g Creatine, 10g BCAA


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Hey folks -
To the right professional, I am more than willing to grant remote access & pay a modest fee. I need for everything to first be backed up in case of error - and then perform a handful of task specific reports.
I am in desperate need of help right now so any assistance would be greatly appreciated -
Sincerely, Paintbrush


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Opulent modern design overlaid on a majestic mountain palette make this Swan River Ranch home one of the finest residences in Breckenridge. Whether roasting marshmallows under the stars or playing in the grass with the family's new puppy this setting is one of a kind with its breathtaking views of the Tenmile Range. This luxurious home will provide constant inspiration with a lavish main level suite, a gourmet kitchen with electronic cabinets, outdoor dining, custom fire-pit, & a 4 car garage.
Listing courtesy of Slifer Smith & Frampton R.E.. Selling Office: .
© 2020 Summit Association of Realtors. Information is provided exclusively for consumers personal, non-commercial use, that it not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing. Data is deemed reliable but is not guaranteed.


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Follow an experienced mountain climber down the wall of the Pieralongia.
The day starts taking the gondola to the Col Raiser and walking to the Pieralongia under the Odle. You will enjoy a rich breakfast in the mountain hut and then experience the abseiling at the Pieralongia, which is famous worldwide for its unique shape. A steep path will take you to the top in about 10 minutes, from there you will hang abseil down about 50m. Adrenaline pure is guaranteed!
price69 Euro/Person
Included servicesMountain guide, Abseiling equipment, breakfast in the hut
DATESevery Tuesday
Meeting PoinTCatores Office at 8 am
duration4 hours
Things to bringHiking equipment, hiking boots
INFOFor personalized requests and more information, send us an email.


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Whether you're fairly new to digital marketing or a bit of an old hand, you can take our totally non-scientific quiz to find out what type of marketer you are. If you're someone who loves a bit of online marketing lingo, or maybe someone who hates it, or perhaps you're a total spread sheet addict, see if your true self shines through by taking our quiz below.
Once you've pigeon-holed yourself, take it up a level by playing the quiz again whilst imagining you're someone else that you work with, for literally seconds of top-notch digital marketing fun!
If you have a business in the financial sector and would like to up your marketing game or receive some expert information about digital marketing for financial services, then get in touch with a member of our team!
Liverpool Honeycomb Edmund Street 2nd Floor Liverpool L3 9NG
LondonKemp House152 - 160 City RoadLondonEC1V 2NX


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Christina's in the kitchen with Miss Teen USA for another great microwave recipe. Apple Oatmeal Bowl is a great way to spice up the most important meal of the day.
Website: http://www.teenkidsnews.com
Facebook: https://www.facebook.com/TEENKIDSNEWSTV
Twitter: https://twitter.com/teenkidsnews
Instagram: http://instagram.com/teenkidsnews#
Teen Kids News is an Emmy Award winning 1/2 hour weekly TV show that is informative, educational and fun! The show has been on the air for over 10 years!


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Leicester City moved into first place on the Premier League ladder with a comprehensive 3-0 win over Newcastle United at St James' Park on Saturday.
Jamie Vardy found the back of the net for a record-equalling 10th consecutive Premier League match when he opened the scoring with a low drive on the stroke of half-time.
Leonardo Ulloa doubled the visitors' advantage in the 62nd minute when he headed home Riyad Mahrez's cross.
Shinji Okazaki put the result beyond any doubt when he scrambled the ball home in from close range after Danny Simpson's shot was saved with seven minutes remaining.
Newcastle United: 0
Leicester City: 3 (Jamie Vardy 45', Leonardo Ulloa 62', Shinji Okazaki 83')
St James' Park, Newcastle Upon Tyne – 50,151
Vardy became just the second player in Premier League history to score in 10 consecutive matches, drawing level with the record set by former Manchester United star Ruud van Nistelrooy, who also scored his 10th goal at St James' Park back in 2003.
Newcastle continue to flounder near the bottom of the Premier League ladder and sit just one point above the relegation zone following the loss to the Foxes.
Newcastle travel to Selhurst Park to take on Crystal Palace on Saturday, while Leicester host Manchester United at the King Power Stadium.
To every single person that has supported me and never doubted me...Thank you.....I'm still pinching myself!
— Jamie Vardy (@vardy7) November 21, 2015
Good morning, Foxes fans! Shall we have a look at the @premierleague table? Of course we should... pic.twitter.com/AZTVsaXEb9
— Leicester City (@LCFC) November 22, 2015
Great team! Great spirit! Amazing performance! #TopOfTheLeague! #FoxesNeverQuit#NewLeipic.twitter.com/Whu6480qYj
— christian fuchs (@FuchsOfficial) November 21, 2015
Newcastle manager Steve McClaren believes his side played their worst match of the season against Leicester:
"That was the worst performance we have had this season and it is very disappointing. I understand the frustration of the fans and we will get back on the training field on Monday to get consistency back in our results. That was nowhere near good enough.
"We have to roll our sleeves up and we know we have the talent. We have to fight for that every day."
Leicester boss Claudio Ranieri heaped praise on the in-form Vardy:
"It is fantastic for Jamie Vardy. He is a great champion and did well in training. I am glad because we played like a team.
"I also had Gabriel Batistuta at Fiorentina score in 11 consecutive matches and I hope Jamie can achieve this."
10 - Jamie Vardy has equalled the Premier League record for consecutive appearances scored in (10 games). Exceptional.
— OptaJoe (@OptaJoe) November 21, 2015


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The Divine Within
with Jo Jayson
Understanding your Divinity to
Radically Shift Your Life
Saturday, November 17th, 2018
Registration: $40
We are often told that we are Divine and powerful beings. Some of us find this an abstract idea, some understand this intellectually, and most struggle to comprehend and/or embrace it.
In this workshop, we will explore how we can understand this Divine Truth within us and in all aspects of ourselves. We will discuss how this knowledge and awareness impacts our 3D physical world and how to use this consciousness to radically shift and change your life. Learning how to access and align with the Divinity within you is the key to ultimate empowerment.
This workshop includes a 20 minute meditation at the end.
THIS WORKSHOP WILL BE FOLLOWED BY A TRUNK SHOW OF JO JAYSON's ART AND SPIRITUAL ITEMS (books, oracle cards, prayer packets, handmade cards, etc..)
About Jo Jayson
British born and bred, Jo Jayson is a self-taught painter. She began her career as a muralist in London, Sydney, and New York. In 2008, she began expressing Divine Feminine energies into her own paintings, completing her much-loved "Goddess Chakra" series. In 2011, she unveiled the beginning of her "Sacred Feminine" series of paintings, unfolding a body of work that contained thirteen channeled feminine energies. Jo has emerged as an internationally acclaimed intuitive artist and spiritual teacher, helping women all over the world find empowerment, healing, and inspiration. She is the author of the award-winning book Self-Love Through the Sacred Feminine and sells her paintings, prints, guidance cards, and meditation tools worldwide. Jo Jayson continues to channel the Divine into her paintings and regularly teaches self-healing workshops online and around the United States.


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Allowing your man to control the initiation of contact is the only sure way to know if you personally are seriously cared about by him. How else would you know of his interest in you if you are always the first to blow his smartphone with cute but desperate cries of focus? In all respects, you're safely use backpage escorts to wind up going mad when finally you realize that your screens of interest have been moving unnoticed unreciprocated, and unrewarded.
If you make it long- winded, the individual who's reading it's going to find the idea that you are the sort of person who would love to keep on speaking about your self, and instead of going on a date with you, they would rather curl up and die. But that does not mean you have to restrict the whole issue. A very brief profile will sound if you don't have time for this, and thatyou're only doing it.
One other shift for women though some Guntersville Alabama wanna have casual sex of prophylactics had existed for centuries- - proved to be the compound birth control pill. Girls who had Guntersville AL dating apps for hispanic to the technology( even now far too few women on the planet do) could control backpage escorts Guntersville if they wanted to, leaving them less burdened than they may be otherwise.
I'd hear stories about different women harassing. Then the day came when I had to work at an event in a club, and we were stuck alongside each other while getting inside. I looked at him and said, " This is what is going to happen at the moment. I will hook you back up and get you into this bar at the moment, however you'll forever stay the hell away from me and not talk about me to anybody. " Done. It had been over. We both held our portion of this deal.
The Filipina will persuade you to send her money. She disappears with your cash. She's either bad or a student and works as a webcam stripper on an fuck buddy luring la website. She claims you can use it to chat with her and the website is free. In your statement you will find charges for adult chat services. The businesses that are chat make it tough to cancel the support, and never issue refunds.
Here's a conversation that happened between a woman and me. We were discussing what the woman wanted in a guy: Her: " I want a tall guy" Me: " Assess" Her: " I love guys that shave" Me: " Assess" ( Although I have a beard) Her: " However, you have a beard" Me: " Oh, were speaking about the facial" Having the ability to use sexual innuendos effectively will make bring sexual tension to your interactions without which makes you look creepy.
' Young inheart'. You are young, if you are middle aged. There are seriously hundreds of the dating profiles of milg fuck buddy placing bare middle- aged hang- ups. Don't do it! You arenot'yearsyoung', that doesn't give you the advantage over your single competitors, even though you would love to believe they are beyond it. I have dated a few of these, hey, I am a sucker for providing the benefit of the doubt. Let's just say, it is not the most fun ifyour'young atheart' suitor feels he has to prance about like Tigger, guffaw loudly at everything, whilst attempting to convert his date tohis'age is just anumber' mindset. And I'mnot'young atheart'of posing for endless selfies are over and drinking shots. Done. We are years old, we are never old years. If that's the case, we would not be here itcouldn't have been great when we were young, could we? Take a peek, be honest. Areyou'mad', ' nuts', ' mad' , ' zany', ' bonkers'? Are you? Probably not. Alright, we can see you've a Sesame Street character as your profile pic but that is not what we would like to see. It's reasonable to guess that we'llbe'up for alaugh' not many of us want to be heading out with Leonard Cohen for good sake. But do not reinvent yourselves, be you. I mean, if you describe yourself as some of the above then fail to provide, no thunderous applause for you, and no repeat dates. And overlook thatthe'oppositesattract' nonsense. They do not.
These are the non- negotiable pieces of ourselves on which we will certainly never ever endanger. . . doing so would risk our identification! Below are some examples of things that categorize as values: Wealth and Cash Frugality Experience Security Modesty Openness Wit Severity Creative Thinking Conformity Variety Traditionalism Compassion Aggression Activity Relaxation Intellect Simplicity Fun Silence Confidence and Religious Beliefs Self- sufficiency Family Achievement Equilibrium Love Self- reliance How important is faith to you? Are you an atheist? Passionate Muslim? Reform Jew? Are you a homebody or a traveler? Exactly how crucial are politics to you? How essential is backpage crack down on escorts to you? How energetic are you? How do you spend your cash, time, life? These are examples. . . the listing of worths and also ideas is going to be customized to your training and also life experiences. Take your time to know on your own and also what' makes you tick. ' This is going to comprise the core of your dating account and dating search.
From them, come up with an concept about what you would love to perform for your backpage for thai escorts. If there is something about yourself you would rather downplay, or do not actually like, start looking for photos that would help you do that.
For our Twin Flame connection, I was initially the runner, I then turned into the chaser and that I attempted to run a little more before I opened my heart to take embracing the idea of a physical union with my Twin Flame.
After completed, I recommend that you read it over about two times or use Google Translate( " Detect language" on one side, " English or your language of choice" on another) . Click on the little speaker and it'll read it back. Post it if it passes.
If anything online relationship can be more challenging because you don't have the time you would to show your personality to them. You have to show them the kind of personyou're through words and pictures. They are you tools in attracting the kind of woman you want utilize them. Hopefully I have given you tools you will find helpful during you are dating experiences and maybe even lead to the woman you have always been looking for.
Can I Overthinking It? Yes! However, you are not alone. Overthinking it is for most people the single biggest obstacle. It's too late When you allow yourself the opportunity to contemplate it. It is much too easy to talk yourself because you know you are currently enjoying the odds each time you do.
We need new techniques and understanding to disengage healthily from relationships. But the very first step starts with admitting thatyou're in an internet relationship, and regardless of what anybody says, it mattered if it strikes, and it is real.
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Her: Hello a girl's gotta keep some keys Me: Nope, I need a radical forthcoming of advice Her: What do you like? Me: Well is a Guntersville online dating profile tips with banter then to some make out. . . it'd just be correct if the buttocks grab occurred then( believing emoji) Describe it. Bring it in to her mind's eye and later, reality. All of this is laying the groundwork for the date. She knows what to expect and it isn't some from the episode that is blue, onceyou're making out with your hands on one another's buttocks.
Why would a man keep hanging out with a woman as her friend, if he really wants to be her boyfriend? Why could he do this? It's because he values her too much. It's what he won't accept from women and because he does not have criteria for what he can accept.
Excuses and rationalizations can provide reassurance to us. If your explanation is, " I don't know what I am doing( or that I can't find the time and the tools) so I can't do it" - - it can provide a convenient buffer to really doing the tough work that you don't want to do. Now that these excuses have been removed with is a choice.
Millionaire match online dating of the most important pieces of advice that you can provide to somebody leaving a poisonous relationship is to enforce the" no contact" rule. This is easier said than done for a lot of people, if the person isn't dedicated to enforcing the principle 29, and it could lead to failure. For instance, they might agree to stop talking with the narcissist, delete their connection with them on social networking and keep themselves busy in a new backpage escorts in life, though they may secretly try to realize their ex- partner, even from a distance. Rather than becoming frustrated, try to be patient and talk it out. There is always another way and this rule may be put into place again, if not successful the first time.


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Hi there,
I'm loving this tool but i'm having trouble with system restore points. the button to create the restore point in the gui claims to create a restore point but when i check there is no new restore point to be found. i can manually create restore points. i have this tool installed on my laptop as well and it works perfectly. i noticed a fix earlier in the thread involving regedit but honestly i would rather not meddle with it if it can be prevented.
thanks in advance for any help.


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- (the) American Automobile Association
- the American Automobile Association [the American Automobile Association] ;» ↑AAA
Useful english dictionary. 2012.
Look at other dictionaries:
American Automobile Association — The AAA logo AAA (pronounced triple A ), formerly known as the American Automobile Association, is a federation of 51 independently operated motor clubs throughout North America. AAA is a not for profit member service organization with more than… … Wikipedia
American Automobile Association — Das Logo des Clubs Typische AAA Niederlassung … Deutsch Wikipedia
American Bicycle Association — The American Bicycle Association (ABA) is a United States based Bicycle Motocross (BMX) sports governing body in Gilbert, Arizona created by Merl Mennenga and Gene Roden in 1977. It is the largest sanctioning body in the United States concerning… … Wikipedia
Automobile Association — may refer to:*Australian Automobile Association in Australia. *Canadian Automobile Association in Canada. *Dominion Automobile Association in Canada. *Allgemeiner Deutscher Automobil Club (ADAC) in Germany. *Western India Automobile Association… … Wikipedia
The Automobile Association — (The AA) was a British motoring association that became a private limited company in 1999, and is owned by two private equity firms.HistoryOn June 29, 1905 a group of motoring enthusiasts met at the Trocadero restaurant in the West End of London … Wikipedia
California State Automobile Association — The California State Automobile Association is a motor club dedicated to improving roads, proposing traffic laws and improvement of overall driving conditions. It was founded in 1907 as an offshoot of the Automobile Club of Southern California… … Wikipedia
Canadian Automobile Association — The CAA logo The Canadian Automobile Association (French: Association canadienne des automobiles), commonly known as CAA, is a non profit federation, founded in 1913, of nine clubs across Canada, providing roadside assistance service, a complete… … Wikipedia
RACE (automobile association) — The Real Autom oacute;vil Club de Espa ntilde;a (RACE) is the Spanish equivialent of the American Automobile Association (AAA) in the United States of America or the Automobile Association (AA) in the United Kingdom.The club was formed in 1903 to … Wikipedia
Dominion Automobile Association — The Dominion Automobile Association (DAA) is a privately owned company that provides roadside assistance and other automotive services to customers in Canada. It is not affiliated with the Canadian Automobile Association, which is a not for… … Wikipedia
Automobile Club of Southern California — The Automobile Club of Southern California was founded December 13, 1900 in Los Angeles as one of the nation s first motor clubs dedicated to improving roads, proposing traffic laws and improvement of overall driving conditions. HistoryEarly… … Wikipedia