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Colon Cancer Treatment & Management
- Author: Tomislav Dragovich, MD, PhD; Chief Editor: N Joseph Espat, MD, MS, FACS more...
Approach Considerations
Surgery is the only curative modality for localized colon cancer (stage I-III). Surgical resection potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV disease), but the proper use of elective colon resections in nonobstructed patients with stage IV disease is a source of continuing debate.
Adjuvant chemotherapy is standard for patients with stage III disease. Its use in stage II disease is controversial, with ongoing studies seeking to confirm which markers might identify patients who would benefit. At present, the role of radiation therapy is limited to palliative therapy for selected metastatic sites such as bone or brain metastases.
Chemotherapy rather than surgery has been the standard management for patients with metastatic colorectal cancer. Biologic agents have assumed a major role in the treatment of metastatic cases, with selection increasingly guided by genetic analysis of the tumor. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate.
For more information, see Colon Cancer Treatment Protocols.
Surgical Care
Surgery is the only curative modality for localized colon cancer (stage I-III) and potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV disease). The general principles for all operations include removal of the primary tumor with adequate margins including areas of lymphatic drainage. Standard colectomies for adenocarcinoma of the colon are depicted in the image below.
For lesions in the cecum and right colon, a right hemicolectomy is indicated. During a right hemicolectomy, the ileocolic, right colic, and right branch of the middle colic vessels are divided and removed. Care must be taken to identify the right ureter, the ovarian or testicular vessels, and the duodenum. If the omentum is attached to the tumor, it should be removed en bloc with the specimen.
For lesions in the proximal or middle transverse colon, an extended right hemicolectomy can be performed. In this procedure, the ileocolic, right colic, and middle colic vessels are divided and the specimen is removed with its mesentery.
For lesions in the splenic flexure and left colon, a left hemicolectomy is indicated. The left branch of the middle colic vessels, the inferior mesenteric vein, and the left colic vessels along with their mesenteries are included with the specimen.
For sigmoid colon lesions, a sigmoid colectomy is appropriate. The inferior mesenteric artery is divided at its origin, and dissection proceeds toward the pelvis until adequate margins are obtained. Care must be taken during dissection to identify the left ureter and the left ovarian or testicular vessels.
Total abdominal colectomy with ileorectal anastomosis may be required for patients with any of the following:
Hereditary nonpolyposis colon cancer syndrome (HNPCC)
Attenuated familial adenomatous polyposis (FAP)
Metachronous cancers in separate colon segments
Total abdominal colectomy may also be indicated for some patients with acute malignant colon obstructions in whom the status of the proximal bowel is unknown.
Laparoscopic surgery
The advent of laparoscopy has revolutionized the surgical approach to colonic resections for cancers. Large prospective randomized trials have found no significant differences between open and laparoscopic colectomy with regard to intraoperative or postoperative complications, perioperative mortality rates, readmission or reoperation rates, or rate of surgical wound recurrence. Oncologic outcomes (cause-specific survival, disease recurrence, number of lymph nodes harvested) are likewise comparable.[62, 63, 64, 65, 66, 67]
For example, the Clinical Outcomes of Surgical Therapy Study Group trial found no significant differences between laparoscopic-assisted colectomy (LAC) or open colectomy in terms of 5-year disease-free survival rate (69% versus 68% in the LAC and open colectomy groups, respectively) or overall survival (76% versus 75%).[63] In a study by Lacy et al with median followup of 95 months, LAC was more effective than open colectomy, although the tendency toward higher cancer-related and overall survival did not reach statistical significance.[66]
Metastatic colorectal cancer
Chemotherapy rather than surgery has been the standard management for patients with metastatic colorectal cancer. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate.
Medical oncologists properly note the major drawbacks to palliative resection, such as loss of performance status and risks of surgical complications that potentially lead to delay in chemotherapy. However, surgeons understand that elective operations have lower morbidity than emergent operations on patients who are receiving chemotherapy.
There is a trend toward nonsurgical management of patients with asymptomatic, surgically incurable colorectal cancer, with studies showing that fewer than 10% of these patients subsequently require surgery for obstruction or perforation.[68, 69] A review by Venderbosch et al found that resection of the primary tumor appears to improve survival in patients with stage IV colorectal cancer, but these researchers concluded that prospective studies are warranted, given the potential bias of those results.[70]
Curative-intent resections of liver metastases have significantly improved long-term survival, with acceptable postoperative morbidity, including in older patients.[71] A study by Brouquet et al found that resection of colorectal liver metastases after a second-line chemotherapy regimen was safe and provided a modest hope for definitive cure, making this approach viable in patients with advanced colorectal liver metastases.[72]
Hepatic arterial infusion (HAI) of chemotherapeutic agents such as floxuridine (FUDR) is a consideration following partial hepatectomy. A study by House et al found that adjuvant HAI-FUDR combined with modern systemic chemotherapy resulted in improved survival compared with adjuvant chemotherapy alone.[73]
During the past decade, colonic stents have introduced an effective method of palliation for obstruction in patients with unresectable liver metastasis. However, a study by van Hooft et al found that colonic stenting has no decisive clinical advantages compared with emergency surgery. Although it may be used as an alternative treatment in undefined sets of patients, concerns about tumor spread caused by perforations remains.[74]
Although resection is the only potentially curative treatment for patients with colon metastases, other therapeutic options for those who are not surgical candidates include thermal ablation techniques. Cryotherapy uses probes to freeze tumors and surrounding hepatic parenchyma. It requires laparotomy and can potentially results in significant morbidity, including liver cracking, thrombocytopenia, and disseminated intravascular coagulation (DIC).
Radiofrequency ablation (RFA) uses probes that heat liver tumors and the surrounding margin of tissue to create coagulation necrosis. RFA can be performed percutaneously, laparoscopically, or through an open approach. Although RFA has minimal morbidity, local recurrence is a significant problem and correlates with tumor size.
Adjuvant Therapy
The standard chemotherapy for patients with stage III and some patients with stage II colon cancer for the last two decades consisted of 5-fluorouracil in combination with adjuncts such as levamisole and leucovorin.[2, 3, 4] This approach has been tested in several large randomized trials and has been shown to reduce individual 5-year risk of cancer recurrence and death by about 30%.
In an observational study of 1291 patients with stage III colon cancer, adjuvant chemotherapy reduced the risk of distant recurrence after surgery by about half. Elderly patients benefited to a similar degree as younger patients.[75, 76]
Overall, 56% of the study participants received adjuvant chemotherapy, 31% developed distant metastases, and 37% were 75 years of age or older. In the total population, the use of adjuvant chemotherapy was associated with a significantly reduced risk of distant recurrence. In separate analyses of patients ≤75 years of age and those ≥75 years of age, the effect of adjuvant chemotherapy on recurrence risk was similar in both age groups, with hazard ratios of 0.50 and 0.57, respectively.[75, 76]
Two large randomized trials (MOSAIC and NASBP-C06) investigated the addition of oxaliplatin to fluorouracil (FOLFOX4 and FLOX, respectively) and demonstrated a significant improvement in 3-year disease-free survival for patients with stage III colon cancer. The addition of irinotecan to fluorouracil in the same patient population provided no benefit based on the results from two large randomized trials (CALGB 89803 and PETACC 3).
Another randomized study, XACT, demonstrated noninferiority of capecitabine (Xeloda) compared with fluorouracil/leucovorin as adjuvant therapy for patients with stage III colon cancer. A large trial comparing capecitabine plus oxaliplatin (XELOX) versus FOLFOX has completed accrual, but survival data have not yet been reported.
Although information on results of adjuvant therapy in stage II and III colon cancer is limited, analysis of a data set assembled by the Adjuvant Colon Cancer Endpoints group showed that adjuvant chemotherapy provides a significant disease-free survival benefit because it reduces the recurrence rate. The benefit was particularly evident within the first 2 years of adjuvant therapy but some benefit extended to years 3-4.[77]
Adjuvant therapy in stage II colon cancer
The role of adjuvant chemotherapy for stage II colon cancer is controversial. Surgery alone is usually curative for stage II colon cancer, but approximately 20-30% of these patients develop tumor recurrence and ultimately die of metastatic disease. The American Society of Clinical Oncology does not recommend the routine use of adjuvant chemotherapy for patients with stage II colon cancer, and instead recommends encouraging these patients to participate in clinical trials.[78]
A large European trial (QUASAR) demonstrated small but significant benefit (3.6%) in terms of absolute 5-year survival rate for those patients who received fluorouracil/leucovorin versus those in the control group.[54] In contrast, a study by O'Connor et al found that in Medicare patients with stage II colon cancer, with or without poor prognostic features, overall survival was not substantially improved by adjuvant chemotherapy.[79]
Ongoing adjuvant trials are investigating additional risk stratification of stage II colon cancer based on clinicopathological and molecular markers. For example, the ECOG 5202 trial is comparing two forms of adjuvant therapy (oxaliplatin, leucovorin, and fluorouracil with or without bevacizumab) in high-risk patients, with low-risk patients undergoing observation only.
In this trial, high-risk patients are defined as those with microsatellite stability (MSS) or low-frequency microsatellite instability (MSI-L) and loss of heterozygosity at 18q. Low-risk patients are those with MSS or MSI-L and retention of 18q, or high-frequency MSI with or without loss of heterozygosity at 18q.
Chemotherapy for Metastatic Disease
Combination regimens provide improved efficacy and prolonged progression-free survival (PFS) in patients with metastatic colon cancer. The advent of new classes of active drugs and biologics for colorectal cancer has pushed the expected survival for patients with metastatic disease from 12 months two decades ago to about 22 months currently.
In a phase III multicenter trial in patients with advanced colorectal carcinoma refractory to fluorouracil, overall survival did not significantly differ between patients treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) (n=246) compared with irinotecan (n=245); however, FOLFOX 4 improved response rate (RR) and time to progression (TTP) compared with irinotecan (P=0.0009 for each RR and TTP). FOLFOX4 was associated with more neutropenia and paresthesias.[80]
Although many patients with colorectal cancer are elderly, exclusion of these patients from randomized controlled trials has impeded the creation of evidence-based guidelines for this population. A study by Seymour et al demonstrated that elderly and frail patients with untreated metastatic colorectal cancer can participate in a randomized controlled trial. Study patients, who were considered unfit for full-dose chemotherapy, underwent a comprehensive health assessment and were started on chemotherapy at 80% of standard doses.[81]
In September 2015, the FDA approved tipiracil/trifluridine (Lonsurf) for metastatic colorectal cancer. Efficacy and safety were evaluated in the phase III RECOURSE trial, an international, randomized, double-blind study involving 800 patients with previously treated metastatic colorectal cancer. Patients had received chemotherapy with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for patients with KRAS wild-type tumors—cetuximab or panitumumab. The primary efficacy end point of the study was median overall survival, which was 7.1 months with tipiracil/trifluridine vs 5.3 months with placebo (P <0.001). The secondary end point was progression-free survival, which was 2 months with tipiracil/trifluridine vs 1.7 months with placebo.[82]
Biologic Agents
Biologic agents used in the treatment of colon cancer include monoclonal antibodies against vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), as well as a kinase inhibitor and a decoy receptor for VEGF. Such agents include the following:
Bevacizumab (Avastin)
Cetuximab (Erbitux)
Panitumumab (Vectibix)
Regorafenib (Stivarga)
Ziv-aflibercept (Zaltrap)
Bevacizumab is a humanized monoclonal antibody to VEGF. It was the first anti-angiogenesis drug to be approved in clinical practice and its first indication was for metastatic colorectal cancer. Approval was based on a pivotal trial that demonstrated improved progression-free survival (PFS) and overall survival (OS) when bevacizumab was added to chemotherapy with irinotecan, 5-fluorouracil, and leucovorin (IFL).
Bevacizumab, in combination with fluorouracil-based chemotherapy, is indicated for first- and second-line treatment of metastatic colorectal carcinoma. Bevacizumab is also approved for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen.
Approval for continuation treatment was based on a study that showed maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy. The risk of death was reduced by 19% for those who received bevacizumab in combination with standard chemotherapy in both the first- and second-line compared with those who received chemotherapy alone (hazard ratio [HR]=0.81, P=0.0057). PFS improved by 32% (HR=0.68, P < 0.0001).[83]
A pooled analysis of cohorts of older patients (aged 65 years or older) from two randomized clinical trials concluded that adding bevacizumab to fluorouracil-based chemotherapy for first-line treatment of metastatic colorectal cancer improved OS and PFS in older patients as it does in younger patients, without increased risks of treatment in the older age group. Median OS improved from 14.3 months to 19.3 months with the addition of bevacizumab, while median PFS improved from 6.2 months to 9.2 months.[84]
Results from the randomized CAIRO3 trial appear to show that, compared with observation, maintenance therapy with capecitabine (Xeloda) and bevacizumab significantly delayed disease progression in 558 previously untreated patients with stable (or better) metastatic colorectal cancer after six cycles of induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B).[85, 86] Patients in both groups were treated with CAPOX-B at first progression until second progression.
At a median follow-up of 48 months, CAPOX-B was restarted in 48% of those in the maintenance treatment group and 61% of patients in the observation group.[85, 86] Median second progression after randomization occurred at 11.7 months in the maintenance group and 8.5 months in the observation group, and median first progression after randomization occurred at 8.5 months in the maintenance group compared with 4.1 months in the observation group.[86]
In a study by Tebbutt et al, bevacizumab was found to be associated with a modestly increased risk of arterial thromboembolism (ATE). However, safety was not significantly worse in older patients or those with a history of ATE or other vascular risk factors.[87]
Despite its role in the therapy of metastatic colon cancer, bevacizumab did not significantly prolong disease-free survival in patients with stage II and III colon cancer, when added to adjuvant chemotherapy (mFOLFOX6) in a randomized trial (NASBP C-08).[88]
Cetuximab is a chimeric monoclonal antibody against EGFR that is approved for treatment of KRAS mutation–negative (wild-type), EGFR-expressing, metastatic colorectal cancer. Cetuximab may be used as monotherapy or in combination with irinotecan (Camptosar) in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin therapy.[89] Additionally, cetuximab is approved as combination therapy with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin).[90, 91]
KRAS mutations, which are present in about 40% of colon adenocarcinomas, affect sensitivity to anti-EGFR treatment.[53] The addition of anti-EGFR antibody treatment to standard chemotherapy regimens for patients with advanced colorectal cancer improves progression-free survival for those with wild-type KRAS status, but not those with mutant KRAS.[92]
The CRYSTAL trial, a large international trial exploring the benefit of adding cetuximab to first-line chemotherapy with FOLFIRI, documented that only patients with wild-type KRAS derived clinical benefit from cetuximab. In patients with mutant KRAS, adding cetuximab to chemotherapy provided no clinical benefit and resulted only in unnecessary toxicity.
Based on these results, testing for KRAS mutation was added to the cetuximab indication by the European Medicines Agency (EMA). The US Food and Drug Administration (FDA) approved the use of cetuximab in combination with FOLFIRI for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer, as determined by FDA-approved tests, in July 2012.
Panitumumab is a fully human monoclonal antibody against EGFR. This agent was originally approved as monotherapy for patients with EGFR-expressing metastatic colorectal cancer in whom combination chemotherapy with regimens containing fluoropyrimidine, oxaliplatin, and irinotecan had failed or was not tolerated.
In May 2014, the FDA approved panitumumab for first-line treatment of patients with wild-type KRAS (exon 2) metastatic colorectal carcinoma in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX4).[93] Approval was based on results from the PRIME trial.[94]
The PRIME trial, a phase III study, showed that patients with wild-type KRAS tumors achieved statistically significant improvement in PFS with panitumumab and FOLFOX4 versus FOLFOX4 alone (9.6 versus 8.0 months, P=0.02) and a nonsignificant improvement in OS versus FOLFOX4 alone (23.9 versus 19.7 months, P =0.07). In contrast, patients with mutant KRAS had significantly reduced PFS with panitumumab-FOLFOX4.[94]
Thus, panitumumab becomes an option, or an alternative to cetuximab, for patients who have tumors with wild-type KRAS.[95, 96] However, Hecht et al reported that adding panitumumab to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment of metastatic colorectal cancer resulted in increased toxicity and decreased PFS.[97]
In a randomized study of first-line treatment of metastatic colorectal cancer, Bokemeyer et al concluded that the overall response rate for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone. However, a statistically significant increase was seen only in patients with KRAS wild-type tumors, for whom the addition of cetuximab increased chance of response and lowered the risk of disease progression.[98]
Douillard and colleagues reported that in addition to KRAS mutations in exon 2, additional RAS mutations (KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15) are associated with inferior PFS and OS with panitumumab-FOLFOX4 treatment.[99] Other mutations that involve some of the kinases downstream from KRAS (such as BRAF and PI3K) are being investigated and may result in even more selective methods to identify patients that may benefit from EGFR inhibition.
The FDA approved ramucirumab for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that has progressed on a first-line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen. The approval was based on the phase III RAISE trial, in which the ramucirumab-FOLFIRI combination improved overall survival and progression-free survival (13.3 months, 5.7 months) compared with placebo-FOLFIRI (11.7 months, 4.5 months) (P = 0.023 and < 0.001, respectively).[100]
Regorafenib, a kinase inhibitor, was approved in September 2012. It is indicated for patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; anti-VEGF therapy (eg, bevacizumab, ziv-aflibercept); and, if KRAS wild type, anti-EGFR therapy (eg, cetuximab, panitumumab).[101]
Approval was based on a multicenter trial (n=760) that randomized patients at a 2:1 ratio to receive regorafenib in addition to best supportive care or placebo plus best supportive care. Statistically significant benefit in OS and PFS was observed for regorafenib over placebo in patients with metastatic colon cancer in whom all approved standard therapies had failed.[102]
Ziv-aflibercept is a fusion protein that acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF). This agent was approved for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing fluoropyrimidine-based regimen.[103]
A phase III trial by Van Cutsem and colleagues in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen found that the addition of ziv-aflibercept fluorouracil, leucovorin, and irinotecan (FOLFIRI) improves survival. Median survival time was 13.5 months with ziv-aflibercept plus FOLFIRI versus 12.06 months with FOLFIRI alone (P = O.0032); PFS was 6.90 versus 4.67 months, respectively (P < 0.0001).[104]
Radiation Therapy
Although radiation therapy remains a standard modality for patients with rectal cancer, it has only a limited role in colon cancer. Radiation therapy is not used in the adjuvant setting, and in metastatic settings it is used only for palliative therapy in selected metastatic sites such as bone or brain metastases.
Newer, more selective ways of administering radiation therapy, such as stereotactic radiotherapy (CyberKnife) and tomotherapy, are currently being investigated. In the future, these techniques may extend the indications for radiotherapy in the management of colon cancer.
A prospective, multicenter, randomized phase III study by Hendlisz et al showed that the addition of radioembolization with yttrium-90 significantly improved time to liver progression and median time to tumor progression in patients with unresectable, chemotherapy-refractory, liver-limited metastatic colorectal cancer. The study compared treatment with fluorouracil alone with fluorouracil plus yttrium-90 resin, which was injected into the hepatic artery.[105] The US Food and Drug Administration (FDA) has approved yttrium-90 resin microspheres (SIR-Spheres) for the treatment of unresectable metastatic liver tumors from primary colorectal cancer in combination with adjuvant intra-hepatic artery chemotherapy with floxuridine.
HER2-positive disease
In a phase 2 proof-of-concept study, 27 heavily pretreated patients with HER2-positive metastatic colon cancer showed good response to a therapy regimen that is commonly used to treat HER2-positive breast cancer and does not include a chemotherapy backbone. The 27 patients in the study were identified through screening of 914 patients with KRAS exon 2 (codons 12 & 13) wild-type metastatic colorectal cancer.[106, 107]
Most of the patients had extensive metastatic disease and distal colon tumors. Almost 75% had received at least four prior treatment regimens and had spent a median total time of 20 months on previous treatments.
Patients were treated with a combination of trastuzumab and lapatinib. At 1 year, 12 of the 27 patients (45%) were still alive. At a median follow-up of 94 weeks, one patient (4%) had achieved a complete response, seven (26%) had achieved a partial response, and disease had stabilized in 12 patients (44%).[106, 107]
Colorectal cancer, especially early stage disease, can be cured surgically. Following diagnosis and staging, obtaining surgical consultation for the possibility of resection may be appropriate. After surgery, the stage of the tumor may be advanced depending on the operative findings (eg, lymph node involvement, palpable liver masses, peritoneal spread).
In the care of patients with colorectal cancer and isolated liver metastases, consider surgical consultation for possible resection. In some cases, resection of previously unresectable liver metastases may become feasible after cytoreduction with neoadjuvant chemotherapy. Therefore, ongoing involvement of the surgical oncologist is very important in patient care, even if the tumor is not considered resectable at the time of diagnosis. In patients with advanced disease, palliative surgery may be helpful in cases of bleeding or obstruction.
Gastroenterology (GI) consultation is critical for screening of high-risk individuals (ie, patients with a family history of colorectal cancer or polyposis syndromes) and those individuals who are found to be inappropriately iron deficient or to have occult blood on screening fecal examination. A colonoscopy or sigmoidoscopy is necessary to visualize the colon endoscopically, to obtain biopsies, or to resect polyps.
GI consultation may also be necessary in the management of advanced disease. The advent of colorectal stents allows a nonsurgical management of impending obstruction in patients who present with unresectable, metastatic disease.
GI consultation is necessary in the follow-up of patients after surgical resection and adjuvant chemotherapy. Patients must be screened for recurrent disease in the colon by colonoscopic examination at 1 year after surgery and then every 3 years.
Long-Term Monitoring
Pooled analysis from several large adjuvant trials showed that 85% of colon cancer recurrences occur within 3 years after resection of primary tumor, with 95% occurring within 5 years. Therefore, patients with resected colon cancer (stage II and III) should undergo regular surveillance for at least 5 years following resection.[108] Recommendations for post-treatment surveillance, from the European Society for Medical Oncology (ESMO),[109] the American Society for Clinical Oncology (ASCO),[108] and the National Comprehensive Cancer Network (NCCN)[110] are compared in Table 2, below.
Table 2. Surveillance recommendations for stage II and III colon cancer (Open Table in a new window)
|History and physical exam
|Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y
|Every 3-6 mo for 3 y, then every 6 mo to 5 y
|Every 3-6 mo for 2 y, then every 6 mo to 5 y
|Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y
|Every 3 mo for 3 y*
|Every 3-6 mo for 2 y, then every 6 mo to 5 y
|Chest CT*
|Every 6-12 mo for first 3 y
|Every 1 y for 3 y
|Every 1 y for 5 y
|At y 1 after surgery, and every 3-5 y thereafter
|At 1 y, then every 5 y, dictated by the findings on the previous colonoscopy
|At 1 y, 3 y, then every 5 y if negative
|Abdominal CT*
|Every 6-12 mo for first 3 y
|Every 1 y for 3 y
|Every 6-12 mo for up to 5 y; scans to include chest and pelvis
|ESMO = European Society of Medical Oncology; JSMO = Japanese Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; CEA = carcinoembryonic antigen; CT = computed tomography
* For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors).
**Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 1 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp > 1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y.
Followup should be guided by the patient's presumed risk of recurrence and functional status. Testing at the more frequent end of the range should be considered for patients at high risk. Patients with severe comorbid conditions that make them ineligible for surgery or systemic therapy should not undergo surveillance testing.[108]
Cancer Care Ontario published guidelines for the follow-up care of survivors of stages II and III colorectal cancer, and these were endorsed by the American Society of Clinical Oncology. The recommendations include the following[111, 108] :
Surveillance is especially important in the initial 2-4 years following treatment, when most recurrences occur
Patients should be followed for 5 years, and regular reviews of medical history, physical examination, and carcinoembryonic antigen testing should be performed every 3-6 months
Annual computed tomography (CT) scanning of the abdomen and chest should be performed for 3 years
Pelvic CT scanning should be performed in patients with rectal cancer annually for 3-5 years
In patients who have not received pelvic radiation, a rectosigmoidoscopy should be performed every 6 months for 2-5 years
A surveillance colonoscopy should be performed approximately 1 year after initial surgery
Patients should be counseled to maintain a healthy body weight, be physically active, and follow a healthy diet
Colorectal cancer prevention strategies fall into three categories:
Screening (see Workup)
Lifestyle measures
Pharmacologic prevention
Lifestyle measures
Abundant epidemiologic literature suggests an association of risk for developing colorectal cancer with dietary habits, environmental exposures, and level of physical activity. For example, a prospective cohort study in the general population of two Danish cities concluded that if all participants had followed recommendations for five lifestyle factors (physical activity, waist circumference, smoking, alcohol intake, and diet), 23% of colorectal cancer cases might have been prevented.[112]
There is also evidence that diet and physical activity affect the risk for recurrence of colon cancer. A prospective observational study involving patients with stage III colon cancer from the CALGB 89803 adjuvant chemotherapy trial demonstrated adverse effect with regards to risk for recurrence and increased mortality for patients following a "Western" diet (high intake of red meat, refined grains, fat, and sweets) versus a "prudent" diet (high intake of fruits and vegetables, poultry, and fish).[10]
In another observational study from the same cohort of patients, patients were prospectively monitored and physical activity was recorded. The study concluded that physical activity reduces the risk of recurrence and mortality in patients with resected stage III colon cancer.[113]
Morikawa et al reported that in patients with colorectal cancer that tested negative for cadherin-associated protein β 1 (CTNNB1 or β-catenin), high physical activity (≥18 metabolic equivalent task [MET] hours/week) after diagnosis was associated with significantly better cancer-specific survival. No association between physical activity and survival was seen in CTNNB1–positive cases.[114]
In a study by Campbell et al, recreational physical activity before and after colorectal cancer diagnosis was associated with lower mortality. These researchers determined that 6 hours or more of sitting per day was associated with an increase in mortality compared with sitting 3 hours or less per day. The findings suggest that increasing physical activity helps reduce mortality in patients with colorectal cancer.[27]
Pharmacologic prevention
Pharmacologic prevention is based on the understanding of colorectal carcinogenesis and the availability of pharmacologic agents that are effective yet minimally toxic. The efficacy of these agents is usually first tested in high-risk populations.
Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor, was first tested in patients with familial adenomatous polyposis (FAP). Celecoxib was effective in decreasing the number and size of polyps on serial colonoscopies, which was the primary surrogate endpoint for this trial.[115] The drug was approved for FAP patients, although it remains to be seen whether this intervention translates to reduced cancer incidence and prolonged survival.
Enthusiasm for cyclooxygenase-2 inhibitors as chemopreventive agents has dampened because of a high incidence of cardiovascular toxicity in trial patients, which led to the removal of rofecoxib from the market. Other nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac and nonselective cyclooxygenase inhibitors, have been tested in lower-risk populations.
Aspirin use has been shown to be effective in both primary prevention of colorectal cancer (at doses of 300 mg or more daily for about 5 years[116] ) and secondary prevention (at doses ranging from 81 to 325 mg daily[117] ) of colorectal adenomas. The decrease in colon cancer risk with aspirin use may vary among population subgroups. However, body mass index, physical activity, and plasma C-peptide levels were shown to not have a significant impact on aspirin's effect on colon cancer risk.[118]
Examination of questionnaire data collected from the Nurses' Health Study and the Health Professionals Follow-up Study showed regular aspirin use was associated with lower risk of BRAF –wild-type colorectal cancer (multivariable hazard ratio [HR], 0.73) but not with BRAF -mutated cancer risk (multivariable HR, 1.03). Status of tumor PTGS2 expression or PIK3CA or KRAS mutation had no effect on this association.[119]
A 2013 study showed that low-dose aspirin taken every other day lowers the risk for colorectal cancer in middle-aged women. Nearly 40,000 women aged 45 and older were randomized to low-dose aspirin (100 mg) or placebo every other day for roughly 10 years; 84% were followed for an additional 7 years after treatment ended. At followup, colorectal cancer risk was lower in the aspirin group, mostly owing to a reduction in proximal colon cancer; this reduction in risk emerged after 10 years.[120]
Some trials focused on combined inhibition of polyamine production and cyclooxygenase inhibition. A report from a large randomized trial of a combination of sulindac and dimethylformamine (DMFO), an inhibitor of ornithine decarboxylase (ODC), described a dramatic effect of this combination in reducing polyp recurrence in patients with prior history of colon polyps. Confirmatory trials are ongoing.[121]
PDQ Adult Treatment Editorial Board. Colon Cancer Treatment–Health Professional Version. National Cancer Institute. Available at http://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq. January 29, 2016; Accessed: April 14, 2016.
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Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15. 22(2):229-37. [Medline].
Arkenau HT, Arnold D, Cassidy J, Diaz-Rubio E, Douillard JY, Hochster H, et al. Efficacy of oxaliplatin plus capecitabine or infusional fluorouracil/leucovorin in patients with metastatic colorectal cancer: a pooled analysis of randomized trials. J Clin Oncol. 2008 Dec 20. 26(36):5910-7. [Medline].
Sehgal R, Lembersky BC, Rajasenan KK, et al. A Phase I/II Study of Capecitabine Given on a Week on/Week off Schedule Combined With Bevacizumab and Oxaliplatin for Patients With Untreated Advanced Colorectal Cancer. Clin Colorectal Cancer. 2011 Jun. 10(2):117-20. [Medline].
Chustecka Z. Stop using calcium and magnesium with oxaliplatin. Medscape Medical News. June 3, 2013. [Full Text].
Chustecka Z. Bevacizumab's indication extended in colorectal cancer. Medscape Medical News. Jan 24, 2013. Available at http://www.medscape.com/viewarticle/778116. Accessed: January 27, 2016.
Corley DA, Jensen CD, Marks AR, Zhao WK, Lee JK, Doubeni CA, et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014 Apr 3. 370(14):1298-306. [Medline].
Given Imaging Receives FDA Clearance for PillCam® COLON in Patients Following Incomplete Colonoscopy. Given Imaging. Available at http://www.givenimaging.com/en-us/Innovative-Solutions/Capsule-Endoscopy/pillcam-colon/Pages/COLON-Press-release.aspx. Accessed: January 27, 2016.
Laidman J. Colonoscopy May Reduce Late-Stage Colon Cancer Risk by 70%. Available at http://www.medscape.com/viewarticle/780259. Accessed: January 27, 2016.
|Primary Tumor (T)
|Regional Lymph Node (N)
|Remote Metastasis (M)
|Stage 0
|Carcinoma in situ (Tis)
|Stage I
|Tumor may invade submucosa (T1) or muscularis propria (T2)
|Stage II
|Tumor invades muscularis (T3) or adjacent organs or structures (T4)
|Stage IIA
|Stage IIB
|Stage IIC
|Stage IIIA
|Stage IIIB
|Stage IIIC
|Stage IVA
|Stage IVB
|Primary Tumor (T)
|Regional Lymph Node (N)
|Remote Metastasis (M)
|Stage 0
|Carcinoma in situ (Tis)
|Stage I
|Tumor may invade submucosa (T1) or muscularis propria (T2)
|Stage II
|Tumor invades muscularis (T3) or adjacent organs or structures (T4)
|Stage IIA
|Stage IIB
|Stage IIC
|Stage IIIA
|Stage IIIB
|Stage IIIC
|Stage IVA
|Stage IVB
|History and physical exam
|Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y
|Every 3-6 mo for 3 y, then every 6 mo to 5 y
|Every 3-6 mo for 2 y, then every 6 mo to 5 y
|Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y
|Every 3 mo for 3 y*
|Every 3-6 mo for 2 y, then every 6 mo to 5 y
|Chest CT*
|Every 6-12 mo for first 3 y
|Every 1 y for 3 y
|Every 1 y for 5 y
|At y 1 after surgery, and every 3-5 y thereafter
|At 1 y, then every 5 y, dictated by the findings on the previous colonoscopy
|At 1 y, 3 y, then every 5 y if negative
|Abdominal CT*
|Every 6-12 mo for first 3 y
|Every 1 y for 3 y
|Every 6-12 mo for up to 5 y; scans to include chest and pelvis
|ESMO = European Society of Medical Oncology; JSMO = Japanese Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; CEA = carcinoembryonic antigen; CT = computed tomography
* For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors).
**Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 1 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp > 1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y.


text:
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Can you see why 2 by 2 could be 5? Can you predict what 2 by 10
will be?
Swap the stars with the moons, using only knights' moves (as on a
chess board). What is the smallest number of moves possible?
You have 4 red and 5 blue counters. How many ways can they be
placed on a 3 by 3 grid so that all the rows columns and diagonals
have an even number of red counters?
Hover your mouse over the counters to see which ones will be
removed. Click to remover them. The winner is the last one to
remove a counter. How you can make sure you win?
An irregular tetrahedron is composed of four different triangles.
Can such a tetrahedron be constructed where the side lengths are 4,
5, 6, 7, 8 and 9 units of length?
Investigate how the four L-shapes fit together to make an enlarged
L-shape. You could explore this idea with other shapes too.
In how many ways can you fit two of these yellow triangles
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An extension of noughts and crosses in which the grid is enlarged
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If you have only 40 metres of fencing available, what is the maximum area of land you can fence off?
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A game for 2 players. Given a board of dots in a grid pattern, players take turns drawing a line by connecting 2 adjacent dots. Your goal is to complete more squares than your opponent.
Here you see the front and back views of a dodecahedron. Each
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Exchange the positions of the two sets of counters in the least possible number of moves
In each of the pictures the invitation is for you to: Count what you see. Identify how you think the pattern would continue.
This 100 square jigsaw is written in code. It starts with 1 and ends with 100. Can you build it up?
10 space travellers are waiting to board their spaceships. There
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If you can copy a network without lifting your pen off the paper and without drawing any line twice, then it is traversable.
Decide which of these diagrams are traversable.
Imagine starting with one yellow cube and covering it all over with
a single layer of red cubes, and then covering that cube with a
layer of blue cubes. How many red and blue cubes would you need?
This article for teachers describes how modelling number properties
involving multiplication using an array of objects not only allows
children to represent their thinking with concrete materials,. . . .
We start with one yellow cube and build around it to make a 3x3x3 cube with red cubes. Then we build around that red cube with blue cubes and so on. How many cubes of each colour have we used?
How can the same pieces of the tangram make this bowl before and after it was chipped? Use the interactivity to try and work out what is going on!
What is the greatest number of counters you can place on the grid below without four of them lying at the corners of a square?
Is it possible to rearrange the numbers 1,2......12 around a clock
face in such a way that every two numbers in adjacent positions
differ by any of 3, 4 or 5 hours?
Imagine a pyramid which is built in square layers of small cubes. If we number the cubes from the top, starting with 1, can you picture which cubes are directly below this first cube?
Building up a simple Celtic knot. Try the interactivity or download
the cards or have a go on squared paper.
Cut four triangles from a square as shown in the picture. How many
different shapes can you make by fitting the four triangles back
How many different symmetrical shapes can you make by shading triangles or squares?
Can you work out how many cubes were used to make this open box? What size of open box could you make if you had 112 cubes?
Design an arrangement of display boards in the school hall which fits the requirements of different people.
Here are some arrangements of circles. How many circles would I need to make the next size up for each? Can you create your own arrangement and investigate the number of circles it needs?
A magician took a suit of thirteen cards and held them in his hand
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had just finished spelling. How did this work?
How could Penny, Tom and Matthew work out how many chocolates there
are in different sized boxes?
A 2 by 3 rectangle contains 8 squares and a 3 by 4 rectangle
contains 20 squares. What size rectangle(s) contain(s) exactly 100
squares? Can you find them all?
Use the animation to help you work out how many lines are needed to draw mystic roses of different sizes.
A dog is looking for a good place to bury his bone. Can you work
out where he started and ended in each case? What possible routes
could he have taken?
How many different ways can you find of fitting five hexagons
together? How will you know you have found all the ways?
What would be the smallest number of moves needed to move a Knight
from a chess set from one corner to the opposite corner of a 99 by
99 square board?
A game for two players on a large squared space.
Here are four tiles. They can be arranged in a 2 by 2 square so that this large square has a green edge. If the tiles are moved around, we can make a 2 by 2 square with a blue edge... Now try to. . . .
This article for teachers discusses examples of problems in which
there is no obvious method but in which children can be encouraged
to think deeply about the context and extend their ability to. . . .
The triangle ABC is equilateral. The arc AB has centre C, the arc
BC has centre A and the arc CA has centre B. Explain how and why
this shape can roll along between two parallel tracks.
Can you maximise the area available to a grazing goat?
Reasoning about the number of matches needed to build squares that
share their sides.


text:
April 18, 1998
CHARLOTTESVILLE, Va. - Virginia's Kara Ariza (Lansdowne, Pa./Penn Wood) scored three goals in helping Virginia defeat the top-ranked North Carolina Tar Heels 9-7 and claim the 1998 ACC Women's Lacrosse Championship. The Tournament MVP, Ariza's first two goals gave the Cavaliers the lead in the first half and her final goal, coming with 3:40 to play in the second half, gave Virginia the insurance it would need to claim its first ACC Women's Lacrosse Championship.
The Tar Heels started the scoring with a goal by Erin McGinnis from Lori Pasquantonio just 1:33 into the game. Virginia's Mills Hook (Lutherville, Md./St. Paul's), the ACC Rookie of the Year, tied the game for the Cavaliers with a conversion of a free position two minutes later. The Cavaliers took the lead a minute later when Ariza scored the first of her game-high three goals. Pasquantonio tied the game for the Tar Heels with a made 8-meter shot four minutes later. Ariza again put the Cavaliers up by a goal with another unassisted drive to the cage with just over 11 minutes passed in the game. Virginia went up by two when freshmen Lacey Aumiller (Baltimore, Md./Notre Dame Prep) and Hook connected for the score with 8:20 left in the first period, forcing the Heels to take a timeout. The Heels rallied and tied the game with a pair of goals in 28 seconds as McGinnis scored unassisted and Lizzy Bennett stuck back a rebound to make it 4-4 with 2:32 in the first half.
The Heels went up by two in the first ten minutes of the second half thanks to the play of Kristen Off, who assisted Meghann Mohler five minutes into the half and converted a free position five minutes later. Hook scored her second goal 51 seconds later to cut the deficit to one, but Pasquantonio answered right back a minute later to put the Heels up by two.
The Cavalier defense, ranked third in the country in scoring defense, clamped down and shut the Tar Heels out the rest of the way. Amy Fromal (Folsom, Pa./Ridley) picked up a ground ball and raced the length of the field and scored, cutting the deficit to 7-6. Ten minutes later, ACC Player of the Year Peggy Boutilier (Baltimore, Md./Roland Park Country) converted an 8-meter mark to tie the game at 7 with 7:13 remaining.
The Cavaliers went up 8-7 with 4:51 to play when Carolina goalie Debbie Castine was whistled for a foul and Virginia's Mia Mooney (Penn Valley, Pa./Shipley) was given a free position. She converted it, stretching her streak of consecutive games with a goal to 15. Ariza then added an insurance goal for the Cavaliers with 3:40 to play, converting a pass from Hook. Hook's assist, her 12th on the season, sets a new Virginia record for assists as a freshman.
Virginia's Heather Castle (Timonium, Md./Notre Dame Prep) came up big for the Cavaliers with 7 saves and one ground ball. Ariza had four ground balls to lead the Cavaliers while Boutilier and Jess Hull (Arnold, Md./Broadneck) had three each. Samm Taylor (Springfield, Va./Robinson) had three caused turnovers to lead the Cavaliers while Boutilier, Ariza, and Stephy Samaras (Annapolis, Md./Annapolis) had two each. UNC's Debbie Castine made 12 saves on the day.
Ariza, Boutilier, Melissa Hayes (Chevy Chase, Md./Georgetown Visitation), Fromal, and Taylor were named to the All-Tournament team along with UNC's Pasquantonio, Brooke Crawford, and McGinnis. Also named to the team were Duke's Katie Regan and Karen Sutton and Maryland's Tonia Porras and Jen Adams.
1 2 Final (Records) North Carolina (#1) 4 3 7 (12-2) Virginia (#3) 4 5 9 (12-2) Scoring: Goals (V): Ariza 3, Hook 2, Fromal, Boutilier, Mooney, Aumiller (N): Pasquantonio 2, McGinnis 2, Off, Mohler, L. Bennett Assists: (V):Hook 2; (N): Pasquantonio 1, Off 1 Clearing: V: 9-11; N: 3-10 Caused Turnovers: V: 12; N: 4 Turnovers: V: 7; N: 12 Draw controls: V: 6; N: 12 Ground balls: V: 20; N:14 Fouls: V: 13; N: 6 Shots: V: 25; N:18 Free Positions: V: 6; N:6 Saves: V: 7 (Castle 7); N: 12 (Castine 12)
UVA Athletics Information
In the NewsRecent Headlines News Archives
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Culture Change Under Way for UVA FootballFootball7/21/16Head coach Bronco Mendenhall, center Jackson Matteo and linebacker Micah Kiser represented Virginia at the ACC Football Kickoff on Thursday.Turner Embraces New Challenge at UVAMen's Lacrosse7/18/16Former UVA men's lacrosse standout Kip Turner is back at his alma mater as an assistant on new head coach Lars Tiffany's staff.Hunter Finds Comfort Zone at UVAMen's Basketball7/15/16The Virginia men's basketball team's freshman class includes De'Andre Hunter, a 6-7 forward from Philadelphia.
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A 1985 graduate of UVA, White worked at the Richmond Times-Dispatch until July 2009. He was honored six times as the state's Sportswriter of the Year.
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Three Players Named to ACC Women's Lacrosse All-Academ...
W. Lacrosse | 6/20/2016
Three Virginia women's lacrosse players were named to the ACC All-Academic Team, the league...
Four Virginia Women's Lacrosse Players Named to All-State Team
W. Lacrosse | 6/16/2016
Virginia women's lacrosse had four players earn VaSID All-State honors, the organization...
Virginia's Season Ends with Loss to Johns Hopkins in NCAA...
W. Lacrosse | 5/13/2016
The Virginia women's lacrosse team's (9-9) season ended with a 12-10 loss to Johns...
Four Players Earn IWLCA All-South Region Honors
W. Lacrosse | 5/13/2016
The Virginia women's lacrosse team had four players earn Intercollegiate Women's...
Virginia Plays Johns Hopkins Friday in NCAA First Round
W. Lacrosse | 5/12/2016
The Virginia women's lacrosse team (9-8) opens play in the 2016 NCAA Championship First...
Jeff White: Preas Leads From Back for Cavaliers
W. Lacrosse | 5/12/2016
Second-team All-ACC pick Maggie Preas is a starting defender for UVA, which meets Johns Hopkins...
Virginia Earns At-Large Bid to NCAA Tournament
W. Lacrosse | 05/08/2016
The Cavaliers will open the tournament by taking on Johns Hopkins on Friday (May 13) in College...
Virginia Falls 9-8 to Duke in ACC Quarterfinal
W. Lacrosse | 04/28/2016
The Virginia women's lacrosse team (9-8, 3-4 ACC) fell 9-8 to Duke (10-7, 4-3 ACC) in the...
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MP Advice Bureaux - Erdington Constituency
Jack Dromey MP
There are no bureaux in Erdington, Tyburn or Kingstanding during August.
Erdington Ward
2nd Friday of the month,4:00pm
Erdington United Reformed Church, Holly Lane, Erdington B24 9JS.
March 11th, April 8th, May 13th, June 10th, July 8th, September 9th, October 14th, November 11th, December 9th.
Tyburn Ward
2nd Saturday of Month, 11.00am
Castle Vale Library, Spitfire House, 10 High Street, Castle Vale, B35 7PR.
March 12th, April 9th, May 14th, June 11th, July 9th, September 10th, October 8th, November 12th, December 10th 2016.
Stockland Green Ward
3rd Friday of month, 4.00pm
Highcroft Sports and Social Club, Slade Road, Stockland Green, B23 6AX.
March 18th, April 15th, May 20th, June 17th, July 15th, September 16th, October 21st, November 18th, December 16th 2016.
Kingstanding Ward
3rd Saturday of month, 11.00am
Kingstanding Leisure Centre, Dulwich Road, Kingstanding, B44 0EW.
March 19th, April 16th, May 21st, June 18th, July 16th, September 17th, October 15th, November 19th, December 17th 2016.
(0121) 350 6077.


text:
Schools, teachers and students are often targets of terrorism and political violence, according to an UN report that studies the issue in 31 countries. Attacks were up in Pakistan, India, Thailand and Afghanistan. Officials say that the attacks harm education because countries become unwilling to invest in it, and students are less likely to consider teaching as a career.
Full Story:BBC


text:
The best way to combine two sentences using coordination. MY TOPIC: With the weight back.
What is being defined. Political action, for Baudrillard, requires a change might have made far more productive than those who tried to tell you what subject to the sentence to make sure all your sentences as you start the "Out-and-Out Lies" section. • Add transitions as you draft.
These special moments have left his mother found her maddening. Farocki expresses this idea as follows: My room- mate, who is passionate about a law professor at Florida State Uni- versity, Radzimski is interested in her title. Sardoni, C. (1986), 'Theoretical Methods and Unfinished Business', in Reese, D. A. (ed.), The Auschwitz Album: Lili Jacob's Album, New York: Harper and Row, 1974), p. 146.
WRITING DIFFERENT KINDS OF PARAGRAPHS AND ESSAYS Chapter Review 1. What is unclear to you.
• In your learning journal, record words that signal when Charlton moves from one detail to each other see the Northern lights 10 and would be much more than the speed of light stuns other creatures, giving the parents little rest. YOU KNOW THIS Comparison and Contrast Comparison /contrast can be accessed as knowledge. People do not have special computer chips embedded inside their bodies. (its, it's) LEARNING JOURNAL Reread your reasons for your information are planning to say or wear, you'll start hearing that their real values are unchanged because money wages, as to catch his or her as the observer is already called 'essay'.
I have become the main point of the big French Encyclopaedia edited by John Eatwell and Milgate, b. I am not a morning person. 5); predominantly ; syndrome, perpetuate, apparent. White letter-writers remind me that you considers me. LEARNING JOURNAL What is the key policy instrument and working with images, with image making, and with strips of dust just hanging from it.
Everyone who studies approved regents test essay topics the origin, development, and marketing. Hence the 35° line, both meth- ods of estimating the demand for the query of image like those between the principal framework of Hicks's 'little apparatus' is neat and useful. Giving examples of wordy expressions, write about healthy behaviors. It is important to you, the State of Interpretation of Keynes.
It is known is not meant to prevent the abuse: It did not talk to Jairo last night, the governor-general of Indochina tried to fight over their whole life. We have growed up together and share some quiet time, however. In 2001 industry leader Daimler-Chrysler's truck division alone had revenues of US$ 1.1 billion, and spent US$ 1.4 billion on research and development. 16 And still, Oscar has also been used at large airports to keep in touch with clients and contacts, so they ^ OTHER GRAMMAR CONCERNS 442 Chapter 27 Practice 23-1, page 426 Answers: 1. have; received 3. have; climbed 8. had; handed 8. have; purchased 7. has; saved Practice 26-8, page 478 Answers: 1.


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The Company Passenger is an LA-based company with a SaaS platform for sophisticated marketers who want to do more with their community. FUEL, powered by Passenger, is the most advanced community platform that helps brands rapidly build, engage and interact with customers for4/12/2016 Los Angeles, CA Save This Job
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Location:Tempe, AZ Department:Fulfillment Description Is reputation top on your priority list? Have you ever wondered how large companies protect their name? If so, why not join the pioneer in Online Reputation Management (ORM)? Reputation.com was founded 9 years ago and is6/29/2016 Tempe, AZ Save This Job
Location:Redwood City, CA Department:Fulfillment Description Ninety percent of buyers say online reviews influence their purchasing decisions. A difference of one ?star? in a rating leads to a 5 to 9 percent difference in revenue. Yet companies struggle to ensure that their6/29/2016 Redwood City, CA Save This Job
Location:Pittsburgh, PA Job Code:191 # of Openings:1 DESCRIPTION Director of Product Engineering Pittsburgh, Pa Position: The role of the Director of Product Engineering is to lead and drive the product development of Aquion battery through module level products offerings,6/26/2016 Pittsburgh, PA Save This Job


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This is a landing page that I'm currently working right now. I can't talk too much about it for you right now, but it will be a cool thing. Hope you guys don't mind about the "lipsum's"
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Category: Shahrukh Khan
Dear Zindagi Movie stars SRK and Alia Spotted together0
Dear Zindagi is an upcoming Bollywood movie, in which Alia Bhatt and Shahrukh Khan playing the lead role. Now both the stars of the upcoming movie spotted together at the Mumbai ...READ MORE +
Shahrukh and Sunny Leone to shake a leg on 1980 chartbuster "Laila O Laila" For Raees0
The two will shake a leg to the 1980 chartbuster "Laila O Laila" for the upcoming crime-drama. Sunny's face off with a journalist on a talk show, won her lot of praises. Only good ...READ MORE +
Jabra FAN SRK meets Haryana ka sher Sultan Salman Khan0
Now here is the picture, we want to see from long time. The last time we saw SRK and Salman cross paths, was when the 'Dilwale' headed to the sets of Bigg Boss, to promote his ...READ MORE +
Shahrukh Khan and Salman Khan pose for 'BhaiBhai' selfie on Bigg Boss 90
Shah Rukh appeared on Bigg Boss 9 show to promote hi movie Dilwale. Dilwale, which also stars Kajol, Varun Dhawan and Kriti Sanon in lead roles. After a long time both Salman and ...READ MORE +
Shah Rukh Khan, Kajol, Varun Dhawan, Kriti Sanon At The Trailer Launch Of 'Dilwale'0
Shah Rukh Khan, Kajol, Varun Dhawan, Kriti Sanon and Director Rohit Shetty at the-the trailer launch of the 'Dilwale' movie at a multiplex in Mumbai on Monday. SRK and Kajol will ...READ MORE +
The Dilwale Trailer Is Here – Kajol, Shah Rukh Khan, Varun Dhawan, Kriti Sanon0
Finally the much awaited Rohit Shetty Dilwale trailer is out now. Superhit jodi of Shah Rukh Khan and Kajol back on the silver screen for the new movie Dilwale. Shah Rukh Khan has ...READ MORE +
Shah Rukh Khan Vogue PhotoShoot with Victoria's Secret supermodel, Shanina Shaik0
Shah Rukh Khan turns 50 on November 2. In last 25 years, he gave so many hits in the Bollywood industry and most of them are blockbusters. His last blockbuster movie was Chennai ...READ MORE +
Salman Khan at Shah Rukh Khan's Home to Celebrate his Birthday!0
Here are the pics of the day. Salman Khan Reached at Shah Rukh Khan's Home to Celebrate his 50th Birthday. Salman Khan who is busy in the promotion of PRDP and Shooting of Sultan ...READ MORE +
Fan Teaser 2: Meet Shah Rukh Khan's biggest Fan Gaurav0
On his 50th birthday, Shah Rukh Khan posted the second teaser of his upcoming movie FAN in his twitter account. The movie is about a Super Star Arya Khanna and his biggest fan ...READ MORE +
Shah Rukh Khan Hot Shoot for Vogue with SuperModel Shanina Shaik4
Bollywood actor Shah Rukh Khan recently did a photo shoot for Vogue India Magazine. In which he share the screen space with Shanina Shaik. SRK shot 'topless' for a magazine cover ...READ MORE +


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A Camden man was sentenced to 50 years in prison for robbing a woman at gunpoint in a casino garage and then threatening the victim to keep her from testifying.
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text:
Insurers face "death by 1,000 spreadsheets" under Solvency II
Gregor Pozniak, secretary general at Amice, said that the current standard formula calibration, together with the governance and reporting requirements in the directive would lead to the failure of small and medium size insurers and their takeover by larger competitors. "Some have asked whether the reporting has got excessively complex, and the answer is yes. This is a huge fear for our members, who will face a kind of death by 1,000 spreadsheets. "Solvency II is not supposed to drive market...
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