Colorectal cancer in the young,many questions,few answers

At a time where the incidence of colorectal cancer, a disease predominantly of developed nations, is showing a decline in those 50 years of age and older, data from the West is showing a rising incidence of this cancer in young individuals. Central to this has been the 75% increase in rectal cancer incidence in the last four decades. Furthermore, predictive data based on mathematical modelling indicates a 124 percent rise in the incidence of rectal cancer by the year 2030 - a statistic that calls for collective global thought and action. While predominance of colorectal cancer (CRC) is likely to be in that part of the large bowel distal to the splenic flexure, which makes flexible sigmoidoscopic examination an ideal screening tool, the cost and benefit of mass screening in young people remain unknown. In countries where the incidence of young CRC is as high as 35% to 50%, the available data do not seem to indicate that the disease in young people is one of high red meat consuming nations only. Improvement in our understanding of genetic pathways in the aetiology of CRC, chiefly of the MSI, CIN and CIMP pathway, supports the notion that up to 30% of CRC is genetic, and may reflect a familial trait or environmentally induced changes. However, a number of other germline and somatic mutations, some of which remain unidentified, may play a role in the genesis of this cancer and stand in the way of a clear understanding of CRC in the young. Clinically, a proportion of young persons with CRC die early after curative surgery, presumably from aggressive tumour biology, compared with the majority in whom survival after operation will remain unchanged for five years or greater. The challenge in the future will be to determine, by genetic fingerprinting or otherwise, those at risk of developing CRC and the determinants of survival in those who develop CRC. Ultimately, prevention and early detection, just like for those over 50 years with CRC, will determine the outcome of CRC in young persons. At present, aside from those with an established familial tendency, there is no consensus on screening young persons who may be at risk. However, increasing awareness of this cancer in the young and the established benefit of prevention in older persons, must be a message that should be communicated with medical students, primary health care personnel and first contact doctors. The latter constitutes a formidable challenge.     

Improved survival with adjuvant chemotherapy in locally advanced rectal cancer patients treated with preoperative chemoradiation regardless of pathologic response

ObjectiveThe aim of this study is to examine the effect of postoperative chemotherapy on survival in patients with stage II or III rectal adenocarcinoma who undergo neoadjuvant chemoradiation (CRT) and surgical resection.MethodsA retrospective review of the National Cancer Database (NCDB) from 2006 to 2013 was performed. Cases were analyzed based on pathologic complete response (pCR) status and use of adjuvant therapy. The Kaplan-Meier method was used to estimate overall survival probabilities.Results23,045 cases were identified, of which 5832 (25.31%) achieved pCR. In the pCR group, 1513 (25.9%) received adjuvant chemotherapy, and in the non-pCR group, 5966 (34.7%) received adjuvant therapy. In the pCR group, five-year survival probability was 87% (95% CI 84%–89%) with adjuvant therapy and 81% (95% CI 79%–82%) without adjuvant therapy. In the non-pCR group, five-year survival probability was 78% (95% CI 76%–79%) with adjuvant therapy and 70% (95% CI 69%–71%) without adjuvant therapy. In the non-pCR and node-negative subgroup (ypN-), five-year survival probability was 86% (95% CI 84%–88%) with adjuvant therapy and 76% (95% CI 74%–77%) without adjuvant therapy. In the non-pCR and node-positive subgroup (ypN+), five-year survival probability was 67% (95% CI 65%–70%) with adjuvant therapy and 60% (95% CI 58%–63%) without adjuvant therapy.ConclusionsAdjuvant chemotherapy in stage II or III rectal adenocarcinoma is associated with increased five-year survival probability regardless of pCR status. We observed similar survival outcomes among non-pCR ypN- treated with adjuvant chemotherapy compared with patients achieving pCR treated with adjuvant chemotherapy.     

Adjuvant chemotherapy for rectal cancer: Current evidence and recommendations for clinical practice

While adjuvant chemotherapy is an established treatment for pathological stage II and especially stage III colon cancer, its role in the multimodal management of rectal cancer remains controversial. As a result, there is substantial variation in the use of this treatment in clinical practice. Even among centres and physicians who consider adjuvant chemotherapy as a standard treatment, notable heterogeneity exists with regard to patient selection criteria and chemotherapy regimens. The controversy around this topic is confirmed by the lack of full consensus among national and international clinical guidelines. While most of the clinical trials do not support the contention that adjuvant chemotherapy may improve survival outcomes if pre-operative (chemo)radiotherapy is also given, these suffer from many limitations that preclude drawing definitive conclusions. Nevertheless, in the era of evidence-based medicine, physicians should be guided by the available data and refrain from extrapolating results of adjuvant colon cancer trials to inform treatment decisions for rectal cancer. Patients should be informed of the evidence gap, be given the opportunity to carefully discuss pros and cons of all the possible management options and be empowered in the decision making. In this article we review the available evidence on adjuvant chemotherapy for rectal cancer and propose a risk-adapted decisional algorithm that largely relies on informed patient preferences.     

Survival outcome of adjuvant radiotherapy after local excision for T2 early rectal cancer: An analysis based on the surveillance,epidemiology, and end result registry database

Background

Major resection (MR) is recommended for cases with T2 finding after local excision (LE) of early rectal cancer, but the revision procedure is accompanied with high morbidity. We evaluated the oncological safety of LE followed by adjuvant radiotherapy as a rectum-preserving alternative to MR for T2 early rectal cancer.

Timing of adjuvant chemotherapy and its relation to survival among patients with stage III colon cancer

BackgroundCurrently available data suggest that delaying the start of adjuvant chemotherapy in colon cancer patients has a detrimental effect on survival. We analysed which factors impact on the timing of adjuvant chemotherapy and evaluated the influence on overall survival (OS).Patients and methodsStage III colon cancer patients who underwent resection and received adjuvant chemotherapy between 2008 and 2013 were selected from the Netherlands Cancer Registry. Timing of adjuvant chemotherapy was subdivided into: ⩽4, 5–6, 7–8, 9–10, 11–12 and 13–16 weeks post-surgery. Multivariable regressions were performed to assess the influence of several factors on the probability of starting treatment within 8 weeks post-surgery and to evaluate the association of timing of adjuvant chemotherapy with 5-year OS.Results6620 patients received adjuvant chemotherapy, 14% commenced after 8 weeks. Factors associated with starting treatment after 8 weeks were older age (Odds ratio (OR) 65–74 versus <65 years 1.3 (95% confidence interval (CI): 1.14–1.58); OR ⩾75 versus <65 years 1.6 (1.25–1.94)), emergency resection (OR 1.8 (1.41–2.32)), anastomotic leakage (OR 8.1 (6.14–10.62)), referral to another hospital for adjuvant chemotherapy (OR 1.9 (1.36–2.57)) and prolonged postoperative hospital admission (OR 4.7 (3.30–6.68)). Starting 5–8 weeks post-surgery showed no decrease in OS compared to initiation within 4 weeks (Hazard ratio (HR) 5–6 weeks 0.9 (0.79–1.11); HR 7–8 weeks 1.1 (0.91–1.30)). However, commencing beyond 8 weeks was associated with decreased OS compared to initiation within 8 weeks (HR 9–10 weeks 1.4 (1.21–1.68); HR 11–12 weeks 1.3 (1.06–1.59); HR 13–16 weeks 1.7 (1.23–2.23)).ConclusionOur data support initiating adjuvant chemotherapy in stage III colon cancer patients within 8 weeks post-surgery.     

Oral cancer survival in young people in South East England

The incidence rate of oral cancer among young people in the UK has been increasing since 1970s. The objective of this study was to compare relative survival of young people (under 45 years of age) diagnosed with oral cancer with that of older people (45 years and older) resident in South East England. Between 1986 and 2002, 5 year relative survival was higher among young people compared with the older group, suggesting age was a strong independent predictor of survival. Apart from age other independent predictors of survival included stage, treatment and affluence but residence was not a significant predictor of survival in either age group. For the young age group (0–44 years) mean relative survival for the period under study was relatively constant but consistently higher in younger women than in younger men.     

Adjuvant radiation therapy for rectal cancer

Since 1976, 104 patients with rectal cancer have been treated with a new approach of combined pre- and postoperative radiation. All patients were given 500 rad preoperative irradiation on the day of or the day before surgery. Surgery in the majority of patients was an abdominal perineal resection. The disease was then staged pathologically according to Astler-Coller's modification of Duke's staging. Patients with early stage cancer (Stages A and B1) were followed with no further therapy. Patients with poor prognostic characteristics (Stages B2, C1, C2) were given postoperative pelvic irradiation (4500 rad in 5 weeks). Twenty-nine patients were found to have Stage A or B1 cancer and were followed with no further therapy. Of these 29 patients, 1 patient developed recurrence and one has died of metastatic disease. The excellent survival of patients with early tumors indicates that minimizing the role of adjuvant therapy in this group has not been detrimental to their survival. Fifteen were found to have liver metastases at laparotomy and had just a colostomy and palliative therapy. Sixty patients had Stage B2 and C disease. Thirty-one received postoperative irradiation as per protocol. Twenty-nine patients did not receive postoperative irradiation for a variety of reasons. Follow-up ranges from 1 to 7 years in these patients. Of the 29 patients with Stage B2 and C disease who should have but did not receive postoperative radiation, 10 patients (34%) have developed a recurrence in the pelvis, and 5 other patients (17%) have developed metastatic disease. Of 31 patients who received postoperative irradiation, only 2 patients (6%) developed a local recurrence and 4 patients (13%) have developed distant metastases. Survival at 3 years was 80% for patients receiving the combined treatment, as compared to 42% for those not receiving the postoperative part of the treatment protocol.     

Centralisation of rectal cancer care has improved patient survival in the republic of Ireland

BackgroundCentralisation of rectal cancer surgery to designated centres was a key objective of the Irish national cancer control program. A national audit of rectal cancer surgery indicated centralisation was associated with improved early surgical outcomes. This study aimed to determine the impact of implementation of the national cancer strategy on survival from rectal cancer.Materials and methodsData were collected from the National Cancer Registry of Ireland to include all patients with Stage I-III rectal cancer undergoing rectal cancer surgery with curative intent between 2003 and 2012. Five-year overall survival and cancer-specific survival was compared between patients in the pre-centralisation (2003–2007) and post-centralisation period (2008–2012) and between patients receiving surgery in designated cancer centres and non-cancer centres.ResultsThe proportion of rectal cancer surgery performed in a designated cancer centre increased from 42% during 2003–2007 to 58% during 2008–2012. Five-year overall survival increased from 66.1% in 2003–2007 to 73.5% in 2008–2012 (p < 0.001). Five-year cancer-specific survival increased from 75.3% in 2003–2007 to 81.9% in 2008–2012 (p < 0.001). Surgery in a cancer centre and surgery post-centralisation were significantly associated with overall and cancer specific survival using Cox proportional hazards regression.ConclusionSurvival following resection of rectal cancer was significantly improved following implementation of a national cancer strategy incorporating centralisation of rectal cancer surgery.     

ⅠB期非小细胞肺癌术后辅助化疗的争议和共识

临床上有20％～25％的非小细胞肺癌（NSCLC）患者可手术治疗,但5年生存率也只有40％左右。辅助化疗是部分早期可切除肺癌的标准治疗方式,可使4％～15％的患者生存获益。但是,ⅠB期NSCLC是否能从辅助化疗中获益仍存在争议。近年来,多个临床研究评价了ⅠB期NSCLC辅助化疗的疗效,我们通过分析这些临床研究,寻找ⅠB期NSCLC的高危人群和辅助化疗的适应证。     

Does delayed initiation of adjuvant chemotherapy following the curative resection affect the survival outcome of gastric cancer patients: A systematic review and meta-analysis

BackgroundAdjuvant chemotherapy(AC) following the curative resection could improve the survival outcome of advanced gastric cancer(GC) patients. However, there is no specific timing interval from radical surgery to initiation of AC. Whether delayed initiation of AC could affect the survival outcome of these patients remains unclear. In this study, we performed a systematic review and meta-analysis to evaluate the relationship between delaying AC and the survival outcome of GC patients.MethodsPubMed, Embase and Cochrane Library databases were systematically searched for eligible studies that evaluated the relationship between time to AC and survival outcome. Survival data for HR and 95% CI were extracted and converted to a regression coefficient(β) corresponding to a continuous representation per 4-week delay of AC. Individual adjusted β were combined using a fixed-effects or random-effects model. Heterogeneity was assessed by I² statistic and publication bias was detected using standard error-based funnel plots.ResultsA total of 11 eligible studies involving 6,017 patients were included in this meta-analysis. Eight studies evaluated the impact of delaying AC on overall survival(OS) and five evaluated the impact of delaying AC on disease-free survival(DFS). The pooled results demonstrated that the initiation of AC per 4-week delay was associated with a significant decrease in OS(HR:1.05, 95% CI: 1.03–1.08, P < 0.001; I² = 18.5%) and DFS (HR:1.06, 95% CI: 1.02–1.10, P = 0.001; I² = 40.6%).ConclusionThe initiation of AC per 4-week delay was associated with worse survival outcomes in GC patients. If physical status and postoperative recovery were appropriated, GC patients should be recommended to receive adjuvant chemotherapy timely.     

Outcomes of young patients diagnosed with locally advanced rectal cancer

BackgroundThe incidence of rectal cancer is higher in the older population. In developed nations, there has been a rise in incidence in young onset colorectal cancer (CRC). We examined the outcomes of locally advanced rectal cancer (LARC) in younger patients (yRC) compared with older patients, using a retrospective audit.MethodsAll cases of LARC referred to two tertiary referral cancer centres in Western Sydney were examined. Patient demographics, presenting symptoms, treatment, relapse free survival (RFS), overall survival (OS) and progression free survival (PFS) were obtained. Under 50 years old was used as the cut-off age for defining yRC.ResultsAll 145 consecutive patients were treated for LARC, including 28 in the yRC and 117 in the older patient group. Median follow-up was 54 months. yRC were more likely to complete neoadjuvant therapy (100% vs. 86%; P=0.032) and to undergo more extensive surgical procedures (24% vs. 2%, P<0.0001). yRC were more likely to have microsatellite high (MSI) tumours (30% vs. 4.7%; P=0.003). yRC demonstrated significantly poorer RFS compared with the standard group (HR 2.79; median RFS 4.67 vs. 16.02 months; P=0.023). In the relapsed setting, yRC had poorer PFS compared with the standard group (median PFS 2.66 vs. 9.70, P=0.006, HR 3.04). A difference in OS was also seen between the two groups, with yRC demonstrating poorer OS (median OS 40.46 vs. 58.26 months, HR 3.48, P=0.036).ConclusionsPatients under 50 years with LARC are more likely to have MSI tumours with a more aggressive disease course and poorer RFS, PFS and OS. Initiatives to improve early detection of these patients may improve outcomes. Further research is necessary to understand this disease and optimise its treatment.     

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer

PURPOSE: 5-Fluorouracil-based chemotherapy with concurrent radiotherapy (RT) is the standard adjuvant treatment in rectal cancer. A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicities of capecitabine combined with standard RT as adjuvant treatment in patients with rectal cancer. METHODS AND MATERIALS: Patients with Stage II-III rectal cancer after surgery were eligible. RT included a total dose of 50.4 Gy in fractions of 1.8 Gy/d, 5 d/wk, for 5.5 weeks. Capecitabine was administered twice daily in escalating doses during the entire period of RT. Dose-limiting toxicity included Grade 4 neutropenia or thrombocytopenia, febrile neutropenia, Grade 3 or greater nonhematologic toxicity, or treatment delay because of unresolved toxicity for >1 week. RESULTS: Thirty-one patients were enrolled at the following dose levels: 1000 mg/m(2)/d (3 patients), 1150 mg/m(2)/d (4 patients) 1300 mg/m(2)/d (6 patients), 1400 mg/m(2)/d (6 patients), 1500 mg/m(2)/d (3 patients), 1600 mg/m(2)/d (3 patients), and 1700 mg/m(2)/d (6 patients). Dose-limiting toxicities were observed in 2 patients at 1300 mg/m(2)/d (Grade 3 diarrhea), and 2 patients at 1400 mg/m(2)/d (skin toxicity in 1 and abdominal pain with fever in 1, resulting in treatment delay), and 3 patients at 1700 mg/m(2)/d (2 patients had Grade 3 diarrhea and 1 had hand-foot syndrome). Four patients presented with chronic postradiation colitis. CONCLUSIONS: The maximal tolerated dose of capecitabine given concurrently with RT was 1600 mg/m(2)/d in this study. This dose is recommended for additional use in Phase II-III studies.     

Postoperative adjuvant chemotherapy with mitomycin C and UFT for curatively resected rectal cancer. Results from the Cooperative Project No.7 Group of the Japanese Foundation for Multidisciplinary Treatment of Cancer

Background. This study was conducted to evaluate the significance of postoperative adjuvant chemotherapy using mitomycin C (MMC) and UFT (tegafur; uracil at 1:4 molar ratio) in combination for rectal cancer. Methods. The Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a prospective randomized controlled trial in 834 patients who had undergone curative resection for rectal cancer (T3 or T4 and/or Nl, N2, or N3 according to TNM classification) from February 1986 to December 1988. The patients were randomly allocated to a treatment group (MMC/UFT, 416 patients) and a control group (surgery alone, 418 patients). For the patients in the treatment group, 20 mg of MMC was sprinkled on the operating field upon completion of surgery. MMC was injected intravenously (6 mg/m²) on day 7, and then once a month for months 1–6 after surgery. UFT was administered at 400mg/day, orally, for 1 year, beginning 3 weeks after surgery. Results. There was no difference, in the 5-year survival rate between the two groups, but the 5-year disease-free survival rate in the MMC/UFT group (68.9%) was significantly higher than that (59.3%) in the control group (P = 0.006). The 5-year cumulative local recurrence rate was significantly lower in the MMC/UFT group (11.6%) than in the control group (19.0%) (P = 0.007). Conclusion. We conclude that the adjuvant use of longterm oral UFT and intermittent MMC (i.v.) improves the disease-free survival rate of patients with curatively resected rectal cancer (T3 or T4 and/or N1, N2, or N3).     

Oncologic benefit of adjuvant chemotherapy for locally advanced rectal cancer after neoadjuvant chemoradiotherapy and curative surgery with selective lateral pelvic lymph node dissection: An international retrospective cohort study

IntroductionIntensive local treatment comprising total mesorectal excision (TME) with selective lateral pelvic lymph node dissection (LPND) after neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) has received attention among clinicians treating rectal cancer. It remains unclear whether adjuvant chemotherapy (ACT) after intensive local treatment is beneficial for these patients. We evaluated the oncologic benefit of ACT for patients with LARC who received intensive local treatment.Materials and methodsThis international multicentre retrospective cohort study included 737 patients treated in Japan and Korea between 2010 and 2017. The effectiveness of ACT on recurrence-free survival (RFS) was evaluated using univariable and multivariable Cox proportional hazards models, with subgroup analyses to identify subpopulations potentially benefiting from ACT.ResultsThe median follow-up was 49 months; the 5-year RFS and local recurrence rates for the entire cohort were 72.1% and 4.9%, respectively; 514 patients (69.7%) received adjuvant chemotherapy, without an oncologic benefit (hazard ratio, 1.14; 95% confidence interval [CI]: 0.79–1.68) demonstrated in the multivariable Cox regression analysis. In subgroup analyses, the distributions of the 95% CI in patients aged ≥70 years and those with ypStage 0 tended to place a disproportionate emphasis that favoured the non-ACT treatment strategy.ConclusionDespite achieving good local control with intensive local treatment strategy, the effectiveness of ACT for the LARC patients with CRT followed by TME with selective LPND was not proved. Elderly patients and those with ypStage0 may not receive benefit from ACT after CRT and TME ± LPND.     

Impact of the interval between short-course radiotherapy and surgery on outcomes of rectal cancer patients

AimsPre-operative radiotherapy has proven to reduce local recurrences after curative surgery for rectal cancer. Radiotherapy is generally well tolerated, although postoperative morbidity and mortality was increased in some patients. Current study was undertaken to analyse whether the interval between preoperative radiotherapy and surgery influences post-operative mortality and recurrence for two cohorts.MethodsAll Dutch patients included in the total mesorectal excision (TME)-trial receiving radiotherapy for resectable rectal cancer were included in this study (n = 642). The verification set consisted of all patients receiving short-course radiotherapy for resectable rectal cancer in two radiotherapy clinics in The Netherlands (n = 600). Univariate and multivariable survival analyses for overall survival, disease-free survival, local recurrence-free survival and non-cancer related survival were calculated.ResultsPatients aged 75 years and older treated during the TME-trial showed a worse overall and non-cancer-related survival when surgically treated 4–7 days after the last fraction of radiotherapy. No differences in survival between the interval groups were found in the verification set.ConclusionPresent study found that elderly patients aged 75 years and older operated 4–7 days after the last fraction of radiotherapy had a higher chance of dying due to non-cancer-related causes during the TME-trial as compared to patients with an interval of 0–3 days. In the verification set similar differences could not be confirmed, which could be due to awareness of the clinicians who avoided delayed surgery after radiotherapy since the results have been presented during congresses. A longer than recommended interval between radiotherapy and surgery should be avoided. Besides, the verification set suggests that radiotherapy duration of 7 days is acceptable.     

Surgical approach for rectal cancer: A network meta-analysis comparing open,laparoscopic, robotic and transanal TME approaches

BackgroundThe optimal approach for total mesorectal excision (TME) of rectal cancer remains controversial.AimTo compare short- and long-term outcomes after open (OpTME), laparoscopic (LapTME), robotic (RoTME) and transanal TME (TaTME).MethodsA systematic search of electronic databases was performed up to January 1, 2020 for randomized controlled trials (RCTs) comparing at least 2 TME strategies. A Bayesian arm-based random effect network meta-analysis (NMA) was performed, specifically, a mixed treatment comparison (MTC).Results30 RCTs (and six updates) of 5586 patients with rectal cancer were included. No significant differences were identified in recurrence rates or survival rates. Operating time was shorter with OpTME (surface under the cumulative ranking curve [SUCRA] 0.96) compared to LapTME, RoTME and TaTME. Although OpTME was associated with the most blood loss (SUCRA 0.90) and had a slower recovery with increased length of stay (SUCRA 0.90) compared to the minimally invasive techniques, there was no difference in postoperative morbidity. OpTME was associated with a more complete TME specimen compared to LapTME (Risk Ratio [RR] 1.05, 95% Credible Interval [CrI] 1.01, 1.11), and TaTME had less involved CRMs (RR 0.173, 95% CrI 0.02, 0.76) versus LapTME. There were no differences between the modalities in terms of deep TME defects, DRM distance, or lymph node yield.ConclusionsWhile OpTME was the most effective TME modality for short term histopathological resection quality, there was no difference in long-term oncologic outcomes. Minimally invasive approaches enhance postoperative recovery, at the cost of longer operating times. Technique selection should be based on individual tumour characteristics and patient expectations, as well as surgeon and institutional expertise.     

A phase I study of concurrent radiotherapy and capecitabine as adjuvant treatment for operable rectal cancer

PURPOSE: To determine the maximum tolerated dose and the dose-limiting toxicity of capecitabine with standard radiotherapy (RT) as adjuvant treatment in patients with rectal cancer. METHODS AND MATERIALS: Patients with Stage II/III rectal cancer after surgery were eligible. Total RT dose was delivered as DT 50 Gy in fractions of 2.0 Gy/day for 5 weeks to the pelvic area. Capecitabine was administered concurrently with RT in escalating doses, twice daily with a 12-h interval, for two cycles of 14 days separated by a 7-day rest. Dose-limiting toxicity included Grade 3 or Grade 4 hematologic and nonhematologic toxicity. RESULTS: Twenty-four patients were enrolled at the following dose levels: 1,000 (3 patients), 1,200 (3 patients), 1,400 (3 patients), 1,500 (3 patients), 1,600 (6 patients), and 1,700 mg/m2/day (6 patients). Dose-limiting toxicity was observed in 1 patient at 1,600 mg/m2/day (Grade 3 diarrhea) and in 2 patients at 1,700 mg/m2/day (1 patient had Grade 3 and 1 Grade 4 diarrhea). CONCLUSION: The maximum tolerated dose (MTD) of capecitabine given concurrently with RT was 1,600 mg/m2, daily from the 1st to the 14th day, with a 7-day rest, for two cycles.