Introduction
1. Guideline objectives
2. How to use these guidelines
3. Users
4. How to develop these guidelines
1) Recording methods
2) Evidence level and strength of recommendations of CQs
2-1) Evidence level
Step 1 (evaluation of individual study): study design, evaluation of bias risk, create structured abstract |
Step 2 (overall rating for each important outcome across studies): |
1. Initial quality of a body of evidence: evaluation of each study design group |
・Systematic reviews, meta-analysis, randomized controlled trials = “initial quality A (high level)” |
・Observation studies, cohort studies, case control studies = “initial quality C (low level)” |
・Case series, case reports = “initial quality D (very low level)” |
2. Five possible reasons for downrating the quality |
・Risk of bias |
・Inconsistency in results |
・Indirectness of evidence |
・Data imprecision |
・High possibility of publication bias |
3. Three possible reasons for uprating the quality |
・Large effect with no confounding factors |
・Dose–response gradient |
・Possible confounding factors are weaker than actual effects |
4. We evaluate 1->2->3, and assess the quality of a body of evidence |
A (high): | We are very confident in the estimate of the effect |
B (moderate): | We are moderately confident in the estimate of the effect: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different |
C (low): | Our confidence in the estimate of the effect is limited: the true effect may be substantially different from the estimate of the effect |
D (very low): | We have very little confidence in the estimate of the effect: the true effect is likely to be substantially different from the estimate of effect |
2-2) Strength of recommendations
Strength of recommendation |
---|
1 Strong recommendation |
Strongly “for” an intervention |
Strongly “against” an intervention |
2 Weak recommendation |
Weakly “for” an intervention |
Weakly “against” an intervention |
5. Literature search
Number of articles retrieved | Number of articles selected | Number of articles retrieved manually | |||
---|---|---|---|---|---|
PubMed | Ichushi | PubMed | Ichushi | ||
(1) Endoscopic treatment of colorectal cancer | 811 | 385 | 80 | 40 | 39 |
(2) Treatment of Stage 0 to Stage III colorectal cancer | 469 | 285 | 92 | 14 | 12 |
(3) Treatment of Stage IV colorectal cancer | 237 | 102 | 97 | 14 | 13 |
(4) Treatment of liver metastases of colorectal cancer | 812 | 357 | 364 | 79 | 25 |
(5) Treatment of lung metastases of colorectal cancer | 96 | 157 | 46 | 35 | 6 |
(6) Treatment of recurrent colorectal cancer | 688 | 302 | 147 | 29 | 13 |
(7) Adjuvant chemotherapy for colorectal cancer | 639 | 228 | 209 | 32 | 41 |
(8) Chemotherapy for advanced or recurrent colorectal cancer | 762 | 149 | 254 | 44 | 154 |
(9) Adjuvant radiotherapy for colorectal cancer | 447 | 95 | 115 | 8 | 27 |
(10) Palliative radiotherapy for colorectal cancer | 708 | 39 | 109 | 6 | 29 |
(11) Palliative care for colorectal cancer | 278 | 181 | 58 | 18 | 10 |
(12) Surveillance after surgery for colorectal cancer | 1,446 | 1,287 | 256 | 57 | 20 |
Total | 7,393 | 3,567 | 1,837 | 376 | 389 |
6. Funding
7. Conflicts of interest
1) The following corporations were disclosed by self-declaration of the Guideline Committee members and Guideline Evaluation Committee members
2) Overcoming possible conflicts of interest
Treatment guidelines for colorectal cancer
Chapter 1: Treatment strategies for Stage 0 to Stage III colorectal cancer [26]
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General principles underlying indications for endoscopic resection
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There is little possibility of lymph node metastasis, and the size and location of the tumor make en bloc resection possible.
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Indication criteria for endoscopic resection:(1)Intramucosal carcinoma or carcinoma with slight submucosal invasion(2)Size does not matter(3)Any macroscopic type
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Endoscopic treatment is a method of endoscopically resecting lesions in the large bowel and of collecting the resected specimens.
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Endoscopic treatment methods are polypectomy,note 1 endoscopic mucosal resection (EMR),note 2 and endoscopic submucosal dissection (ESD).note 3
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In determining the indication for endoscopic treatment and the method of treatment, information on the size, predicted depth of invasion, and morphology of the tumor is essential.
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Comments
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2 cm is the largest size of a tumor that can be easily resected en bloc by polypectomy or snare EMR [27] (CQ-2).
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Colorectal ESD is an “endoscopic resection technique which enables en-bloc resection of a tumor, irrespective of size”, which was approved for implementation under health insurance in April 2014 with regard to “early-stage malignant tumors”. Given the high likelihood of technically difficult complications (perforations), however, it should only be implemented after sufficient consideration of the level of skill of the endoscopist performing the procedure. Tumors with a diameter between 2 and 5 cm are currently covered by insurance (CQ-3).
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EMRC (EMR using a cap) is reported to involve a high risk of perforation when used for colon lesions.
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If the preoperative diagnosis is cancer accompanied by adenoma (intramucosal carcinoma), piecemeal resection of the adenoma can be performed while avoiding division of the cancerous area. It should be noted, however, that piecemeal resection is associated with a high incidence of incomplete resection and high local recurrence [27].
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The extent of lymph node dissection to be performed during colorectal cancer surgery is determined on the basis of the preoperative clinical findings, and on the extent of lymph node metastasis and depth of tumor invasion by the tumor observed intraoperatively.
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If lymph node metastasis is recognized, or suspected on the basis of the preoperative/intraoperative findings, D3 dissection is performed.
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If no lymph node metastases are observed on the basis of preoperative and/or intraoperative diagnostic findings, lymph node dissection is performed on the basis of the depth of tumor invasion [29].(1)Lymph node dissection is unnecessary for pTis (M) cancer (D0), because pTis (M) cancer is not accompanied by lymph node metastasis; however, D1 dissection can be performed because the accuracy of the preoperative diagnosis of invasion depth may be insufficient.(2)D2 dissection is necessary for pT1 (SM) cancer, because the incidence of lymph node metastasis is approximately 10 % and because pT1 (SM) cancer is often accompanied by intermediate lymph node metastasis.(3)Although there is insufficient evidence of the extent of lymph node dissection for cT2 (MP) cancer, at least D2 dissection is necessary. However, D3 dissection can be performed, because approximately 1 % of cT2 (MP) cancer is accompanied by main lymph node metastases (Table 5) and because preoperative diagnosis of depth of invasion is not very accurate.Table 5Lateral lymph node dissection and lateral lymph node metastasis of rectal cancerNo. of patientsNo. of patients who underwent lateral dissectionPrevalence of lateral dissectionNo. of patients with lateral metastasisIncidence of metastasis (percentage of all patients)Incidence of lateral metastasis (percentage of patients who underwent lateral dissection)RSsm1240000.00.0mp12764.7 %00.00.0ss/a1316247.5 %00.00.0se/a217784.5 %00.00.0si/ai321443.8 %13.17.1Total776526.7 %10.11.9Rasm13853.6 %00.00.0mp1491812.1 %00.00.0ss/a12305825.2 %41.76.9se/a21815932.6 %73.911.9si/ai15853.3 %00.00.0Total71314820.8 %111.57.4RaRb + Rbsm2343715.8 %20.95.4mp37221858.6 %205.49.2ss/a135023065.7 %287.712.2se/a241231977.4 %7518.023.5si/ai594881.4 %1728.835.4Total1,42785259.7 %1429.816.7
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[Indications for lateral lymph node dissection]
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Lateral lymph node dissection is indicated when the lower border of the tumor is located distal to the peritoneal reflection and the tumor has invaded beyond the muscularis propria [30].
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[Local excision for rectal cancer]
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Local excision is indicated for cTis (M) cancer and cT1 (SM) cancer (slight invasion) located distal to the second Houston valve (peritoneal reflection).
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Histological investigation of the resected specimen enables determination of the likelihood that treatment will cure the condition completely, and the need for additional treatment (intestinal resection accompanied by lymph node dissection).
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[Autonomic nerve-preserving surgery]
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The autonomic nervous system of concern in surgery for rectal cancer comprises the lumbar splanchnic nerves, superior hypogastric plexus, hypogastric nerves, pelvic splanchnic nerves, and pelvic plexus. Taking into consideration such factors as the extent of cancer progression and the presence or absence of macroscopic nerve invasion, preservation of autonomic nerves is attempted to preserve urinary and sexual function as much as possible, if curability is unaffected.
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Laparoscopic surgery:
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The indications for laparoscopic surgery are determined by considering the surgeon’s experience and skills and characteristics of the tumor, for example the location and extent of progression of the cancer, and patient factors, for example obesity and history of open abdominal surgery (CQ-4).
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Comments
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[Lateral lymph node dissection]①An analysis of 2,916 cases of rectal cancer in the project study by the JSCCR showed that the incidence of lateral lymph node metastasis was 20.1 % among patients whose lower tumor border was located distal to the peritoneal reflection and whose cancer invaded beyond the muscularis propria (only patients who underwent lateral lymph node dissection) (Table 5). After performing lateral lymph node dissection for this indication, it is expected that the risk of intrapelvic recurrence decreases by 50 %, and 5-year survival improves by 8 to 9 % [34].②The incidence of lateral lymph node metastasis was 27 % among patients whose lower tumor border was located distal to the peritoneal reflection and who had lymph node metastasis in the mesorectum.③Urinary function and male sexual function may be impaired after lateral dissection, even if the autonomic nervous system is completely preserved.
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[Aggregate data from the colorectal cancer registry]①The incidence of lymph node metastasis according to site and depth of tumor invasion, prevalence of curative resection, and 5-year survival is shown in Tables 6, 7, and 8 [29].Table 6Incidence of lymph node metastasis according to primary site and depth of tumor invasionNo. of patientsExtent of lymph node metastasis detected histologicallyn 0 (%)n 1 (%)n 2 (%)n 3 (%)n 4 (%)All sitessm3,15190.77.31.90.00.1mp3,59077.317.44.20.90.3ss/a111,27254.629.912.02.31.2se/a26,10135.934.420.25.73.8si/ai1,50243.027.616.46.76.3Total25,61757.126.311.92.91.9Colonsm1,95791.46.81.80.00.0mp1,74779.316.33.50.60.3ss/a17,33356.628.111.72.41.2se/a23,36337.434.019.35.63.7si/ai96044.628.614.75.56.6Total15,36058.625.411.32.81.8Rectosigmoidsm33788.79.51.80.00.0mp42980.417.02.60.00.0ss/a11,58453.933.010.21.31.7se/a278934.238.420.83.23.4si/ai18744.924.619.34.86.4Total3,32655.729.311.41.62.0Rectumsm83989.77.72.00.10.4mp1,37373.919.25.41.40.1ss/a12,31048.833.314.22.71.0se/a21,90433.933.621.56.84.1si/ai32838.126.219.810.45.5Total6,75454.327.013.33.61.8Anal canalsm1894.40.05.60.00.0mp4170.79.87.37.34.9ss/a14560.022.28.96.72.2se/a24632.621.723.915.26.5si/ai2733.325.914.818.57.4Total17754.817.513.010.24.5Table 7Curative resection rate according to stage (lower rows: no. of patients)StageIIIIIIaIIIbIVAll stagesAll patients98.7 %96.2 %91.9 %81.8 %−78.0 %5,4557,3365,6352,5724,30025,298Colon99.1 %96.6 %92.4 %83.6 %−77.2 %3,0284,6883,2081,3792,78715,090Rectosigmoid99.5 %96.6 %92.5 %80.2 %−78.0 %6159618352885603,259Rectum97.9 %95.0 %90.9 %80.5 %−79.9 %1,7641,6441,5648669296,767Anal canal95.8 %86.0 %78.6 %61.5 %−70.9 %4843283924182Table 8Cumulative 5-year survival according to site (lower rows: no. of patients)Stage0IIIIIIaIIIbIVAll StagesCecum91.0 %93.7 %83.5 %73.0 %65.4 %12.5 %68.2 %791852492071132041,037Ascending colon93.9 %91.2 %85.8 %79.1 %63.4 %19.1 %71.4 %1253386564162114102,156Transverse colon88.9 %91.4 %85.2 %78.5 %65.7 %20.8 %74.0 %1052774282441382101,402Descending colon100.0 %94.1 %85.3 %82.0 %52.9 %21.1 %75.4 %4314622416652117748Sigmoid colon94.2 %92.3 %85.8 %83.0 %64.7 %22.0 %73.7 %1548521,1248373637364,066Rectosigmoid89.4 %91.5 %84.8 %78.0 %60.0 %19.8 %71.6 %543665394731753221,929Upper rectum98.0 %95.3 %84.6 %75.9 %57.7 %11.6 %72.4 %673564644711732631,794Lower rectum97.5 %88.3 %81.7 %70.0 %51.4 %11.6 %70.5 %1427184864733322982,449Anal canal100.0 %78.7 %90.9 %46.9 %61.2 %15.7 %60.0 %4161416191786Colon93.0 %92.3 %85.4 %80.4 %63.8 %19.9 %72.8 %5061,7982,6811,8708771,6779,409Rectum97.6 %90.6 %83.1 %73.0 %53.5 %14.8 %71.3 %2091,0749509445055614,243All sites94.0 %91.6 %84.8 %77.7 %60.0 %18.8 %72.1 %7733,2544,1843,3031,5762,57715,667②Five-year survival after curative resection of pStage 0 to pStage III colorectal cancer according to site was: all sites 82.2 %, colon 83.8 %, rectosigmoid 81.7 %, Ra-Rb rectum 79.3 % (patients in years 2000–2004).
Chapter 2: Treatment strategies for Stage IV colorectal cancer [26] (Fig. 3)
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Stage IV colorectal cancer is associated with synchronous distant metastasis to any of the organs: liver, lung, peritoneum, brain, distant lymph nodes, or other organ (e.g., bone, adrenal gland, spleen).
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If both the distant metastases and the primary tumor are resectable, curative resection of the primary tumor is performed, and resection of the distant metastases is considered.
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If the distant metastases are resectable but the primary tumor is unresectable, in principle, resection of the primary tumor and distant metastases is not performed, and another treatment method is selected.
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If the distant metastases are unresectable but the primary tumor is resectable, the indication for resection of the primary tumor is determined on the basis of the clinical symptoms of the primary tumor and the effect on prognosis (CQ-5).
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Comments①The incidence of synchronous distant metastasis is shown in Table 9.Table 9Incidence of synchronous distant metastasis of colorectal cancerLiverLungPeritoneumOther sitesBoneBrainVirchowOtherTotalColon cancer11.8 %2.2 %5.7 %0.3 %0.0 %0.1 %1.3 %1.8 %No. of patients 15,3911,81533887547623205281Rectal cancer9.5 %2.7 %2.6 %0.5 %0.0 %0.1 %1.1 %1.7 %No. of patients 10,2219702732664956112172Total no. of patients10.9 %2.4 %4.5 %0.4 %0.0 %0.1 %1.2 %1.8 %25,6212,7856111,141961129317453②Distant metastasis associated with peritoneal dissemination (CQ-6).
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Complete resection is desirable for P1.
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Complete resection is considered for P2 when easily resectable.
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The efficacy of resection of P3 has not been demonstrated.
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The efficacy and safety of adjuvant chemotherapy after resection of distant metastases in colorectal cancer have not been established, and no randomized controlled trials have been implemented regarding whether or not this extends survival [37, 38] (CQ-8). Ideally, appropriately planned clinical trials should be conducted.
Chapter 3: Treatment strategies for recurrent colorectal cancer (Fig. 4)
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The purpose of treatment of recurrent colorectal cancer is improvement of prognosis and the patient’s QOL.
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Treatment methods include surgery, systemic chemotherapy, arterial infusion chemotherapy, thermal coagulation therapy, and radiotherapy.
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An appropriate treatment method is selected with the informed consent of the patient, taking into consideration a variety of factors, for example prognosis, complications, and QOL expected after treatment.
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If recurrence is observed in a single organ and complete surgical resection of the recurrent tumor(s) is possible, resection is strongly considered.
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Some authors believe that resection of liver or lung metastases should be performed only after a specific period of observation to rule out occult metastases [40].
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Treatment methods for hematogenous metastases are discussed in Chapter 4 “Treatment strategies for hematogenous metastases”).
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Local recurrences of rectal cancer take the form of anastomotic recurrences and intrapelvic recurrences.(1)Resection is considered for resectable recurrences.(2)Radiotherapy and systemic chemotherapy, either alone or in combination, are considered for unresectable recurrences.
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Comments
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[Local recurrence of rectal cancer]①The extent of spread of the recurrent tumor is evaluated by diagnostic imaging, and resection is considered only for patients in whom complete resection can be expected, after taking into consideration such factors as the pattern of recurrence, symptoms, and physical findings (CQ-10).
Chapter 4: Treatment strategies for hematogenous metastases (Fig. 5)
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Treatment of liver metastases is broadly divided into hepatectomy, systemic chemotherapy, hepatic arterial infusion therapy, and thermal coagulation therapy.
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Hepatectomy is recommended for liver metastases when curative resection is possible.
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Hepatectomy consists of systematic resection and partial (non-systematic) resection.
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Indication criteria for hepatectomy(1)The patient is capable of tolerating surgery.(2)The primary tumor has been controlled or can be controlled.(3)The metastatic liver tumor can be completely resected.(4)There are no extrahepatic metastases or they can be controlled.(5)The function of the remaining liver will be adequate.
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Systemic chemotherapy is considered for patients with unresectable liver metastases whose general condition can be maintained at a specific level or higher (PS 0 to PS 2).
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Thermal coagulation therapy consists of microwave coagulation therapy (MCT) and radiofrequency ablation (RFA).
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If the patient’s general condition is poor (PS ≥ 3), or there is no effective chemotherapy, best supportive care (BSC) is provided.
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Comments
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[Hepatectomy]①②The efficacy of systemic chemotherapy and hepatic arterial infusion therapy after hepatectomy has not been established (CQ-8).③The safety of preoperative chemotherapy for resectable liver metastases has not been established (CQ-11).
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[Treatment methods other than resection]①Systemic chemotherapy is performed for patients with unresectable liver metastases (CQ-9).②In cases of inoperable liver metastasis, the primary lesion should, ideally, be managed if hepatic arterial infusion therapy or heat coagulation therapy is being used (CQ-17, CQ-12).③Heat coagulation therapy is advantageous in that it is minimally invasive, in addition to having been reported as improving local control and long-term survival in some cases [44, 45]. However, there have not yet been any studies or reports of long-term prognosis involving sufficiently cumulative case studies; consequently, its efficacy has not been established. There is a high incidence of recurrence in comparison with resection, however, and long-term survival is reported to be poor [46], so it is not recommended as an alternative to surgical resection [47] (CQ-12).
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Treatment of lung metastases consists of pneumonectomy and systemic chemotherapy, and radiotherapy.
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Pneumonectomy is considered if the metastatic lung tumor is resectable.
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Pneumonectomy consists of systematic resection and partial (non-systematic) resection.
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Indication criteria for pneumonectomy(1)The patient is capable of tolerating surgery.(2)The primary tumor has been controlled or can be controlled.(3)The metastatic lung tumor can be completely resected.(4)There are no extrapulmonary metastases or they can be controlled.(5)The function of the remaining lung will be adequate.
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Systemic chemotherapy is considered for patients with unresectable lung metastases whose general condition can be maintained at a specific level or higher.
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Even if the patient cannot tolerate surgery, stereotactic body radiotherapy is considered if the primary tumor and extrapulmonary metastases are controlled or can be controlled and the number of lung metastases less than 5 cm in diameter is no more than three [48].
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If the patient’s general condition is poor, appropriate BSC is provided.
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Brain metastases are often detected as part of a systemic disease, and surgical therapy or radiotherapy is considered for lesions for which treatment can be expected to be effective.
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The optimum treatment method is selected after considering the patient’s general condition and status of other metastatic tumors, and after evaluating the size and location of metastatic brain tumors and the number of brain lesions.
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Radiotherapy is considered for patients with unresectable metastases.
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[Surgical therapy]
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Indications for brain resection [49](1)The patient has a life expectancy of at least several months.(2)Resection will not cause significant neurological symptoms.(3)There are no metastases to other organs or they can be controlled.
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[Radiotherapy]
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The purpose of radiotherapy is to relieve such symptoms as cranial nerve symptoms and intracranial hypertension symptoms, and to prolong survival time by reducing locoregional relapse.
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Whole-brain radiotherapy is considered for patients with multiple brain metastases and for patients with a solitary brain metastasis for which surgical resection is not indicated.
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Stereotactic irradiation is considered when the number of brain metastases is about no more than three or four and the maximum diameter of each metastasis does not exceed 3 cm.
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Resection is also considered for other hematogenous metastases, for example the adrenal glands, skin, and spleen, if they are resectable. However, patients with such metastases often have metastasis to more than one organ, and chemotherapy or radiotherapy is often indicated.
Chapter 5: Chemotherapy
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Chemotherapy consists of adjuvant chemotherapy to prevent postoperative recurrence and systemic chemotherapy to treat unresectable colorectal cancer.
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Commonly used anticancer drugs that have been approved for the indication of colorectal cancer and are covered by Japanese National Health Insurance are:Oral drugs5-FU, tegafur, UFT, doxifluridine (5′-DFUR), carmofur (HCFU), S-1 (S), UFT + leucovorin (LV), capecitabine (Cape), regorafenib, among othersInjection drugs5-FU, mitomycin C, irinotecan (IRI), 5-FU + l-leucovorin (l-LV), oxaliplatin (OX), bevacizumab (Bmab), cetuximab (Cmab), panitumumab (Pmab), among others
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Postoperative adjuvant chemotherapy is systemic chemotherapy that is performed after surgery to prevent recurrence and improve the prognosis of patients who have undergone R0 resection [50].
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General principles of indications for adjuvant chemotherapy(1)Stage III colorectal cancer (colon and rectal cancer) for which R0 resection has been performed. See CQ-8 for Stage IV resection cases.(2)The function of major organs is maintained. The following guidelines are provided.
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Bone marrow: Peripheral blood WBC count >3500/mm3; platelet count >100,000/mm3
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Liver function: Total bilirubin <2.0 mg/dL; AST/ALT <100 IU/L,
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Renal function: Serum creatinine concentration no higher than the upper limit of the normal at the institution.
(3)Performance status (PS) of 0 or 1.(4)The patient has recovered from postoperative complications, if any.(5)The patient has provided written informed consent.(6)The patient has no serious complications (especially, no intestinal obstruction, diarrhea, or fever). -
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Recommended therapy (listed in the order of the date of their coverage by Japanese National Health Insurance)
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5-FU + l-LV note
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UFT + LV
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Cape
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FOLFOX
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CapeOX
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Recommended administration period (CQ-15)
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In principle, the administration period is 6 months.
NoteThe Roswell Park Memorial Institute (RPMI) method of 5-FU + LV therapy as adjuvant chemotherapy (drip infusion of l-LV 250 mg/m2 administered for 2 h; intravenous infusion of 5-FU 500 mg/m2 slowly administered within 3 min at 1 h after the start of administration of l-LV; once-weekly administration for 6 consecutive weeks followed by a 2-week rest period, 3 cycles every 8 weeks [53]) -
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In best supportive care (BSC) without any chemotherapy, median survival time (MST) for patients with unresectable colorectal cancer has been reported to be approximately 8 months. Although their MST has been extended to approximately 2 years as a result of recent chemotherapy, unresectable colorectal cancer is still difficult to cure.
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The purpose of chemotherapy is to prolong survival time and control symptoms by delaying tumor enlargement.
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Initially unresectable colorectal cancer may become resectable after successful chemotherapy.
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Ideally, patients should be divided into two groups and their treatment policy selected according to whether or not they are appropriate for intensive therapy.
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Patients not appropriate for intensive therapy are defined according to the two aspects patient factors and tumor-related characteristics. Patient factors include patients with a preference for avoiding the occurrence of serious adverse events or those believed to be unable to withstand OX, IRI, or molecular target drugs during first-line treatment because of severe complications. Tumor-related characteristics includes cases of multiple-organ (or multiple) metastases, in which it is considered unlikely that resection will be possible in the future, or patients determined as having asymptomatic, slow progression (those with limited risk of rapid deterioration).
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Cmab and Pmab are only used in response to wild-type KRAS.
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Combination with molecular target drugs, for example Bmab or anti-EGFR antibodies, etc., is recommended, but for patients who are not candidates, chemotherapy alone is conducted.
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General principles underlying the indications for systemic chemotherapy(1)Clinical diagnosis or histopathological diagnosis has been confirmed.(2)The metastatic or recurrent tumor can be confirmed by imaging.(3)Performance status (PS) is 0 to 2.(4)The function of major organs is maintained (administration guidelines are given as 1–3, below).1Bone marrow: peripheral blood WBC count >3500/mm3; platelet count >100,000/mm32Liver function: total bilirubin <2.0 mg/dL; AST/ALT <100 IU/L3Renal function: serum creatinine concentration no higher than the upper limit of the normal range at the institution.(5)The patient has provided written informed consent.(6)The patient has no serious complications (especially, no intestinal obstruction, diarrhea, or fever).
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First-line therapy
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The following are regimens whose usefulness has been demonstrated in clinical trials and that are available as initial therapy covered by Japanese National Health Insurance.
(1)Patients appropriate for intensive therapy -
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Secondary therapy
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The following regimens are considered as chemotherapy for 2nd-line treatment (CQ-16).
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BSC
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If possible, consider the regimen judged to be optimum
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Comments①Careful attention is required when using IRI to treat patients with constitutional jaundice, such as that caused by Gilbert’s syndrome, or to treat patients with high serum bilirubin values. Relationships between genetic polymorphisms of enzymes that metabolize IRI and toxicity have been suggested (attached Side Memo 2).②Although hepatic arterial infusion therapy results in a good response for liver metastasis, no survival benefit has been demonstrate in comparison with systemic chemotherapy [93] (CQ-17).Note 1FOLFOX—infusional 5-FU + l-LV + OXNote 2CapeOX—Cape + OXNote 3FOLFIRI—infusional 5-FU + l-LV + IRINote 4FOLFOXIRI—Infusional 5-FU + l-LV + IRI + OXNote 5IRIS—S-1 + IRI
Chapter 6: Radiotherapy
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Radiotherapy is used to treat patients with locally advanced rectal cancer, either as adjuvant therapy after surgery, to prevent recurrence, or before surgery, to reduce tumor volume and preserve the anal sphincter, and also as palliative care to relieve the symptoms and prolong the survival of patients with unresectable colorectal cancer who have symptomatic lesions.
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Adjuvant radiotherapy is classified into three categories, according to the timing of surgery and radiation therapy: preoperative radiotherapy, intraoperative radiotherapy, and postoperative radiotherapy.
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The purpose of adjuvant radiotherapy is to improve local control and the survival of rectal cancer patients. The purpose of preoperative radiotherapy includes improving anal sphincter preservation and improving resection rate. However, insufficient evidence of improved survival has been found to make this the objective of adjuvant radiotherapy.
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Preoperative radiotherapy is indicated for patients with T stage clinically diagnosed as “invasion depth cT3 (SS/A) or deeper or cN-positive”; postoperative radiotherapy is indicated for patients with T stage pathologically diagnosed after surgery as “invasion depth cT3 (SS/A) or deeper or pN-positive, where the existence of a surgical dissection plane positive (RM1) or penetration of the surgical dissection plane by the cancer (RMX) is unclear”; and intraoperative radiotherapy is indicated for “surgical dissection plane positive (RM1) or penetration of the surgical dissection plane by the cancer (RMX) is unclear”.
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Radiotherapy is delivered with a linear accelerator, with electron beams being used for intraoperative radiotherapy and photon beams for external radiotherapy.
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Comments①Preoperative radiotherapy (CQ-18)1)Preoperative radiotherapy has the following advantages: seeding during surgery can be prevented by inactivating lesions with irradiation; a high percentage of tumor cells are normo-oxic and radiosensitive, because blood flow to the tumor is maintained; there is little damage to the digestive tract, because the small bowel is not fixed within the pelvic cavity, thereby resulting in low radiation-induced delayed toxicity, which means a less toxic postoperative setting; improvement in R0 resection and anal sphincter preservation can be expected because of tumor size reduction [94].2)Preoperative radiotherapy has the following disadvantages: early-stage patients may be subjected to overtreatment and postoperative complications may increase.3)Twelve phase III clinical trials of preoperative radiotherapy (without chemotherapy) have been reported [94], and in 5 of these trials local control was significantly higher in the group that received preoperative radiotherapy than in the surgery alone group. However, improved survival was observed in 1 trial only [95].4)5)6)In the Dutch CKVO 95-04 trial, which compared preoperative radiotherapy (25 Gy delivered in five fractions in 1 week) + TME and TME alone to investigate the significance of adding short-course radiotherapy to TME, 5-year and 10-year local control were significantly higher in the combination therapy group, but 5-year and 10-year survival were not significantly different in the two groups [98‐100]. The incidences of sexual dysfunction and bowel dysfunction were higher in the preoperative radiation combination therapy group than in the surgery-alone group [101, 102].7)The effect of preoperative radiotherapy in reducing the size of the primary tumor may enable sphincter preservation. When the purpose of the preoperative radiotherapy is sphincter preservation, it is desirable to perform surgery after allowing an appropriate period for the tumor to decrease in size (6 to 8 weeks after the completion of radiotherapy) [103].8)In Europe, four randomized controlled trials, including the EORTC trial, were performed to investigate the usefulness of adding chemotherapy to preoperative radiotherapy. The incidence of acute-phase adverse events was significantly higher in the preoperative chemoradiotherapy groups, but pathologic complete response (pCR) was significantly higher than in the preoperative radiotherapy alone groups. In two trials, the exception being the short-course radiotherapy trials, local recurrence was significantly lower in the preoperative chemoradiotherapy group, and sphincter preservation and survival were not significantly different in the two groups [104‐107].9)In a randomized controlled trial that compared preoperative and postoperative chemoradiotherapy, there was no significant difference in the 5-year survival but local recurrence and incidence of grade 3 or higher adverse events were significantly lower in the preoperative chemoradiotherapy group. Among the patients for whom abdominoperineal resection (APR) was considered necessary at the time of enrollment, the percentage of patients for whom sphincter preservation was possible was significantly higher in the preoperative chemoradiotherapy group [108].10)A randomized controlled trial of 5-FU versus Cape combination chemotherapy for preoperative chemoradiotherapy indicated that the two drugs had the same level of efficacy and safety [109, 110]. NCCN guidelines allow the use of either 5-FU or Cape as standard combination chemotherapy for preoperative chemoradiotherapy. The indications and use of Cape as an adjuvant therapy for rectal cancer, however, have not been approved for use under health insurance in Japan. It is believed possible to try using it, within an appropriate volume range, and with the permission of the ethics committee, for appropriate selected cases.11)In randomized controlled trials into the efficacy of adding OX to pyrimidine fluoride as combination chemotherapy for preoperative chemoradiotherapy, OX increased harmful phenomena in three tests and had no efficacy with regard to pCR ratio, localized control ratio, and survival [109, 111‐113]; moreover, in one test, although harmful phenomena were no different and no analysis of disease-free survival was conducted at the primary endpoint, the pCR ratio was significantly higher [114].2.Palliative radiotherapya.Intrapelvic lesions (CQ-19)
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The purpose of palliative radiotherapy for intrapelvic lesions is to relieve symptoms such as pain, hemorrhage, and bowel movement disorders caused by intrapelvic tumors.
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The target volume includes the tumor that is causing the symptoms.
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[Dose and fractionation]
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A total dose of 45 to 50 Gy is administered in 1.8 to 2.0 Gy fractions.
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Depending on the patient’s general condition, for example performance status, and the severity of the symptoms, radiotherapy may be completed more quickly with a larger fraction size, for example 30 Gy in 10 fractions over 2 weeks.
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The purpose of palliative radiotherapy for bone metastases is to achieve pain relief, prevent pathological fractures, and prevent and treat spinal cord paralysis.
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The target volume includes the metastatic bone lesions causing the symptoms.
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[Dose and fractionation]
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Local field radiotherapy, for example 30 Gy in 10 fractions and 20 Gy in 5 fractions, is widely performed.
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Hematogenous metastases are discussed in Chapter 4 “Treatment strategies for hematogenous metastases”.
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[Dose and fractionation]
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When whole brain radiotherapy is performed, 30 Gy in 10 fractions is the standard treatment. If long-term survival is expected, fractionated radiotherapy, for example 37.5 Gy in 15 fractions and 40 Gy in 20 fractions, is considered.
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When stereotactic radiosurgery is performed, a peripheral dose of 16 to 25 Gy is delivered in a single fraction.
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Chapter 7: Palliative care
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Palliative care is a general term for palliative treatment of a variety of mental and physical symptoms related to cancer.
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Palliative care extends from the time the cancer is diagnosed until the end stage, and different care should be provided depending on the disease stage and symptoms.
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In principle, cancer treatment should be performed under conditions in which symptom relief is achieved [115], and palliative care should be started at the same time as surgical treatment and chemotherapy.
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Palliative care to improve the QOL of patients with end-stage colorectal cancer includes:(1)Pain relief(2)Surgical treatment(3)Chemotherapy(4)Radiotherapy(5)Counseling for psychiatric symptoms
Chapter 8: Surveillance after surgery for colorectal cancer
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In principle, the duration of surveillance is 5 years after surgery, but surveillance examinations should be scheduled at shorter intervals during the first 3 years after surgery.
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It should be noted that there is a higher incidence of lung metastasis and local recurrence in rectal cancer than in colon cancer.
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As a general rule, the duration of surveillance for anastomotic recurrence is until 3 years after surgery.
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The following is an example of a surveillance schedule after curative resection of Stage I to Stage III colorectal cancer that was designed on the basis of the results of a retrospective investigation of such factors as the common sites and incidence of recurrence and the efficacy of treatment and clinical practice in Japan (Fig. 7).×
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Colonoscopy is performed for surveillance of metachronous multicentric colorectal cancer.
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Comments①Purpose of surveillance
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The purpose of surveillance is to improve the patient’s prognosis by early detection and treatment of recurrences. Meta-analyses of RCTs conducted in Europe and the United States have shown that surveillance after curative surgical resection of colorectal cancer contributes to improving the likelihood of resection of recurrent tumors and to improving the prognosis [116‐120] (CQ-20-1).
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The results of the project study by the JSCCR are shown in Figs. 8, 9 and Tables 10, 11, 12, 13. The subjects were patients who underwent curative resection of colorectal cancer between 1991 and 1996 at the 14 institutions that participated in the project, and the follow-up period was 6–11 years.Table 10Recurrence after curative resection of colorectal cancer according to stage, and cumulative incidence of recurrence according to number of years after surgeryStage (no. of patients)Incidence of recurrence (no. of patients with recurrence)Cumulative incidence of recurrence according to number of years after surgery (cumulative no. of patients with recurrence)Percentage of patients experiencing recurrence more than 5 years after surgery among all patients (no. of patients)3 years4 years5 yearsI (1,367)3.7 % (51)68.6 % (35)82.4 % (42)96.1 % (49)0.15 % (2)II (1,912)13.3 % (255)76.9 % (196)88.2 % (225)92.9 % (237)0.94 % (18)III (1,957)30.8 % (600)87.0 % (522)93.8 % (563)97.8 % (587)0.67 % (13)All (5,230)17.3 % (906)83.2 % (753)91.6 % (830)96.4 % (873)0.63 % (33)Table 11Recurrence of Stage I colorectal cancer (RS cancer was counted as colon cancer)Stage INo. of patientsNo. of patients with recurrenceRecurrence (%)p valueTumor locationColon891242.70.0056Rectum476275.7Depth of tumor invasionSM71491.3<0.0001MP653426.4Tumor location and depth of tumor invasionColonSM52871.30.0024MP363174.7RectumSM18621.10.0005MP290258.6Table 12Recurrence according to site of first recurrence after curative resection of colorectal cancer, and cumulative incidence of recurrence according to number of years after surgerySite of first recurrenceIncidence of recurrence (no. of patients with recurrence including overlaps)Cumulative incidence of recurrence according to number of years after surgery (cumulative no. of patients with recurrence)Percentage of patients experiencing recurrence more than 5 years after surgery among all patients (no. of patients)3 years4 years5 yearsLiver7.1 % (373)87.9 % (328)94.1 % (351)98.7 % (368)0.10 % (5)Lung4.8 % (250)78.0 % (195)88.8 % (222)94.8 % (237)0.25 % (13)Local4.0 % (209)80.9 % (169)90.4 % (189)96.2 % (201)0.15 % (8)Anastomotic0.4 % (22)95.5 % (21)95.5 % (21)95.5 % (21)0.02 % (1)Other3.8 % (199)79.4 % (158)91.0 % (181)95.5 % (190)0.17 % (9)All (5,230)17.3 % (906)Table 13Comparison of recurrence of colon cancer and rectal cancer according to the site of the first recurrence (RS cancer was counted as colon cancer)Site of recurrenceColon cancer (3583 patients)Rectal cancer (1647 patients)p valueLiver7.0 % (252)7.3 % (121)NSLung3.5 % (126)7.5 % (124)p < 0.0001Local1.8 % (64)8.8 % (145)p = 0.0001Anastomotic0.3 % (9)0.8 % (13)p = 0.0052Other3.6 % (130)4.2 % (69)NSAll14.1 % (506)24.3 % (400)p < 0.0001××
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More than 80 % of the recurrences were detected within 3 years after surgery, and more than 95 % of the recurrences were detected within 5 years after surgery.
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The overall incidence of recurrence more than 5 years after surgery was less than 1 %.
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Among lung recurrences, 5 % of recurrences were detected more than 5 years after surgery.
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More than 95 % of the anastomotic recurrences were detected within 3 years after surgery.
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Local recurrence and lung recurrence were more frequent for rectal cancer than for colon cancer.
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There have been reports of recurrence after curative resection in Europe and the United States showing that approximately 50 % of recurrences were detected within 1 year after surgery, that approximately 70 % of the recurrences were detected within 2 years after surgery [121, 122]; and that for most patients recurrence was detected within 5 years after surgery [122].
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The incidence of recurrence of pT1 (SM) cancer was approximately 1 % for both colon and rectal cancer.
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Overall recurrence of pT2 (MP) cancer was 6.4 %; it was 5.0 % for colon cancer and 8.3 % for rectal cancer.
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Two thirds of the recurrences were detected within 3 years after surgery; overall recurrence more than 5 years after surgery was less than 0.2 % among all patients.
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The incidence of recurrence increased with Stage.
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78 to 90 % of recurrences were detected within 3 years after surgery, and the overall incidence of recurrence more than 5 years after surgery was less than 1 % among all patients.
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A past history of colorectal cancer, irrespective of stage, is a risk factor for metachronous colorectal cancer [123].
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The recommended period between colonoscopy ranged from 1 to 5 years, depending on the report [124].
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The need for surveillance targeting multiple cancers should be determined by distinguishing hereditary colorectal cancer [125]. There is little evidence of a need for periodic minute examinations for cancer in other organs after surgery for sporadic colorectal cancer (CQ-20-2).
Clinical Questions
CQ-1: What are the indication criteria for additional treatment after endoscopic resection of pT1 (SM) [26]? (Fig. 10)
SM invasion distance (μm) | Pedunculated | Non-pedunculated | ||
---|---|---|---|---|
Number of lesions |
n (+) (%) | Number of lesions |
n (+) (%) | |
Head invasion | 53 | 3 (5.7) | ||
0 < X < 500 | 10 | 0 (0) | 65 | 0 (0) |
500 ≤ X < 1,000 | 7 | 0 (0) | 58 | 0 (0) |
1,000 ≤ X < 1,500 | 11 | 1 (9.1) | 52 | 6 (11.5) |
1,500 ≤ X < 2,000 | 7 | 1 (14.3) | 82 | 10 (12.2) |
2,000 ≤ X < 2,500 | 10 | 1 (10.0) | 84 | 13 (15.5) |
2,500 ≤ X < 3,000 | 4 | 0 (0) | 71 | 8 (11.3) |
3,000 ≤ X < 3,500 | 9 | 2 (22.2) | 72 | 5 (6.9) |
3,500 ≤ X
| 30 | 2 (6.7) | 240 | 35 (14.6) |
CQ-2: What are the criteria for selecting endoscopic resection with regard to lesions with a maximum diameter of 2 cm or greater?
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Accurate preoperative endoscopic diagnosis is essential in endoscopic resection with regard to lesions with a maximum diameter of 2 cm or greater, and whether resection by EMR, piecemeal EMR, or ESD is indicated is determined after taking the operator’s skill in performing endoscopic resection into consideration. (Recommendation/Evidence level 1B)
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Side Memo 1
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■ Method for measuring depth of SM invasion (Fig. 11)
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When it is not possible to identify or estimate the location of the muscularis mucosae, the depth of SM invasion is measured from the surface of the lesion. The phrase “possible to identify or to estimate” means that there is no “deformity”, i.e., disarray, dissection, rupture, fragmentation, etc., of the muscularis mucosae as a result of SM invasion. If a deformed muscularis mucosa is used as the baseline of the measurement, the depth of SM invasion may be underestimated. Although judging whether there is a “deformity” is not always straightforward, if a desmoplastic reaction is present around the muscularis mucosae, it is assumed to be “deformed.”
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For pedunculated lesions with a tangled muscularis mucosae, depth of SM invasion is measured as the distance between the point of deepest invasion and the reference line, which is defined as the boundary between the tumor head and the stalk (the boundary between the tumor area and the non-tumor area in the mucosa). Invasion by pedunculated lesions that is limited to within the head is defined as “head invasion.”
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Attention to arteries is a key factor in assessing venous invasion. Venous invasion is highly likely when a circular, semicircular, or oblong cancer cell nest with regular margins is located in the vicinity of an artery and distant from the main lesion. Such a cancer cell nest surrounded by venous wall structures (for example internal elastic membrane or perivascular smooth muscle) can be regarded as indicative of venous invasion. However, the venous wall structures are often displaced or obliterated by the cancer cell nest, and it is difficult to recognize in hematoxylin and eosin stained sections.
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The presence of cancer cells and cancer cell nests in the interstitial space suggests lymphatic invasion. A space filled with lymph and lymphocytes is especially likely to be a lymph vessel. When endothelial cells are identified around the space, the space can be regarded as a lymph vessel. However, it is often difficult to identify endothelial cells in specimens stained with hematoxylin and eosin, and spaces may be artifacts created during the process of preparing the specimen.
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As stated above, evaluation of vascular invasion, which is an important indicator for determining treatment strategies for SM cancer, is often difficult for hematoxylin and eosin stained specimens. Special staining methods are useful for evaluating vascular invasion, for example elastica van Gieson staining or Victoria blue staining for venous invasion, and D2-40 immunostaining for lymphatic invasion.
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■ Method for the assessing tumor budding (Fig. 15)
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Grade 1: 0 to 4
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Grade 2: 5 to 9
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Grade 3: 10 or more
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The incidence of lymph node metastasis for Grade 2/3 tumors is significantly higher than for Grade 1 tumors. A multi-center study conducted by the Budding Investigation Project Committee (2005–current) of the JSCCR in which Grade 1 was defined as “low grade” and Grade 2/3 as “high grade” showed that “high grade” is an independent predictor of lymph node metastasis.
CQ-3: What cautions should be noted when using colorectal ESD to implement endoscopic resection of colonic lesions?
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When ESD is being considered for use in cases of “early-stage malignant tumors”, accurate preoperative endoscopic diagnosis and the level of skill of the operator with regard to endoscopic resection should be considered before deciding to proceed. (Recommendation/Evidence level 1B)
CQ-4: Is laparoscopic surgery for colorectal cancer effective?
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According to randomized controlled trials held overseas and the Cochrane Database of Systematic Reviews, the safety and long-term outcome of laparoscopic surgery for cases of colonic and RS cancers are similar to those for open surgery. Because D3 dissection is difficult under laparoscopic conditions, laparoscopic surgery for cStage II—cStage III disease should be implemented when it is considered that the individual surgical team is sufficiently experienced. Laparoscopic surgery is also difficult for patients with transverse colon cancer, for severely obese patients, and for patients with severe adhesions.
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The efficacy and safety of laparoscopic surgery for rectal cancer has not been established. Ideally, appropriately planned clinical trials should be implemented. (Recommendation/Evidence level 1B)
CQ-5: Resection of the primary tumor for patients with unresectable distant metastases
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The efficacy of primary tumor resection for cases with unresectable distant metastases differs depending on such individual factors as symptoms caused by the primary lesion, the state of distant metastasis, the patient’s general condition, etc.
CQ-6: In cases where peritoneal dissemination is noted, is it effective to resect peritoneal dissemination at the same time as the primary lesion?
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The efficacy of resecting peritoneal dissemination has not been proved. Some cases of long-term survival have been reported in which localized dissemination (P1, P2) was resected with the primary tumor, suggesting that if the resection is not significantly invasive peritoneal dissemination should be resected at the same time as the primary tumor. (Recommendation/Evidence level 2D)
CQ-7: What are the indications for resection for cases in which metastasis is simultaneously noted in the liver and the lungs?
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The efficacy of resection for patients who have liver and lung metastases at the same time has been shown, and thus resection should be considered for patients with resectable liver and lung metastases. However, there are insufficient data to determine the indication criteria for surgery. It is necessary to obtain informed consent after informing the patient of the rather low cure rate and the absence of outcome predictors. (Recommendation/Evidence level 2D).
CQ-8: Is adjuvant chemotherapy effective subsequent to distant metastatic lesion resection?
-
The efficacy and safety of adjuvant chemotherapy subsequent to distant metastatic lesion resection in cases of colorectal cancer have not yet been established. Ideally, appropriately planned clinical trials should be implemented. (Evidence level C)
CQ-9: Is resection of liver/lung metastasis effective, if it becomes possible as a result of the effects of chemotherapy?
-
Resection should be performed for cases in which chemotherapy has successfully made localized metastasis to the liver or lungs operable. (Recommendation/Evidence level 2D)
CQ-10: What are the surgical indications in cases of local recurrence of rectal cancer?
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Resection should be considered for local recurrence of rectal cancer when R0 resection is considered possible. (Recommendation/Evidence level 2D)
CQ-11: Is preoperative adjuvant chemotherapy effective in cases of operable liver metastasis?
-
The efficacy and safety of preoperative chemotherapy for resectable liver metastases has not been established. It should be evaluated in properly designed clinical trials. (Evidence level D)
CQ-12: Is heat coagulation therapy effective with regard to liver metastatic lesions?
CQ-13: Is postoperative adjuvant chemotherapy effective for patients aged 70 or over?
-
Even for patients 70 years old or older, postoperative adjuvant chemotherapy is recommended if their PS is good, if the function of their major organs is adequate, and if there are no complications that may be a risk for performing chemotherapy. (Recommendation/Evidence level 1A)
CQ-14: Should postoperative adjuvant chemotherapy be conducted for Stage II [26] colorectal cancer?
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The usefulness of postoperative adjuvant chemotherapy for Stage II colorectal cancer has not been proved, and it is recommended not to routinely administer adjuvant chemotherapy to all patients with Stage II colorectal cancer. (Recommendation/Evidence level 1A)
CQ-15: Is the appropriate duration of postoperative adjuvant chemotherapy 6 months?
-
Although no definitive conclusion regarding the duration of postoperative adjuvant chemotherapy has been reached, the current standard duration of treatment by 5-FU-based adjuvant chemotherapy is 6 months. (Recommendation/Evidence level 1A)
CQ-16-1: Is bevacizumab administration effective as second-line chemotherapy?
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Combination chemotherapy using bevacizumab is effective as second-line chemotherapy, irrespective of whether bevacizumab was administered as part of initial therapy. (Recommendation/Evidence level 2B)
CQ-16–2: Is administration of molecular target drugs (anti-EGFR antibodies) effective as second-line chemotherapy?
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For wild-type KRAS cases, treatment with anti-EGFR antibodies (cetuximab and/or panitumumab) is effective. (Recommendation/Evidence level 2C)
-
■ IRI and UGT1A1 genetic polymorphism
CQ-17: Is hepatic arterial infusion therapy effective in cases of liver metastases?
-
Comparisons between hepatic arterial infusion therapy using fluoropyrimidine alone and systemic chemotherapy showed no clear difference in survival. The effectiveness of hepatic arterial infusion therapy in comparison with systemic chemotherapy using multi-drug combination has not been established. (Recommendation/Evidence level 1C)
CQ-18: Is preoperative chemoradiotherapy effective in patients with rectal cancer?
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In the USA and Europe, although preoperative chemoradiotherapy has reduced the incidence of local recurrence in comparison with TME-only, reports suggest that it has not contributed to improved survival. In Japan, where surgical methods differ from the USA and Europe, the efficacy of preoperative chemoradiotherapy has not been established with regard to rectal cancers for which the lower margin of the tumor is closer to the anus than the peritoneal reflection. (Evidence level B)
CQ-19: Is chemoradiotherapy effective for unresectable locally advanced and locally recurrent rectal cancer?
CQ-20-1: Is surveillance subsequent to curative surgery for colorectal cancer effective?
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It has been suggested that the efficacy of surveillance is its contribution to improving prognosis by enabling early detection of recurrence, and, as such, regular postoperative surveillance is desirable. (Recommendation/Evidence level 1A)
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However, an optimum surveillance protocol incorporating a health-economical perspective has not been sufficiently established.