1. به نام او که زندگی از او رنگ می گیرد

2. تاره های درمان سیستمیک در سرطان کولون غیر متاستاتیک
تاره های درمان سیستمیک در سرطان کولون غیر متاستاتیک
دکتر زهرا مذهب
فوق تخصص خون و سرطان بالغین

3. Which doctors treat colorectal cancer?
Based on your treatment options, you might have different types of doctors on your treatment team. These doctors could include:
A gastroenterologist: a doctor who treats disorders of the gastrointestinal (digestive) tract
A surgical oncologist (oncologic surgeon): a doctor who uses surgery to treat cancer
A colorectal surgeon: a doctor who uses surgery to treat diseases of the colon and rectum
A radiation oncologist: a doctor who treats cancer with radiation therapy
A medical oncologist: a doctor who treats cancer with medicines such as chemotherapy or targeted therapy

4. Colorectal cancer (CRC) is a common malignancy with more than one million new cases occurring each year and is the second leading cause of cancer deaths in Western countries.
Surgical resection is the only curative treatment for loco-regional colon cancer.
Outcome is most closely related to the extent of disease at presentation.
For patients who have undergone potentially curative resection, disease recurrence is thought to arise from clinically occult micrometastases that are present at the time of surgery.
The goal of postoperative (adjuvant) therapy is to eradicate these micrometastases, thereby increasing the cure rate.

5. The benefits of adjuvant chemotherapy have been most clearly demonstrated in stage III (node-positive) disease, whereas benefit in stage II disease remains controversial. 
Disease stage remains the strongest prognostic variable and is the key determinant of patient management.
Most cases (85%) of CRC develop through a CIN (chromosomal instability) pathway, approximately 15% of cases [sporadic or inherited (Lynch syndrome) ]are characterized by microsatellite instability (MSI), a molecular marker of defective DNA mismatch repair (dMMR).
The frequency of MSI varies according to the tumor stage with highest rates in early stage cancers that decreases with progression to locoregional and distant metastases

6. Trials in combined populations
 multiple trials of fluoropyrimidine-based chemotherapy enrolling a mix of patients with stage II and III disease have shown an overall survival and DFS benefit in the combined population compared with surgery alone .
In almost all cases, benefits were clinically and statistically significant only for stage III disease; in subgroup analysis, however, almost all of the trials conducted in combined populations have shown a trend toward improved overall survival and/or significantly better DFS, favoring adjuvant chemotherapy in stage II disease.

7. Trials in stage II disease
Three large trials that specifically address the benefit of fluoropyrimidine-based chemotherapy in populations consisting either entirely or predominantly of stage II disease have been undertaken, all of which fail to show unequivocal benefit for adjuvant chemotherapy. The largest of these, the QUASAR trial.
Based upon the available data, adjuvant chemotherapy cannot be considered as a standard of care for all patients with resected stage II disease. In keeping with  (NCCN) guidelines, we suggest discussing the risks and estimated benefits of adjuvant chemotherapy with all patients who have resected stage II disease.
ASCO guidelines emphasize patient choice in the decision-making process. The oncologist should help the patient to make an informed decision by estimating the relative risk of recurrence and/or death with and without adjuvant chemotherapy and discussing the expected side effects of treatment.

8. The QUASAR trial randomly assigned 3238 patients with an "uncertain indication for adjuvant therapy" (91 percent node-negative) to fluorouracil (FU) plus leucovorin (LV) with or without levamisole, or observation following resection of colon (71 percent) or rectal cancer.
Adjuvant chemotherapy was associated with a significant 22 percent lower risk of disease recurrence and an 18 percent reduction in death, which translated into a 3 to 4 percent absolute benefit in five-year overall survival.

9. Two meta-analyses of early trials evaluated the benefit of adjuvant fluoropyrimidine-based chemotherapy in patients with resected colon cancer, with one (IMPACT B2) finding a small but not statistically significant improvement in event-free and overall survival at five years for patients receiving adjuvant treatment,
and the other (Cancer Care Ontario) finding a small but significant absolute improvement in DFS that ranged from 5 to 10 percent.
Based largely upon the Ontario group analysis, an expert panel convened by the American Society of Clinical Oncology (ASCO) in 2004 concluded that:
direct evidence from randomized trials does not support the routine use of adjuvant chemotherapy for stage II colon cancer.

10.  Long-term results from both the MOSAIC and the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 (described in detail below):
trials show that there is not any clinically meaningful benefit from the addition of oxaliplatin to adjuvant leucovorin-modulated fluorouracil (FU/LV) for patients with stage II colon cancer.
In the five randomized trials that comprised the ACCENT database. Among patients with stage II disease, the addition of oxaliplatin significantly reduced the risk of recurrence within the first 14 months posttreatment but not thereafter, and there was no overall survival benefit.

11. It is recommended the following issues into consideration when assessing the risk of recurrence and estimated benefit from chemotherapy

13. molecular findings
Despite encouraging preliminary data linking molecular findings to prognosis and potentially better prognostic stratification relative to TNM stage alone, no single molecular marker, multiple marker profile, or gene expression panel has emerged that has predictive utility. However, there are two potential exceptions:
The presence of MSI (the biologic footprint of deoxyribonucleic acid [DNA] dMMR) appears to be associated with a relative resistance to fluoropyrimidines.
In an early report, lack of expression of the transcription factor CDX2 was associated with significantly inferior DFS compared with CDX2-positive colon cancers, and lack of expression also appeared to identify a subgroup of stage II patients who benefited from adjuvant chemotherapy. However, these data require independent confirmation.  

14. 'MSI and MMR enzyme deficiency‘
MSI tumors have distinct phenotypic features and are consistently associated with a better stage-adjusted prognosis compared with microsatellite stable (MSS) tumors.
Among non-metastatic CRCs, the difference in prognosis between MSI and MSS tumors is larger for stage II than stage III patients.
On the other hand, the predictive impact of MMR status for adjuvant chemotherapy remains a contentious issue in that most studies demonstrate a lack of benefit for 5-fluorouracil (5-FU)-based adjuvant chemotherapy in stage II MSI-H CRCs, whereas it remains unclear in MSI-H stage III tumors.

15. MSI testing can be performed on paraffin-embedded tumor tissue using a PCR-based assay for detection of instability in selected microsatellite loci.
On the basis of the MSI status, CRCs can be categorized into three groups:
MSI-H, if 2 or more of the 5 microsatellite markers show instability (that is, have insertion/deletion mutations);
MSI-L (low-frequency MSI), if only one of the five markers shows instability;
and microsatellite stable (MSS) if none of the markers show instability .
MSI-H corresponds to defective DNA mismatch repair (dMMR), whereas MSI-L and MSS indicate proficient MMR (pMMR).

16. Analysis of MMR protein expression by immunohistochemistry (IHC) is an alternative test that is widely available with the advantages of not requiring a molecular laboratory and the ability to identify the affected gene by detecting loss of its protein product.
Using IHC, tumors that demonstrate loss of an MMR protein can be collectively referred to as dMMR and expected to be MSI-H.
Tumors with intact MMR proteins can be classified as proficient MMR that are MSS or MSI-low (MSI-L)

17. RISK STRATIFICATION
 Using clinicopathologic and molecular features of the tumor to guide decision-making for adjuvant chemotherapy in patients with stage II disease, although the evidence to support any of these practices is weak.
Patients without high-risk features who have MSI-unstable (MSI-H)/dMMR tumors have a favorable prognosis and are not likely to derive significant benefit from adjuvant fluoropyrimidine-based therapy. We suggest observation alone for these patients.

18. The presence of MSI (the biologic footprint of deoxyribonucleic acid [DNA] dMMR) appears to be associated with a relative resistance to fluoropyrimidines.
The best approach for patients with stage II MSI-H/dMMR tumors that have high-risk features is uncertain.
Few data are available to guide the use of adjuvant therapy in this subset, and the decision to pursue chemotherapy must be individualized, based upon the number of high-risk features, the patient's overall medical condition, and age.

19. An oxaliplatin-containing regimen is a reasonable alternative to fluoropyrimidine therapy alone for patients with higher risk stage II disease whose tumor displays a MSI-H/dMMR proteins.
For most patients with proficient MMR (pMMR) tumors and clinicopathologic high-risk features, particularly those with T4 cancers or multiple high-risk features, adjuvant chemotherapy were suggested.

20. TIMING OF ADJUVANT THERAPY
 Adjuvant chemotherapy is typically started only after recovery from surgery. There is no agreement as to the optimal time to initiate adjuvant chemotherapy.
Guidelines from ASCO and the NCCN do not explicitly state a time interval within which chemotherapy should commence. Adjuvant colon cancer trials typically mandate initiation of chemotherapy within six to eight weeks of resection.
In clinical practice, the interval between surgery and initiation of chemotherapy is often longer than eight weeks; the reasons are often multifactorial:
The dominant reason is delayed recovery from surgery. A major advantage of laparoscopic as compared with open resection is its association with earlier initiation of adjuvant chemotherapy.
 In adjuvant therapy trials in which time between surgery and initiation of chemotherapy has been examined as a prognostic factor for outcome, delay beyond six to eight weeks has not been associated with inferior outcomes.
Delay beyond two months may compromise the effectiveness of chemotherapy, but it is unknown whether there is any cutoff point beyond which the benefits of adjuvant chemotherapy are lost.

21. DURATION OF THERAPY 
At least three randomized trials show no added benefit from 12 as compared with 6 to 8 months of fluorouracil/leucovorin-containing adjuvant chemotherapy.
A Cochrane review concluded that a shorter duration of chemotherapy (three to six months) compared with a longer duration of chemotherapy (9 to 12 months) was not associated with inferior relapse-free or overall survival.
However, there were no data upon which to base a recommendation for six months versus a shorter duration.
Guidelines from the NCCN suggest six months of adjuvant therapy, regardless of the regimen that is chosen.

22. Choice of regimen 
Choice of regimen — For patients with resected colon cancer who are going to receive FU-based adjuvant chemotherapy (ie, without oxaliplatin), the best adjuvant regimen is not conclusively established. Although most of the trials demonstrating the benefit of FU/LV used the Mayo regimen (daily treatment for five days once per month), the more favorable toxicity profile of the weekly RPMI regimen (four courses of FU 500 mg/m2 plus LV 500 mg/m2 both given for six of every eight weeks) has led many to consider this the preferred regimen.
Protracted infusion FU alone (three courses of 250 mg/m2 per day for 56 of every 63 days) and short-term infusional FU/LV both provide oncologic outcomes that are at least as good and less toxic as compared with bolus FU/LV. However, it is unclear whether the added inconvenience and cost of a central venous line and ambulatory infusion pump is justified in patients who are to receive a nonoxaliplatin-based regimen.

23. Infusional versus bolus FU — A lack of superiority but more favorable side effect profile for continuous infusion FU over bolus FU plus LV has been shown in at least four trials.
Compared with bolus FU/LV, treatment with high-dose infusional FU caused less mucositis and neutropenia, similar rates of diarrhea, and more hand-foot syndrome.

24. The oral fluoropyrimidines capecitabine and UFT (uracil and tegafur) are at least as effective as bolus-FU plus LV;
In Japanese patients, S-1 is at least as effective as UFT plus LV.
However, reimbursement policies for oral cytotoxic agents such as capecitabine vary greatly between countries and even regionally within the United States. The higher out of pocket costs for capecitabine compared with IV FU-based regimens must often be considered in choosing the best treatment for individual patients.

25. Oxaliplatin is the only platinum-type drug with activity in colorectal cancer; it is used only in combination with a fluoropyrimidine.
The survival benefit of adding oxaliplatin to adjuvant fluoropyrimidine-based therapy after resection of node-positive colon cancer has been demonstrated in randomized trials,
MOSAIC trial — Benefit for adding oxaliplatin to FU/LV was first suggested in the MOSAIC trial, which randomly assigned 2246 patients with resected stage II (40 percent) or III colon cancer to a six-month course.

26. For patients with a contraindication to oxaliplatin (eg, preexisting neuropathy) or who are not considered fit enough to tolerate an oxaliplatin-containing regimen, treatment with a fluoropyrimidine alone is an acceptable option, although outcomes may not be as favorable as with an oxaliplatin-based regimen.
One option for patients with dMMR tumors who are felt unlikely to tolerate an oxaliplatin-based regimen is to start with half-dose oxaliplatin

27. When an oxaliplatin regimen is chosen, we prefer FOLFOX (oxaliplatin plus LV and short-term infusional FU). While FOLFOX4 was used in the adjuvant registration trials, many American oncologists use
modified FOLFOX6 (mFOLFOX6) because it does not require the day 2 bolus of FU and LV.
Modified FOLFOX7 (mFOLFOX7), which eliminates bolus FU completely, is significantly less myelosuppressive.
Oxaliplatin plus oral capecitabine (XELOX) is an acceptable, albeit potentially more toxic alternative to FOLFOX. Patients receiving capecitabine in the adjuvant setting should probably avoid concomitant use of a proton pump inhibitor due to concerns about capecitabine absorption.

28. At present, the use of oxaliplatin in combination with adjuvant 5-FU chemotherapy is the standard of care for stage III colon cancer patients .
Preclinical studies have shown that dMMR tumor cells are susceptible to oxaliplatin despite displaying resistance to 5-FU.
In a retrospective study that included 303 unselected stage III colon cancer patients who received adjuvant FOLFOX, MMR status was a prognostic factor conferred a better DFS for patients with dMMR compared to pMMR tumors.
The authors found that the DFS benefit from FOLFOX compared with 5-FU alone was also evident in patients with dMMR colon cancers.
Taken together, available data suggest a potential benefit for oxaliplatin in node-positive dMMR colon cancers and therefore, do not support any change in the current therapy of these patients.

29. Patients treated with 5-FU plus irinotecan-based adjuvant therapy
It is important to emphasize that two randomized phase III studies [Cancer and Leukemia Group B (CALGB) and Pan-European Trials in Alimentary Tract Cancers 3 (PETACC-3) trials ], failed to show the benefit of adding irinotecan to 5-FU as adjuvant chemotherapy in the treatment of stage III colon cancer patients.
Thus unlike oxaliplatin, irinotecan is not used in the adjuvant setting.
Preclinical studies including in vitro and xenograft model systems found that dMMR tumor cells exhibited sensitivity to irinotecan

30. Patients treated with targeted therapies in an adjuvant setting
Recent success of biologic agents in the metastatic setting such as the use of antibodies directed against (VEGF) or (EGFR), resulted in the evaluation of these agents in the adjuvant setting.
However, phase III adjuvant trials failed to show a significant survival benefit for anti-VEGF or anti-EGFR antibodies combined with adjuvant chemotherapy in patients with stage III colon cancer.
In the NSABP C-08 trial where no benefit for the addition of bevacizumab to FOLFOX therapy was observed, a post hoc analysis found that patients with dMMR tumors derived a statistically significant survival benefit from the addition of bevacizumab (HR =0.52; 95% CI, ; P=0.02) compared with patients with pMMR tumors (HR =1.03; 95% CI, ; P=0.78). The mechanism responsible for bevacizumab benefit in dMMR tumors is unknown, and confirmation of these data is needed.

31. CETUXIMAB
The use of cetuximab in the adjuvant setting is not indicated in any group of patients with resected colon cancer. A lack of benefit from cetuximab in the adjuvant setting was shown in the N0147 trial, in which patients with resected, stage III colon cancer (1760 of whom had wild-type KRAS, and 658 KRAS mutant tumors) were randomly assigned to FOLFOX with or without cetuximab [96].
The trial was closed prematurely after it was determined in an interim analysis that no group of patients benefited from cetuximab.
A lack of benefit from adjuvant cetuximab added to FOLFOX in patients with RAS and BRAF wild-type stage III colon cancer was also noted in the European PETACC8 trial

36. Conclusions
Abundant evidence suggests that MMR status is a valuable prognostic and predictive biomarker for non-metastatic CRC.
To improve the identification of these patients in clinical practice, it has been recommended that all resected CRC be analyzed for MMR status.
The excellent prognosis of resected stage II colon cancers with dMMR and evidence of lack of 5-FU benefit supports the recommendation to not administer adjuvant 5-FU chemotherapy in this population.
In stage III CRC patients in whom oxaliplatin-based adjuvant chemotherapy is the current standard of care, there remain no convincing evidence to exclude such patients with dMMR tumors from receiving adjuvant FOLFOX.
Accordingly,. MMR status does not influence chemotherapy decisions in stage III patients

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