Stage
T
N
M
Dukesa
MACb
0
Tis
N0
M0
–
–
I
T1
N0
M0
A
A
T2
N0
M0
A
B1
IIA
T3
N0
M0
B
B2
IIB
T4a
N0
M0
B
B2
IIC
T4b
N0
M0
B
B3
IIIA
T1–T2
N1/N1c
M0
C
C1
T1
N2a
M0
C
C1
IIIB
T3–T4a
N1/N1c
M0
C
C2
T2–T3
N2a
M0
C
C1/C2
T1–T2
N2b
M0
C
C1
IIIC
T4a
N2a
M0
C
C2
T3–T4a
N2b
M0
C
C2
T4b
N1–N2
M0
C
C3
IVA
Any T
Any N
M1a
–
–
IVB
Any T
Any N
M1b
–
–
TNM 7th – Definitions [43]
Primary Tumor (T)
TX – Primary tumor cannot be assessed
T0 – No evidence of primary tumor
Tis – Carcinoma in situ: intraepithelial or invasion of the lamina propria
T1 – Tumor invades the submucosa
T2 – Tumor invades the muscularis propria
T3 – Tumor invades through the muscularis propria into the pericolorectal tissues
T4a – Tumor penetrates into the surface of the visceral peritoneum
T4b – Tumor directly invades or is adherent to other organs or structures
Regional Lymph Nodes (N)
NX – Regional lymph nodes cannot be assessed
N0 – No regional lymph node metastasis
N1 – Metastasis in 1–3 regional lymph nodes
N1a – Metastasis in one regional lymph node
N1b – Metastasis in 2–3 regional lymph nodes
N1c – Tumor deposit(s) in the subserosa mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis
N2 – Metastasis in four or more regional lymph nodes
N2a – Metastasis in 4–6 regional lymph nodes
N2b – Metastasis in seven or more regional lymph nodes
Distant Metastasis (M)
M0 – No distant metastasis
M1 – Distant metastasis
M1a – Metastasis confined to one organ or site (e.g. liver, lung, ovary, or nonregional node)
M1b – Metastasis in more than one organ/site or the peritoneum
12.7 Surgical Management
Surgery is the cornerstone treatment for colon cancer. Only surgery can cure colon cancer. Therefore, efforts are necessary to train skilled surgeons to perform the operations. The choice of the approach (open versus laparoscopic) and extent of resection (partial or total colectomy) are planned based on the clinical staging and risk assessment (i.e., FAP, etc.). The goal of surgical resection of primary cancer is the complete removal of the tumor, major vascular pedicles, and lymphatic drainage of the affected colonic segment. When possible, the laparoscopic approach is preferred. Laparoscopic colectomy demonstrates faster recovery with no detrimental impact on the recurrence or survival compared to open colectomy [45–51].
12.8 Adjuvant Treatment
The decisions for adjuvant treatment are mainly based on the pathological staging. Therefore, we describe the recommendations according to the stage.
12.8.1 Stage I
Surgery resection alone confers >95 % overall survival in 5 years, and adjuvant treatment is unnecessary [52]. Endoscopic resection of a malignant polyp containing invasive carcinoma (pT1) must be individualized. Endoscopic resection is only sufficient for tumors involving the submucosa superficially (Sm1), polyp without fragmentation, clear margins (1 mm), grade 1 or 2 and no lymphovascular invasion [53–55].
12.8.2 Stage II
En bloc tumor resection (colectomy and lymphadenectomy) is sufficient in the majority of cases. Adjuvant chemotherapy is reserved for selected patients with the following poor prognostic factors: perforation or intestinal obstruction, T4 tumors, poorly differentiated histology and MSI-high, lymphovascular invasion, perineural invasion, and inadequately sampled nodes (<12 lymph nodes). For those cases, chemotherapy can be offered after balancing the risks and benefits, including patient discussion.
The most important trials that specifically address the benefit of fluoropyrimidine-based chemotherapy are the following: QUASAR, IMPACT B2, and INTERGROUP ANALYSIS [56–58]. The Ontario Group Analysis included a systematic review of 37 trials and 11 meta-analyses that were published after 1987 on adjuvant therapy for stage II colon cancer performed in Cancer Care Ontario. An analysis of a subset of 12 trials (4,187 patients) with surgery exclusive in the control arm and fluoropyrimidine-based chemotherapy in the experimental arm showed a significant improvement in the disease free survival (DFS) without significant improvement in the overall survival (OS). These results do not support the routine use of adjuvant chemotherapy for stage II colon cancer [59].
Two important trial analyses, MOSAIC and NSABP C-07, describe the benefit of adding oxaliplatin to fluoropyrimidine (5-FU) in the adjuvant setting [60, 61]. Again, a subgroup analysis of the stage II patients showed a trend of improving the DFS without improving the OS.
One strategy to facilitate the decision about whether to offer adjuvant chemotherapy is MSI evaluation. Patients with poor differentiated histology and MSI-H may have a good prognosis and do not benefit from adjuvant fluoropyrimidine-based chemotherapy [60].
12.8.3 Stage III
After surgery, adjuvant chemotherapy is recommended in the majority of cases.
The benefit for adjuvant 5-FU plus levamisole was initially reported in a North Central Cancer Treatment Group (NCCTG). In that study, patients with stages II and III colon cancer were randomly assigned to observation for 1 year of levamisole with or without 5-FU [62]. After the demonstration of the inferiority of 5-FU/levamisole compared to 5-FU plus leucovorin (LV), the use of levamisole for adjuvant therapy was abandoned [63, 64]. 5-FU plus LV became the standard treatment until 2004, which is when the MOSAIC trial was published, showing the benefit of adding oxaliplatin to 5-FU/Leucovorin (FOLFOX4) in the adjuvant setting for stage III colon cancer [60]. After 6-year follow-up, patients who receive FOLFOX achieved a 20 % reduction in risk of death [65]. Better outcomes with oxaliplatin were also reported with the FLOX and XELOX protocols [66]. In summary, the chemotherapy recommendations are as follows:
FOLFOX or XELOX or FLOX are the approved regimens in the adjuvant setting.
The duration of the treatment is 6 months.
Chemotherapy with fluoropyrimidines without oxaliplatin remains an option for elderly patients (>70 years) and patients with contraindications for oxaliplatin. 5-FU/Leucovorin or capecitabine have similar efficacy based on the European/Canadian X-ACT study that randomly assigned 1987 patients with resected stage III colon cancer to 6 months of capecitabine alone (1,250 mg/m2 twice daily for 14 of every 21 days) or monthly bolus 5-FU/LV (the Mayo regimen). The trial was statistically powered to demonstrate therapeutic equivalence, and the DFS was the primary endpoint [67].
There is no consensus about the optimal time for initiating adjuvant chemotherapy. The majority of the medical societies recommended the initiation of chemotherapy within 6–8 weeks of resection, which has become an accepted approach [68, 69].
The benefit of the addition of oxaliplatin to 5-FU/leucovorin in patients aged 70 and older has not been proven [70].
12.8.4 Stage IV (Metastatic Disease)
In the stage IV, patients are divided into the following three categories:
Metastatic with resectable disease.
Metastatic with potentially resectable disease.
Metastatic with unresectable disease.
Metastatic with Resectable Disease
The patients can be treated with upfront surgery (primary tumor and metastatic tumor) followed by adjuvant chemotherapy for 6 months (see adjuvant stage III chemotherapy), or patients can be treated with upfront chemotherapy neoadjuvant (2 or 3 months) followed by surgery [71, 72]. In the upfront chemotherapy strategy, it is possible to identify the patients with a tumor response. FOLFOX4 and XELOX are the preferential regimens of this strategy [73].
Metastatic with Potentially Resectable Disease
Approximately 80–90 % of patients with metastatic colorectal cancer (mCRC) who are referred to specialist centers have unresectable metastatic liver disease [74]. The role of chemotherapy in these patient populations is to downstage the liver lesions in an attempt to convert their disease from unresectable to resectable. In 2008, a major systematic review on irinotecan and oxaliplatin for treating advanced colorectal cancer, published by the United Kingdom Health Technology Assessment Agency, evaluated all studies in which irinotecan or oxaliplatin were combined with 5-FU to downstage patients with unresectable colon liver metastases (CLM). The reported resection rates ranged from 9 % to 35 % for patients receiving irinotecan and 5-FU, while the rates for those receiving oxaliplatin and 5-FU ranged from 7 % to 51 %. There is no conclusive evidence that one is superior to the other as first-line therapy for downstaging CLM in terms of the progression free survival (PFS) and OS [75]. The current practice for patients whose metastases may be rendered resectable by conversion chemotherapy is to treat them with the most effective regimen that offers a high response rate (RR), according to the resection rate and PFS, coupled with the recommendation that surgery should be conducted as early as possible to minimize chemical damage to the liver. A phase III randomized trial that compared FOLFOXIRI with a standard infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) regimen demonstrated an improvement in the RR in the FOLFOXIRI arm of patients with unresectable mCRC (60 % vs 34 %, P < 0.0001). The PFS and OS were both significantly improved in the FOLFOXIRI arm (median PFS, 9.8 vs 6.9 mo, P = 0.0006; median OS, 22.6 mo vs 16.7 mo, P = 0.032) [76].
The roles of adding cetuximab, an EGFR inhibitor, to chemotherapy to increase the RR, PFS and OS were studied in several mCRC trials. Optimistic results from two first-line therapy randomized trials, CRYSTAL (cetuximab combined with irinotecan) and OPUS (oxaliplatin and cetuximab) reinforced the role of cetuximab on the improvement of the RRs and resection rates when combined with standard first-line chemotherapy in patients with advanced CRC [77, 78]. However, the latest results from two randomized phase III studies unexpectedly challenged the benefit of adding cetuximab to oxaliplatin-based combination chemotherapy. In the MRC COIN study, 1,394 patients received the oxaliplatin combination (CAPOX/FOLFOX) as standard chemotherapy with or without cetuximab. An analysis according to the KRAS status did not result in any difference in either the OS or PFS between the patients treated with CAPOX/FOLFOX and those treated with CAPOX/FOLFOX plus cetuximab, even in the KRAS wild-type group [79]. Cetuximab combined with triple cytotoxic drug therapy is also being evaluated. The results from the preoperative chemotherapy for the hepatic resection (POCHER) study revealed an RR of 79 % and complete resection rate of 63 % for FOLFOXIRI plus cetuximab [80]. Another phase II trial that evaluated cetuximab in combination with FOLFIRINOX demonstrated an ORR as high as 82 % and raised the question of this new therapeutic combination in first-line mCRC patients [81]. Cetuximab is only approved for patients with N-RAS wild type.
The addition of bevacizumab, a VEGF inhibitor, to chemotherapy in the perioperative setting for initially unresectable metastasis was evaluated in two large multi-center prospective trials (First BEAT and NO16966). The First BEAT trial reported a 6 % R0 hepatic resection in an unselected population and 12.1 % among patients with isolated liver metastasis alone. The resection rates were highest in patients who received oxaliplatin-based combination chemotherapy (P = 0.002). However, bevacizumab did not improve the RRs when added to XELOX or FOLFOX in the NO16966 study [82]. When added to FOLFIRI, bevacizumab showed an increase in the RR [83]. Recent data from a small phase II trial by the GONO group revealed that FOLFOXIRI plus bevacizumab yielded an ORR of 76 % [84]. However, these small benefits have come at the cost of significant treatment-related toxicity and will be used cautiously.
Metastatic with Unresectable Disease
The majority of patients with unresectable mCRC cannot be cured. For these patients, the treatment is palliative and generally consists of systemic chemotherapy. For decades, 5-FU was the unique active agent. This changed with the approval of irinotecan, oxaliplatin and three humanized monoclonal antibodies that target the vascular endothelial growth factor (bevacizumab) and epidermal growth factor receptors (cetuximab and panitumumab) in 2000. These new combinations shifted the median OS from 6 to 30 months.
What we learned in the last 40 years:
Fluoropyrimidine (5-FU or capecitabine)-based chemotherapy is the most active agent and used alone to increase the PFS and OS [85, 86].
Infusional 5-FU is more active and safe than bolus 5-FU [87].
Bolus 5-FU 5 days a week, every 4 weeks, in the classic Mayo Clinic protocol, has high risk toxicity and is not recommended. A weekly schedule, as presented in the QUASAR study, is preferred for patients selected to receive a 5-FU bolus [88].
Adding oxaliplatin to 5-FU or capecitabine (FOLFOX, XELOX) increases the PFS and OS; [89].
Adding irinotecan to 5-FU (FOLFIRI) increases the PFS and OS [90].
Adding cetuximab to FOLFIRI in select RAS wild type patients increases the PFS and OS [77].
Adding cetuximab or bevacizumab to FOLFIRI in selected RAS wild type patients results in a similar RR and PFS. The OS favored the cetuximab group with a median OS 28.7 months versus 25 months (p = 0.017). The primary end point of the FIRE-3 study was an objective response [91].
Adding panitumumab to FOLFOX in selected RAS wild type patients was FDA approved as a first-line therapy. This combination increased the PFS and OS in the PRIME trial [92].
Adding cetuximab to the oxaliplatin-based regimen increases the RR without benefiting the OS [78, 93].
Adding bevacizumab to chemotherapy increases the PFS and OS, mainly in association with “weaker” regimen (IFL, 5FU/LV, and Capecitabine) [94]. The benefit of adding bevacizumab to a very active regimen (FOLFIRI, FOLFOX, and XELOX) will be the balancing of side effects, mainly in patients RAS WT, where cetuximab appears to perform better [91].
FOLFOXIRI is a very active regimen and, compared with FOLFIRI, increased the PFS and OS, but the toxicity was high, and this regimen should be reserved to selected patients [95].
Regorafenib was approved by the FDA to treat patients with mCRC who have been previously treated with fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, an anti-VEGF agent; if the patient is KRAS wild type, an anti-EGFR therapy may be used [96].
12.9 Patient Surveillance
There available data for recommending surveillance and secondary prevention measures for the survivors of CRC stages II and III. For patients with stage I and resectable metastatic disease, data are minimal for providing guidance. In December 10th, 2013, the American Society of Clinical Oncology published some Key Recommendations. Our summary recommendations after treatment are as follows: [12, 97]
Surveillance is especially important in the first 2–5 years, which is when the risk of recurrence is the greatest and should be guided by the presumed risk of recurrence. The functional status of the patient should be considered because early detection would lead to aggressive treatment, including surgery and/or systemic therapy. Patients who are not candidates for aggressive therapy should not be included in active surveillance;
For stage I patients:
There are no recommendations for testing CEA or routinely performing a CT scan. Colonoscopy is recommended in the first year after surgery as well as in the third year and then every 5 years if no alteration (polyp) is detected.
For stage II and III patients:
In the first 2.5 years, a medical history, physical examination, and CEA testing should be performed every 3 months and then every 6 months for 5 years. The data showing the risk of recurrence are 80 % in the first 2–2.5 years from the date of surgery and 95 % occur by 5 years.
Routine abdominal and chest imaging using a CT scan is recommended annually for 5 years. It is reasonable to consider imaging every 6 months for the first 3 years in patients who have a high risk of recurrence.
PET scans are not recommended for surveillance.
Colonoscopy should be performed approximately 1 year after the initial surgery as well as in the third year and then every 5 years if the findings of the previous one are normal. A complete colonoscopy should be performed reasonably soon after the completion of adjuvant therapy in patients who have not undergone a colonoscopy before diagnosis.
For stage IV patients (after curative surgery of metastasis):
There are few evidence-based data for guidance. Based on the published data, we recommend surveillance similar to stage III.
We recommend a characteristic lifestyle to improve the outcome in CRC survivors. It is reasonable to counsel patients on maintaining a healthy BMI, engaging in regular physical activity and eating a healthy diet (more fruits, vegetables, poultry, and fish; less red meat; more whole grains; and fewer refined grains and concentrated sweets).
We recommend that a written treatment plan from the specialist should be sent to the primary care physician, who will be assuming cancer surveillance responsibilities.
Finally, is very important to identify a patient who is not a surgical candidate or a candidate for systemic therapy (due to severe comorbid conditions) because surveillance tests should not be performed. This recommendation is based on cost-benefit analysis.
References
2.
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