Colorectal cancer (CRC)

CRC treatment

• The treatment of CRC depends on the disease stage.
• Patients with colon cancer that has no distant metastasis usually have a surgery as their main or first treatment.
• According to indications, adjuvant/neoadjuvant CT, RT, CRT are additionally performed.

Colon cancer, stage 0-I

The mucosa is removed via endoscopic resection, along with dissection in the submucosal layer. To determine the appropriate treatment approach, prognostic factors must be considered. If any unfavorable prognosis indicators are detected, an extra resection of the corresponding segment of the intestine is performed. Adjuvant therapy is not administered.

Unfavorable prognostic factors:

• stage ≥ G3,
• affected resection margins,
• lymphatic, vascular or perineural invasion,
• IV stage of invasion (involvement of the submucosa of the colon), > pT1sm1,
• affected resection margins,
• lymphatic, vascular, perineural invasion.

Resectable localized and locally advanced cancer stages I-III

Surgical treatment — the extent of the surgery depends on factors such as the location and spread of the tumor. In cases where the patient has cT4 or cN+ tumors without a high MSI level and is not experiencing symptoms, an alternative option to neoadjuvant chemotherapy is to undergo treatment with oxaliplatin and fluoropyrimidines for 6-8 weeks before proceeding to surgery.

A second opinion at a reference surgical center is recommended for patients with unresectable colon cancer before palliative chemotherapy is considered

As an alternative the prolonged chemotherapy — a combination of oxaliplatin and fluoropyrimidines — may be administered for a maximum of 6-12 weeks. Subsequently, patients can be evaluated for the possibility of removing the tumor through large therapy-based surgeries. However, if surgical treatment is not feasible due to volume limitations, the only options available are high-risk operations that are limited to the formation of bypass anastomoses, colostomy, or ileostomy. In the future, systemic antitumor therapy may be considered as an option.

Generalized cancer with resectable/potentially resectable synchronous liver or lung metastases (M1a)

Surgical interventions — resection of organs with metastases in the volume R0. Tactics depends on the initial resectability of metastatic foci.

For best results are considered when the resection margin be at least 1 mm. Chemotherapy may extend and increase the frequency of toxic liver damage, as well as make it more difficult to identify metastases during resection. If the primary tumor is symptomatic and poses a threat of intestinal obstruction or bleeding, surgical removal of the tumor with lymph node dissection is usually performed as the first step. For liver metastases, radiofrequency ablation or stereotactic radiation exposure can be used in addition to liver resection for a more comprehensive approach, or as a standalone method if surgery is not an option. Intra-arterial chemotherapy is still considered an experimental method and is not recommended for routine use as a first-line therapy.

Recurrent colon cancer

Recurrence may be local (near the area of the original tumor) or may be in distant organs.

In case of local recurrence of colon cancer, it is recommended to consider the possibility of repeated surgical treatment; if repeated surgical treatment is not possible, systemic chemotherapy is recommended.

With a distant recurrence — more often first in the liver — surgical treatment, if not possible — chemotherapy with subsequent removal. Ablation or embolization techniques may also be a treatment option for some liver tumors.

If the cancer has spread too far to be treated with surgery, chemotherapy and/or targeted therapy. Possible treatment regimens are the same as in stage IV of the disease.

Recurrent cancer is often difficult to treat, so you might also want to ask your doctor if clinical trials for new treatments are available.

Colon cancer treatment by stage

0 stage

Colon cancer of Stage 0 does not extend beyond the inner lining of the colon, so surgery is the only treatment needed. In most cases, it is sufficient to remove the polyp through a colonoscope (local excision). Removal of part of the colon (partial colectomy) may be required if the tumor is too large for local excision. When determining treatment tactics, prognostic factors should be taken into account.

Negative prognosis factors:

• stage ≥ G3
• affected resection margins
• lymphatic, vascular or perineural invasion
• IV stage of invasion (involvement of the submucosa of the colon), > pT1sm1

I stage

Colon cancer of stage I grows deeper into the layers of the colon wall, but does not spread beyond the wall itself or to nearby lymph nodes.

If the polyp is completely removed during a colonoscopy and there are no cancer cells at the margins (edges) of the removed fragment, no other treatment may be required.

If the cancer in the polyp is high grade or there are tumor cells at the edges of the polyp, additional surgery may be recommended. If the polyp cannot be completely removed, or if it has to be removed step-by-step, a second surgery may be required.

If the tumor is located outside the polyp, the standard treatment is partial colectomy — removal of the affected area of the colon and nearby lymph nodes.

II stage

In stage II CRC, the tumor often grows through the wall of the colon, may spread to nearby tissues, but does not spread to the lymph nodes.

Partial colectomy with nearby lymph nodes may be the only treatment needed. But if there is a high risk of recurrence, adjuvant chemotherapy (after surgery) may be added:

• high grade tumor,
• the tumor has grown into nearby blood or lymph vessels,
• the surgeon did not remove at least 12 lymph nodes,
• the tumor was found at or near the edge of the removed tissue, what means that some malignant cells may have remained,
• the tumor blocked the intestinal lumen,
• the tumor has caused a perforation (hole) in the wall of the colon.

Genetic testing for microsatellite instability (MSI) or dMMR testing can help decide whether adjuvant chemotherapy will be beneficial.

The decision to prescribe chemotherapy is up to the physician, the main options include 5-FU and leucovorin (Modified De Gramont regimen), oxaliplatin or capecitabine (XELOX/FOLFOX), but other combinations are possible (FLOX).

III stage

Colon cancer has spread to nearby lymph nodes but has not yet spread to other organs.

The standard treatment is partial colectomy along with nearby lymph nodes followed by adjuvant chemotherapy: FOLFOX, XELOX. If the tumor cannot be completely removed by surgery, neoadjuvant chemotherapy may be indicated along with radiation (chemoradiotherapy) to reduce the size of the tumor for removal. If, after removal of the tumor, it is found to be attached to an adjacent organ or if resection margins are positive (adjuvant irradiation may be recommended). Radiation therapy and/or chemotherapy may be options if surgery is not possible.

IV stage

The cancer has spread to distant organs and tissues: most often to the liver, it can also spread to the lungs, brain, peritoneum, or distant lymph nodes.

In most cases, surgery is not the treatment of choice. But if there are liver or lung metastases that can be removed along with CRC and nearby lymph nodes, surgery may help increase life expectancy. Chemotherapy is given after surgery. An experimental treatment is hepatic artery infusion if the cancer has spread to the liver. For potentially resectable metastatic foci, the most effective chemotherapy is recommended (FOLFOX, XELOX or FOLFIRI, XELIRI, FOLFOXIRI).

If metastases cannot be removed because they are too large or too numerous, neoadjuvant chemotherapy (preferably FOLFOXIRI) may be given before surgery. Then, if the size of the tumor decreases, surgery and subsequent chemotherapy may be suggested. For liver tumors, ablation or embolization may be another option.

If surgical treatment is not possible, chemotherapy is the main treatment. Surgery may be needed if a tumor is blocking the colon. To prevent bowel obstruction, a stent (hollow metal tube) is placed in the colon during a colonoscopy to keep it open. Otherwise, operations such as a colectomy or diverting colostomy (dissecting the colon above the tumor and attaching the end to an opening in the skin on the abdomen to let the waste out) may be used.

Chemotherapy for CRC

• FOLFOX, FLOX: leucovorin, 5-FU and oxaliplatin
• FOLFIRI: leucovorin, 5-FU and irinotecan
• XELOX: capecitabine and oxaliplatin
• FOLFOXIRI: leucovorin, 5-FU, oxaliplatin, and irinotecan
• Modified De Gramont regimen (leucovorin, 5-FU)
• XELIRI: capecitabine, irinotecan
• Irinotecan
• Capecitabine

Targeted therapy for CRC

• If there are no mutations in the RAS genes (KRAS, HRAS, NRAS) and BRAF, the addition of anti-EGFR targeted therapy (cetuximab or panitumumab) is recommended, regardless of the primary tumor location. In right-sided tumor localization, bevacizumab is an alternative to anti-EGFR antibodies.
• In the presence of a KRAS/HRAS/NRAS mutation, the addition of bevacizumab, regardless of the location of the primary tumor.
• In the absence of mutations in the RAS and BRAF genes, it is also necessary to prescribe anti-angiogenic therapy. If in the 1st line there was cetuximab or panitumumab, in the 2nd line it is optimal to prescribe regimens with the inclusion of VEGF inhibitors: bevacizumab or aflibercept or ramucirumab. Continued administration of cetuximab or panitumumab when progressing on this drug class does not improve survival.
• If there is a BRAF mutation, the chemotherapy regimen FOLFOXIRI + bevacizumab is recommended.With the disease progression during the 1st line of therapy with a mutation in the BRAF gene, it is possible to prescribe the FOLFIRI regimen using aflibercept / bevacizumab / ramucirumab or a combination of anti-EGFR antibodies with BRAF +/- MEK inhibitors:
  • FOLFIRI
  • Irinotecan + BRAF inhibitor (vemurafenib) + cetuximab
  • BRAF inhibitor (dabrafenib) + MEK inhibitor (trametinib) + panitumumab (or cetuximab)
  • BRAF inhibitor (vemurafenib) + MEK inhibitor (cobimetinib)
  • BRAF inhibitor (dabrafenib/vemurafenib) + anti-EGFR antibodies (panitumumab/cetuximab)
• Anti-EGFR antibodies should not be used in combination with capecitabine (capecitabine monotherapy, XELOX and XELIRI regimens) or fluoropyrimidine bolus regimens (Mayo regimen, FLOX, IFL).
• In the 3rd and subsequent lines of therapy with overexpression or amplification of the HER2 gene in the absence of mutations in the RAS genes (KRAS / HRAS / NRAS), combinations of trastuzumab and lapatinib or trastuzumab and pertuzumab may be prescribed.
• In patients with disease progression while using oxaliplatin, irinotecan and fluoropyrimidines, bevacizumab and anti-EGFR antibodies (if indicated), regorafenib may be considered.
• Aflibercept (in the 2nd line of therapy + FOLFIRI/irinotecan/De Gramont).

Immunotherapy for CRC

With MSI-H, it is possible to prescribe monotherapy with anti-PD-1 antibodies — nivolumab (Opdivo) or pembrolizumab (Keytruda) alone or in combination (characterized by a higher frequency of achieving an objective response).