Colorectal Cancer (Colon Carcinoma): Drug Therapy

Therapeutic Targets

  • Cure or improvement of prognosis
  • If necessary, also improvement of symptoms, reduction of tumor mass, palliative (palliative treatment).

Therapy recommendations (according to current S3 guideline)

  • The most important therapeutic procedure is surgery; also in advanced stages (see below “Surgical therapy“).
  • In the case of extensive tumor growth in the rectum (rectum), neoadjuvant therapy (radiotherapy (radiatio) or chemotherapy preceding surgery, sometimes a combination of both treatments) is performed to reduce the tumor (shrink the tumor).
  • Adjuvant chemotherapy (used to support surgical therapy):
    • Adjuvant chemotherapy 5-FU (FOLFOX: folinic acid, 5-FU, oxaliplatin) may be given to patients with curatively resected UICC stage II colon cancer.
    • In UICC stage II, adjuvant chemotherapy should be considered in selected risk situations (T4, tumor perforation/rupture, surgery under emergency conditions, number of examined lymph nodes too low).
    • Adjuvant chemotherapy should be given to patients with R0 resected UICC stage III colon carcinoma.
  • In metastatic disease and in the palliative situation (palliative therapy/palliative treatment):
    • Metastasis
      • In resectable tumor manifestations and favorable risk constellation, metastasectomy should be primarily targeted.
      • The choice of chemotherapy regimen depends critically on the molecular pathologic profile of the tumor: determination of (ALL) RAS and BRAF mutations (from primary tumor tissue or metastases) should be performed before initiation of first-line therapy, if possible.
      • Patients who show a RAS wild type (RAS-wt) in an extended RAS analysis (KRAS and NRAS, exons 2-4) and have a left-sided localization of the primary tumor (colon carcinoma) should be preferentially treated with a chemotherapy doublet plus anti-EGFR therapy in the first-line therapy of metastatic disease.
      • In first-line chemotherapy, fluoropyrimidine-based combination regimens with infusional administration of 5-fluorouracil, such as FOLFIRI, FOLFOX, or FOLFOXIRI, or with the oral fluoropyrimidine capecitabine (predominantly with oxaliplatin, CAPOX) should be used primarily if the patient is in good general health and highly motivated.
      • With regard to chemotherapy, fluoropyrimidine monotherapies (5-fluorouracil/folinic acid or capecitabine) can usually be used in combination with bevacizumab if the general condition is depressed.
      • Trifluridine/tipiracil should be used in patients who have undergone or are not suitable for all available chemotherapies/antibodies.
    • Palliative therapy
      • Enteral nutrition, e.g., feeding via a PEG (percutaneous endoscopic gastrostomy: endoscopically created artificial access from the outside through the abdominal wall into the stomach)
      • Infusion therapy via a port catheter (port; permanent access to venous or arterial blood circulation).
      • Supplementation (“complementary therapy”) of micronutrients.
      • Pain therapy (according to WHO stage scheme; see below “Chronic pain“).
  • See also under “Further therapy”.

Chemotherapy for colon carcinoma

Neoadjuvant chemotherapy (NACT).

Neoadjuvant chemotherapy, which means chemotherapy before surgery: for this purpose, combined radiochemotherapy (RCTX) may be used in locally advanced rectal cancer (rectal cancer) to shrink tumor tissue and improve surgical prospects. This is followed by total mesorectal excision (TME; rectal cancer surgery) and adjuvant chemotherapy with 5-FU if necessary in combination with oxaliplatin. Adjuvant chemotherapy

Adjuvant chemotherapy is used to support surgical therapy. The prerequisite for adjuvant therapy is R0 resection (removal of the tumor in healthy tissue; no tumor tissue is detectable in the resection margin on histopathology) of the primary tumor. In patients up to 70 years of age, oxaliplatin-containing therapy for 6 months is the standard of care.A meta-analysis showed that survival times are dependent on the time between surgery and the start of adjuvant therapy; patients survived longest when adjuvant chemotherapy started 4 weeks after surgery. In patients with stage III colon cancer, shortening adjuvant chemotherapy from 6 to 3 months spared the neurotoxicity (“nerve toxicity”) of oxaliplatin with a slight decrease in disease-free survival (disease-free survival at 3 years after 3 months of adjuvant chemotherapy 74.6% and after 6 months of adjuvant chemotherapy 75.5%.) in 6 randomized clinical trials. Note: In patients older than 75 years, there is insufficient evidence to support the use of adjuvant chemotherapy.However, in stage III patients younger than 70 years, oxaliplatin-containing therapy remains the standard of care for adjuvant chemotherapy. Contraindications to adjuvant chemotherapy for colon cancer (according to current S3 guidelines):

  • General condition worse than 2 (ECOG).
  • Uncontrolled infection
  • Liver cirrhosis Child B and C
  • Severe coronary artery disease (CAD; coronary artery disease), heart failure (heart failure: NYHA III and IV).
  • Preterminal and terminal renal failure (process leading to a slowly progressive reduction in renal function).
  • Impaired bone marrow function
  • Other comorbidities (concomitant diseases) determining life expectancy.
  • Inability to participate in regular check-ups

Palliative – to halt the progression of the disease as long as possible and improve the quality of life in the case of disease that can no longer be cured. The following chemotherapeutic agents are used in this case:

  • 5-fluorouracil (5-FU)
  • Folinic acid (FS)
  • Irinotecan
  • Oxaliplatin

No information on doses of cytostatic drugs is given below, because treatment regimens are constantly being modified. Colon Cancer

  • Stage UICC II – usually no indication for chemotherapy; consider fluoropyrimidine monotherapies (5-fluorouracil/folinic acid or capecitabine) in selected high-risk situations (see above ).
  • Stage UICC III – adjuvant chemotherapy with oxaliplatin in combination with 5-FU/folinic acid (FS).
  • Stage UICC IV – palliative chemotherapy with 5-fluorouracil, folinic acid, oxaliplatin, capecitabine, irinotecan; bevacizumab, cetuximab, panitumumab, regorafenib (third-line and in fourth-line).

In patients > 70 years of age, adjuvant therapy with fluoropyrimidines can be performed without restriction. Rectal carcinoma (rectal cancer).

  • Stage UICC* II and III – neoadjuvant radiochemotherapy with 5-fluorouracil.

Multiple liver metastases

  • Chemotherapy with 5-fluorouracil, folinic acid and oxaliplatin or irinotecone.
  • Monoclonal antibodies such as bevacizumab are currently being tested in trials

Peritoneal carcinomatosis/metastasis (formation of daughter tumors) to the peritoneum (peritoneum) (in up to 15% of all patients with metastatic colorectal cancer):

  • Surgical cytoreduction (tumor reduction) and intraoperative hyperthermic intraperitoneal chemotherapy (as curative intervention).

Legend: UICC – Union internationale contre le cancer.

Further notes

  • Note: Retrospective analysis of several studies has consistently shown no benefit for EGFR antibody therapy in right-sided tumors (C. transversum, C. ascendens, coecum). In such cases, a combination of 5-FU and oxaliplatin or irinotecan with or without bevacizumab is indicated.
  • When second-line therapy fails in patients with metastatic colorectal cancer, third-line therapeutics such as trifluridine/tipiracil or regorafenib should be used instead of relying on a rechallenge with classical chemotherapeutic agents, according to one study.
  • Approximately 40% of all colorectal cancers have mutations in the KRAS gene that render targeted therapies with cetuximab or panitumumab (see above) unsuccessful.
  • Approximately 10% of all colorectal cancers have a failed BRAF gene, which normally controls the cell cycle. These tumors are particularly aggressive.
  • Ramucirumab (monoclonal antibody that binds to the cell surface angiogenesis-inducing VEGF receptor-2 and interrupts the downstream signaling cascade to the nucleus; thus, angiogenesis is prevented) in combination with FOLFIRI (5-fluorouracil, folinic acid, irinotecan) for the treatment of adults with metastatic colorectal cancer (mCRC) whose disease has become progressive.
  • Fruquintinib (VEGF receptor blocker) doubled progression-free survival in patients with locally advanced or metastatic colorectal cancer who had received at least two prior chemotherapies, including fluoropyrimidine, oxaliplatin, and irinotecan.Patients on the VEGF receptor blocker lived a median of 9.3 months, while those on placebo lived only 6.6 months.
  • Triple therapy with the MAK inhibitor encorafenib, the MEK1 inhibitor binimetinib, and the EGFR antibody cetuximab extended survival in patients with metastatic colorectal cancer and BRAF V600E mutations in the tumor in an open-label phase III trial.
  • High-dose vitamin C therapy is able to kill colon tumor cells with BRAF or KRAS mutations. The tumor cells with KRAS or BRAF mutations on their surface produce more glucose transporter GLUT1. Dehydroascorbic acid (DHA) enters the cells via the GLUT1 transporter. DHA is the oxidized variant of vitamin C. It is transported intracellularly by antioxidants. This is converted back into vitamin C intracellularly by antioxidants. An excess of intracellular DHA (high dose vitamin C therapy) depletes the antioxidant resources of the cell resulting in an accumulation of oxygen free radicals. This in turn leads to oxidative damage to the tumor cells. The team led by Lewis Cantley of Weill Cornell Medical College in New York was able to confirm this in animal experiments. In metastatic colon carcinoma, intensive combination therapy often resulted in many inoperable patients still being able to undergo surgery and possibly living longer. In patients with non-resectable, metastatic RAS wild-type CRC, a triple combination modified-dose FOLFOXIRI regimen in combination with the EGFR antibody panitumumab was compared with normal-dose FOLFOXIRI alone. This leads to the following result: higher response rate of 87.3% versus 60.6% (p=0.004); also the prognostically relevant secondary resection rate was higher with 33.3% versus 12.2 percent % (p=0.029).Conclusion: better to “Hit Hard” than “Go Slow”.
  • Pembrolizumab (immune checkpoint inhibitors: PD-1 inhibitor): first-line pembrolizumab therapy for metastatic colorectal cancer (mCRC) with high microsatellite instability extends patient progression-free survival from a median of 8.2 months with the previous cytostatic standard to a median of 16.5 months.

Tertiary Prevention

  • In a population-based cohort study, statin therapy was shown to reduce the risk of mortality specific to colorectal cancer and was associated with higher survival.