Chemotherapy for colon cancer: approaches

Chemotherapy for colorectal cancer has three main goals: to eliminate microscopic remnants of disease after surgery (adjuvant regimen), to shrink the primary tumor and/or lymph nodes before surgery (neoadjuvant portion of total neoadjuvant therapy for rectal cancer), and, in metastatic cases, to prolong survival, control symptoms, and, in selected patients, make metastases resectable. Most regimens are based on fluoropyrimidines (5-fluorouracil "in a pump" or oral capecitabine), to which oxaliplatin or irinotecan are added. Cytostatics themselves are increasingly combined with targeted or immune therapy, if tumor biology allows it. [1]

In colorectal cancer, the following names are commonly used for "dual" and "triple" regimens: FOLFOX (5-FU/leucovorin + oxaliplatin), CAPOX (capecitabine + oxaliplatin), FOLFIRI (5-FU/leucovorin + irinotecan), and FOLFOXIRI (the addition of irinotecan to FOLFOX). The choice of a "dual" or "triple" regimen depends on the goal (rapid debulking or safe maintenance of control), age, comorbidities, and potential toxicity. In metastatic settings, antiangiogenic therapy (bevacizumab) is often added to the dual regimen, and in some patients, an anti-EGFR antibody (cetuximab/panitumumab) instead of bevacizumab. These decisions are made after molecular profiling. [2]

A key change in recent years has been the active use of immune therapy in patients with high microsatellite instability or mismatch repair defects (MSI-H/dMMR). For these patients, first-line treatment may not include chemotherapy at all: PD-1 inhibitors (pembrolizumab) or PD-1 + CTLA-4 combinations (nivolumab + ipilimumab) have demonstrated superiority over chemotherapy in terms of duration of control. This does not "cancel" chemotherapy, but it does change the sequence and emphasis for certain biomarkers. [3]

It's important to understand that "bowel cancer" encompasses two clinically distinct conditions: colon cancer and rectal cancer. In the rectum, chemotherapy is almost always combined with radiation therapy as part of total neoadjuvant therapy (TNT) before surgery; in the colon, adjuvant chemotherapy is administered postoperatively at stages with a risk of recurrence. This determines both the composition of the regimen and the duration of treatment. [4]

When and to whom is it prescribed: postoperative, preoperative and "first lines"

Postoperative (adjuvant) chemotherapy is indicated for most patients with stage III colon cancer and selected patients with high-risk stage II disease (perforation/obstruction, small lymph node sample, T4, etc.). The classic choice is CAPOX or FOLFOX. According to the IDEA consortium, the duration can be reduced to 3 months in a significant proportion of patients without loss of efficacy, especially with the CAPOX regimen and "not too high" risk, which significantly reduces the likelihood of cumulative neuropathy. For stage II disease without high-risk factors, chemotherapy is not routine. [5]

For rectal cancer, the standard has shifted to total neoadjuvant therapy: all systemic chemotherapy (usually 3-4 months of FOLFOX or CAPOX) plus chemoradiation therapy are administered before surgery. This approach increases the rate of complete clinical response, improves the chances of organ preservation, and better controls micrometastases. The sequence of treatment blocks may differ between protocols, but the logic is the same: "get the most important things done before surgery." [6]

In metastatic disease, physicians select the first-line approach individually. For RAS-wildcard, left-sided primary tumors, the addition of an anti-EGFR antibody to dual chemotherapy yields the most profound responses and a higher chance of secondary resectability of metastases compared with an anti-VEGF approach. For right-sided tumors or those with RAS/RAF mutations, chemotherapy ± bevacizumab is preferred. Finally, in MSI-H/dMMR patients, immune therapy is now often the first-line treatment, rather than chemotherapy. [7]

An important practice is "maintenance" after intensive cycles: when the tumor has responded well, a less toxic maintenance regimen (e.g., 5-FU/leucovorin or capecitabine ± bevacizumab) is switched to maintain control and reduce the risk of neuropathy from oxaliplatin. This is a standard way to extend the overall treatment duration without "accumulating" side effects. [8]

Modes and how they are chosen in practice

In adjuvant therapy, two regimens predominate: CAPOX and FOLFOX. CAPOX is more convenient in patients with good renal function and disciplined pill intake; FOLFOX is suitable if the patient has severe hand-foot toxicity with capecitabine or there are contraindications to the oral form. In stage III with intermediate risk, it is reasonable to aim for 3 months of CAPOX, and in high-risk T4/N2 patients, 6 months should be discussed or the risk/benefit balance should be assessed on an individual basis. [9]

In metastatic cancer, the FOLFOX and FOLFIRI "two-drug regimens" are therapeutically equivalent; the choice is dictated by comorbidities and expected toxicity (neuropathy versus diarrhea/neutropenia). The FOLFOXIRI "three-drug regimen" offers the highest tumor shrinkage rate and the highest chance of secondary resectability, but is not suitable for everyone due to toxicity—it is chosen for young, healthy patients when the goal is to maximize tumor shrinkage. In patients with a left-sided RAS-wildcard profile, anti-EGFR is added to the two-drug regimen; in other situations, bevacizumab is more commonly used. [10]

For rectal cancer, FOLFOX or CAPOX is typically used as part of a TNT regimen for 3-4 months: this provides systemic control and increases the rate of pathological/clinical complete response during (chemo)radiotherapy. Various sequences are used routinely (short course radiation → chemotherapy, or vice versa), but the ultimate goal is to opt for maximally radical surgery or, in carefully selected patients, a careful observation strategy for complete clinical response. [11]

In certain biological subgroups, chemotherapy is being augmented or replaced by other approaches. Thus, in MSI-H/dMMR patients, first-line immunotherapy is superior to chemotherapy in terms of duration of control and quality of life; in left-sided RAS-wild-type tumors, the addition of anti-EGFR determines the depth of response; in refractory RAS-wild-type tumors, anti-EGFR rechallenge after clone purification by liquid biopsy is being discussed. These decisions do not eliminate the role of cytostatics, but they change the balance of power. [12]

Personalization and biomarkers: who will receive "regular chemotherapy" and who will receive its alternatives

Every patient with metastatic colorectal cancer is now recommended to have RAS (KRAS/NRAS), BRAF, microsatellite instability/repair defect (MSI/MMR) status, and, if possible, primary localization (left/right) tested - these markers determine whether chemotherapy should be supplemented or replaced. In practice, this means: (1) MSI-H/dMMR - immune therapy (nivo + ipilimumab or pembrolizumab) as the preferred first line; (2) left-sided RAS-wildcard - chemotherapy + anti-EGFR; (3) RAS- or BRAF-mutant - chemotherapy ± bevacizumab in the first line, and mutation-targeted therapy in the subsequent lines. [13]

In addition to "susceptibility tumor markers," pharmacogenetic safety testing is becoming increasingly important. DPYD genotyping is increasingly being implemented in Europe before prescribing fluoropyrimidines: carriers of functionally significant variants have a high risk of severe early toxicity and require a reduced starting dose. This approach has already demonstrated a reduction in fatal complications and hospitalizations and is reflected in updates to several guidelines and regulatory recommendations. [14]

The UGT1A1*28 mutation is important for irinotecan: the homozygous variant increases the risk of neutropenia and diarrhea, and it is recommended to reduce the starting dose by approximately 30%, followed by titration based on tolerability (this approach is supported by the DPWG/RNPGx pharmacogenetic consensus). In real-world practice, more and more centers are combining DPYD and UGT1A1 into a single pre-treatment "safety profile." [15]

Finally, even with "pure chemotherapy," personalization includes fine-tuning the duration and composition. An example is switching to maintenance therapy without oxaliplatin after 8-12 administrations to avoid developing severe neuropathy, and individualizing the duration of adjuvant therapy (3 vs. 6 months) based on the risk of relapse. This is modern "tailored chemotherapy," not "one size fits all." [16]

Toxicity and How to Cope with It: Practical Techniques

Oxaliplatin causes cumulative sensory neuropathy: initially, cold-induced "shock" attacks, then persistent numbness. The best "cure" is dose prevention: limit the cumulative number of cycles, promptly switch to oxaliplatin-free maintenance ("stop-and-go"), and carefully monitor symptoms. Calcium/magnesium infusions have been studied, but randomized data have not confirmed a clear benefit for prophylaxis; they are not routinely used. [17]

Capecitabine causes hand-foot syndrome, stomatitis, and diarrhea. Intervals, dose reduction, preventative skin care, and loperamide for diarrhea can help. In patients with DPYD variants, the starting dose must be reduced, which significantly reduces the risk of severe toxicity without compromising efficacy. For 5-FU in a pump, maintaining the infusion rate and monitoring hydration/electrolyte levels is critical. [18]

Irinotecan is associated with early (cholinergic) and late diarrhea, as well as neutropenia. Early diarrhea responds well to atropine during infusion; late diarrhea requires aggressive therapy with loperamide using a high-dose regimen, sometimes hospitalization, and antibiotics. For UGT1A1*28/*28, it is safer to start with a reduced dose and titrate upward if well-tolerated. [19]

Skin rashes, dryness, and hypomagnesemia are expected in the presence of anti-EGFR antibodies; prophylaxis includes hydration, sun protection, and, if necessary, topical/systemic antibiotics. Bevacizumab increases the risk of hypertension, bleeding, and delayed wound healing; it is temporarily discontinued before surgery, and blood pressure and urine protein levels are closely monitored. These are all standard elements of "chemotherapy hygiene" that patients should be aware of in advance. [20]

Special clinical situations: the elderly, concomitant diseases, organ preservation

In elderly and fragile patients, it's reasonable to choose less intensive regimens and plan for maintenance therapy: tolerability and quality of life are more important than maximizing response. Capecitabine is convenient as an oral option, but in cases of severe renal impairment, its dose is reduced or infusional 5-FU is preferred. In patients with a history of neuropathy, it's best to start with FOLFIRI, and in patients with chronic diarrhea, with FOLFOX. [21]

In locally advanced rectal cancer, some patients achieve a complete clinical response after TNT. In such cases, a watch-and-wait strategy is possible instead of immediate surgery. This is not a "cancellation" of treatment, but a different approach to disease control that requires disciplined monitoring and an experienced team. The choice of chemotherapy regimens in TNT and their duration (usually 3-4 months) are supported by current clinical guidelines. [22]

In oligometastatic disease, the goal is maximal response with the prospect of secondary resection of liver/lung lesions. More intensive regimens (up to FOLFOXIRI) and a "left-sided" strategy with anti-EGFR in a RAS-wild-type profile are acceptable. Once a window for resection opens, chemotherapy is temporarily discontinued, surgery is performed, and then a decision is made about resuming treatment. [23]

Finally, don't forget the "little things" that make all the difference: nutritional support, thrombosis prevention, adequate antiemetic therapy, early correction of anemia, and blood pressure and sugar control. Well-designed support is often more important than exotic regimens and makes "conventional" chemotherapy much safer. (These measures are detailed in clinical guidelines and standard practice for caring for patients on systemic therapy.)

Frequently asked questions (briefly)

How long does adjuvant chemotherapy last for stage III disease? For a significant proportion of patients, 3 months is sufficient, especially with the CAPOX regimen; for higher-risk patients, 6 months is considered. The decision is individual. [24]

Is chemotherapy necessary in stage II? Not always. It is indicated in cases of high-risk factors (T4, perforation/obstruction, <12 examined nodes, etc.). [25]

What should be chosen in the first line for metastases? For MSI-H/dMMR - immunotherapy; for left-sided RAS-wild type - chemotherapy + anti-EGFR; in other cases - chemotherapy ± bevacizumab. Details depend on the goals and tolerability. [26]

Is it possible to reduce the risk of serious toxicity in advance? Yes: DPYD testing is increasingly recommended before fluoropyrimidines, and UGT1A1 testing before irinotecan; if variants are identified, reduced doses are started. [27]