Stage III colon cancer: oxaliplatin for three or six months

A 63-year-old accountant underwent surgery for adenocarcinoma of the transverse colon. The pathology report shows a pT3 tumor, 2 of 21 lymph nodes involved, no perforation, with preserved mismatch repair. It is a lower-risk stage III, pT3N1. She plays piano as a hobby and, on hearing that chemotherapy with oxaliplatin can cause tingling in the hands, asks whether she really needs six months of treatment and whether she can take tablets instead of being connected to an infusion pump. The scene is fictional and was written for teaching.

This text uses the case as a scenario for clinical reasoning for students and health professionals. The question comes from Dr. Alexei's list for the oncology series: what is the benefit of oxaliplatin in the adjuvant treatment of stage III colon cancer, and when are three months enough? The reference studies are MOSAIC, which established FOLFOX in the adjuvant setting, and the IDEA collaboration, which compared three and six months of treatment. The text does not replace your country's guideline or your institution's protocol. If you play the case of the day on NEXO, you will recognize the challenge: weighing a small gain in efficacy against a harm that can last for years.

Key points

• In stage III, oxaliplatin added to a fluoropyrimidine reduced recurrence and death in the MOSAIC study.
• Peripheral sensory neuropathy is the adverse effect that most limits oxaliplatin and depends on the cumulative dose.
• The IDEA collaboration pooled 6 studies and more than 12 thousand patients to compare three and six months of treatment.
• With CAPOX, three months were non-inferior to six months, especially in the lower-risk group, pT1 to pT3 and N1.
• With FOLFOX, and in the high-risk group, pT4 or N2, six months kept a small advantage in disease-free survival.
• Three months of treatment substantially reduced grade 2 or higher neuropathy.

Why this is a reasoning scenario

In stage III colon cancer, regional lymph nodes are involved and the risk of recurrence is high enough that adjuvant chemotherapy is standard. The question is no longer whether to treat but with what and for how long. Oxaliplatin adds benefit, but it also adds a neuropathy that can persist for years and affect fine activities, such as playing piano, buttoning a shirt or typing.

The accountant in the scenario has lower-risk stage III disease and a concrete concern about her hands. She also prefers tablets to an infusion pump. These preferences are not details: they enter into the choice between CAPOX, which uses oral capecitabine, and FOLFOX, which uses 5-fluorouracil by continuous infusion, and into the choice of duration.

The post on why the multidisciplinary team differs in colon and rectal cancer shows who takes part in the decisions. The post on chemotherapy in stage II covers the group in which the gain is smaller.

The mistake the scenario aims to avoid

The most common mistake is prescribing six months of FOLFOX for every stage III out of habit, without classifying risk or considering neuropathy. The opposite mistake is shortening treatment for someone with a pT4 or N2 tumor without discussing the small loss of efficacy. Another mistake is continuing oxaliplatin despite neuropathy that already interferes with function.

MOSAIC: the place of oxaliplatin

MOSAIC compared the FOLFOX4 regimen, with 5-fluorouracil, leucovorin and oxaliplatin, with 5-fluorouracil and leucovorin, both for six months, in patients with stage II and III colon cancer, according to the protocol of the IDEA collaboration (André et al., 2013). Among patients with stage III disease, 5-year disease-free survival was 66.4 in 100 with FOLFOX4 and 58.9 in 100 without oxaliplatin, with a hazard ratio of 0.78 (André et al., 2013). Overall survival at 6 years was 72.9 in 100 with FOLFOX4 and 68.7 in 100 in the control group, with a hazard ratio of 0.80 (André et al., 2013).

These numbers show an absolute gain of about 4 points in overall survival in stage III. It is a moderate but important benefit in a disease treated with curative intent. The NSABP C-07 study, with oxaliplatin added to bolus 5-fluorouracil, also showed a gain, according to the same protocol (André et al., 2013).

And in stage II?

In stage II, the gain from oxaliplatin is less clear. A post hoc analysis of MOSAIC showed that only patients with high-risk stage II and postoperative CEA above 2.35 nanograms per milliliter benefited from oxaliplatin (Auclin et al., 2019). Three-year disease-free survival was 88.5 in 100 with CEA up to that value and 78.7 in 100 above it (Auclin et al., 2019). It is an exploratory analysis, useful for understanding that CEA after surgery carries prognostic information.

The neuropathy that remains

Oxaliplatin causes two types of neurotoxicity. The acute form, triggered by cold, appears in the hours and days after the infusion and usually passes. The chronic, cumulative form produces numbness and tingling in the hands and feet, worsens with the total dose and may persist after the end of treatment.

How long it lasts

In MOSAIC, 48 months after the end of chemotherapy, grade 1, 2 and 3 peripheral sensory neuropathy was present in 11.9, 2.8 and 0.7 in 100 patients evaluated, respectively (André et al., 2013). In the long-term evaluation of the NSABP C-07 and LTS-01 studies, oxaliplatin doubled the chance of numbness and tingling in the hands, with an odds ratio of 2.00, and nearly tripled it in the feet, at 2.78 (Kidwell et al., 2012). The authors concluded that the total neurotoxicity score did not increase in a clinically significant way, but that numbness and tingling in the hands and feet remained more frequent (Kidwell et al., 2012).

For the accountant in the scenario, who plays the piano, this data point is central. Grade 1 neuropathy may look mild on the scale, but it can interfere with an activity she values. The conversation needs to translate the grades into everyday functions.

Signs the team should ask about

Chronic neuropathy has signs the team can look for at each cycle:

• Numbness or tingling at the fingertips that does not go away between cycles.
• Difficulty buttoning clothes, writing or picking up small objects.
• Loss of balance or a feeling of walking on cotton.
• Burning pain in the hands or feet.
• Dropping objects from the hands without noticing.

When neuropathy starts to interfere with function, the usual approach is to reduce the dose or suspend oxaliplatin and keep the fluoropyrimidine. ACHIEVE provided for this switch from mFOLFOX6 to 5-fluorouracil and leucovorin, and from CAPOX to capecitabine alone, when the adverse effects of oxaliplatin made continuation difficult (Kotaka et al., 2018).

IDEA: three or six months

Because neuropathy depends on the cumulative dose, shortening treatment was the most direct way to reduce it. The IDEA collaboration brought together 6 randomized studies, conducted in Italy, the United Kingdom and Australia, France, Japan, Greece and the United States and Canada, to test whether three months were non-inferior to six (André et al., 2013).

What non-inferiority means

A non-inferiority study does not ask whether the shorter treatment is better. It asks whether it is worse beyond a margin accepted before the study began. In IDEA, this margin was defined for the hazard ratio of disease-free survival, and the result depends on where the upper limit of the confidence interval falls (Grothey et al., 2018). Therefore, a result may fail to confirm non-inferiority in the total population and at the same time show small absolute differences. The clinical reading requires looking at the absolute numbers, the risk subgroups and the adverse effects that the shorter treatment avoids. The protocols of the six teams also differed in the allowed regimen and in the proportion of high-risk patients, which makes the combined analysis richer and harder to interpret (André et al., 2013).

The main result

In the 2018 analysis, with 12,834 patients, non-inferiority of three months was not confirmed in the total population, with a hazard ratio of 1.07 and an interval of 1.00 to 1.15 (Grothey et al., 2018). With CAPOX, three months were non-inferior, with a hazard ratio of 0.95, but with FOLFOX they were not, with a hazard ratio of 1.16 (Grothey et al., 2018).

In the exploratory analysis by risk, among patients with pT1 to pT3 and N1 tumors, 3-year disease-free survival was 83.1 in every 100 with three months and 83.3 in every 100 with six months (Grothey et al., 2018). Among patients with pT4, N2 or both, six months were superior, with 64.4 versus 62.7 in every 100 (Grothey et al., 2018).

IDEA group	Three months	Six months
Lower risk, pT1 to pT3 and N1, 3-year disease-free survival	83.1 in every 100	83.3 in every 100
High risk, pT4 or N2, 3-year disease-free survival	62.7 in every 100	64.4 in every 100
Grade 2 or higher neuropathy with FOLFOX	16.6 in every 100	47.7 in every 100
Grade 2 or higher neuropathy with CAPOX	14.2 in every 100	44.9 in every 100

Source of the numbers in the table: Grothey et al., 2018 (Grothey et al., 2018).

Overall survival

In the final IDEA analysis, with a median follow-up of 72 months, 5-year overall survival was 82.4 in every 100 with three months and 82.8 in every 100 with six months (André et al., 2020). With CAPOX, it was 82.1 versus 81.2 in every 100, and with FOLFOX, 82.6 versus 83.8 in every 100 (André et al., 2020). The authors concluded that the absolute difference of 0.4 point must be seen in context and that the data support three months of CAPOX for the vast majority of patients with stage III (André et al., 2020). In the high-risk group treated with CAPOX, the difference in overall survival was about 1 point, not significant, in favor of six months (André et al., 2020).

Neuropathy with three months

In IDEA, grade 2 or higher neurotoxicity during treatment fell from 47.7 to 16.6 in every 100 with FOLFOX and from 44.9 to 14.2 in every 100 with CAPOX when shortened to three months (Grothey et al., 2018). In the British SCOT study, grade 2 or higher neuropathy appeared in 58 in every 100 patients in the six-month group and in 25 in every 100 in the three-month group, in the subset with safety data, and it was long-lasting and associated with worse quality of life (Iveson et al., 2018). In the Japanese ACHIEVE, neuropathy that persisted 3 years later was 9.7 in every 100 with three months and 24.3 in every 100 with six months (Yoshino et al., 2019).

CAPOX or FOLFOX

CAPOX combines intravenous oxaliplatin every three weeks with oral capecitabine. In SCOT, oxaliplatin was given at a dose of 130 mg per square meter on the first day, and capecitabine, 1,000 mg per square meter twice a day for the first 14 days of each cycle, with 4 cycles in three months and 8 in six months (Iveson et al., 2018). The protocol allowed starting capecitabine at 75 in every 100 of the dose in patients with creatinine clearance between 30 and 50 milliliters per minute (Iveson et al., 2018).

The mFOLFOX6 of ACHIEVE used oxaliplatin 85 mg per square meter over 2 hours, 5-fluorouracil bolus of 400 mg per square meter, levoleucovorin 200 mg per square meter and a 5-fluorouracil infusion of 2,400 mg per square meter over 46 hours, every 14 days (Kotaka et al., 2018). Check the doses in your service's protocol and in the package insert before prescribing.

How to choose

The choice between the two regimens weighs several factors:

• Patient preference between tablets and infusion with a portable pump.
• Need for a central venous catheter, more frequent with FOLFOX.
• Kidney function, which calls for adjusting capecitabine.
• Ability to manage hand-foot syndrome and diarrhea at home.
• Expected adherence to the oral tablet.
• Intended duration, since three months have more support with CAPOX.

In ACHIEVE, patients treated with CAPOX and with creatinine clearance up to 50 milliliters per minute had more grade 3 or higher adverse events, with an odds ratio of 1.67 (Kotaka and colleagues, 2018). Neuropathy that persisted 3 years later was also lower with CAPOX than with mFOLFOX6, both in the three-month and the six-month groups (Yoshino and colleagues, 2019).

A Turkish retrospective comparison of CAPOX and FOLFOX in the adjuvant setting found no difference in overall survival and showed that patients treated with CAPOX were older (Degirmencioglu and colleagues, 2019). Retrospective data carry selection bias and do not replace the randomized comparison.

The cost

A Dutch cost-effectiveness model in high-risk stage II concluded that three months of CAPOX should be considered standard, because they resulted in the same number of deaths, more quality-adjusted life years and lower cost (Jongeneel and colleagues, 2020). For FOLFOX, three months resulted in more colon cancer deaths in the model, 393 versus 316 per thousand patients (Jongeneel and colleagues, 2020).

How to define risk in stage III

IDEA divided stage III into two simple groups: lower risk, pT1 to pT3 with N1, and high risk, pT4 or N2 (Grothey and colleagues, 2018). This division is the basis for the decision on duration, but other findings in the pathology report also carry information.

Lymphovascular and perineural invasion

In a Chinese series of patients with stage III, lymphovascular invasion was present in 35.1 per 100 and was associated with worse 3-year disease-free survival, 76.3 versus 86.5 per 100 (Zhang and colleagues, 2023). Among patients with lymphovascular invasion, those who completed 6 to 8 cycles had 3-year disease-free survival of 80.0 per 100, versus 64.9 per 100 with fewer than 6 cycles (Zhang and colleagues, 2023). These are retrospective data, but they suggest that lymphovascular invasion may weigh on the decision about duration in those who would be in the lower-risk group.

Mismatch repair

Mismatch repair must be known in every colon cancer. In stage III, repair deficiency does not remove the need for oxaliplatin-based chemotherapy, but it is part of the prognostic assessment and guides the investigation of Lynch syndrome. The post on clinical decision-making covers how to choose tests that change management.

For the accountant in the scenario, with pT3N1, no perforation and no other risk findings, the group is the lower risk one. Three months of CAPOX is an option with direct support from the IDEA data (Grothey and colleagues, 2018) (André and colleagues, 2020).

How to conduct treatment

Conducting adjuvant chemotherapy in stage III follows some practical steps:

• Start chemotherapy, preferably, in the first weeks after surgical recovery.
• Assess renal function and the ability to manage the oral tablet.
• Explain acute cold neurotoxicity and advise avoiding cold drinks and objects on infusion days.
• Ask about neuropathy at each cycle, with questions about concrete functions.
• Reduce or suspend oxaliplatin if neuropathy interferes with function.
• Give guidance on diarrhea, hand-foot syndrome and fever, with a contact channel between visits.

Follow-up

After chemotherapy ends, follow-up includes visits, CEA, CT and colonoscopy at defined intervals. Neuropathy should continue to be asked about in follow-up, because it can persist for years (Kidwell and colleagues, 2012) (Yoshino and colleagues, 2019). The post on diagnostic uncertainty helps with conversations about small benefits and risks that last.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code. Adjuvant treatment in stage III is a good exercise because the decisive clue may be in the pathology report, such as N2 or pT4, and in the history, such as the hobby that depends on the hands. The post on differential diagnosis with clues shows how to train with progressive clues.

Three exercises with cases

Change the report. Say what changes if the tumor is pT4 with 5 involved lymph nodes.

Change the kidney. Say how to adjust the choice if creatinine clearance is 40 milliliters per minute.

Change the neuropathy. Say what to do if, in the third cycle of CAPOX, the patient reports dropping objects from her hands.

The limits on using the game are on the NEXO Economy page. If you research the teaching of clinical reasoning, the page for Researcher explains how to get in touch.

Frequently asked questions

Is three months of CAPOX enough in low-risk stage III?

For pT1 to pT3 with N1, IDEA showed similar 3-year disease-free survival with three and six months, and the final analysis supported three months of CAPOX (Grothey et al., 2018) (André et al., 2020).

And in high-risk stage III?

With pT4 or N2, six months had a small advantage in disease-free survival in the combined analysis (Grothey et al., 2018). With CAPOX, the difference in overall survival was about 1 point, not significant (André et al., 2020).

Does oxaliplatin neuropathy go away?

In many patients it improves, but it can persist for years. In ACHIEVE, it persisted 3 years later in 9.7 out of every 100 with three months and in 24.3 out of every 100 with six months (Yoshino et al., 2019).

What is the oxaliplatin dose in CAPOX?

130 mg per square meter on the first day of each 3-week cycle, with capecitabine 1,000 mg per square meter twice a day on days 1 to 14, as in SCOT (Iveson et al., 2018). Check the package insert and your service's protocol.

Can I stop oxaliplatin and keep the fluoropyrimidine?

Yes. The IDEA protocols provided for this switch when the adverse effects of oxaliplatin made continuation difficult (Kotaka et al., 2018).

Final checklist

• I classified stage III as lower or high risk by pT and pN.
• I reviewed lymphovascular invasion, perineural invasion and mismatch repair.
• I discussed CAPOX and FOLFOX with the patient's preferences.
• I defined the duration based on risk and regimen.
• I assessed kidney function before capecitabine.
• I explained acute and chronic neurotoxicity.
• I agreed to ask about neuropathy at each cycle.
• I planned follow-up after treatment.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. André T, Iveson T, Labianca R, et al. The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: Prospective Combined Analysis of Phase III Trials Investigating Duration of Adjuvant Therapy with the FOLFOX (FOLFOX4 or Modified FOLFOX6) or XELOX (3 versus 6 months) Regimen for Patients with Stage III Colon Cancer: Trial Design and Current Status. Curr Colorectal Cancer Rep. 2013. PMID 24032000.
2. André T, Meyerhardt J, Iveson T, et al. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020. PMID 33271092.
3. Auclin E, André T, Taieb J, et al. Association of post-operative CEA with survival and oxaliplatin benefit in patients with stage II colon cancer: a post hoc analysis of the MOSAIC trial. Br J Cancer. 2019. PMID 31296923.
4. Degirmencioglu S, Tanrıverdi O, Demiray AG, et al. Retrospective comparison of efficacy and safety of CAPOX and FOLFOX regimens as adjuvant treatment in patients with stage III colon cancer. J Int Med Res. 2019. PMID 31099282.
5. Grothey A, Sobrero AF, Shields AF, et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med. 2018. PMID 29590544.
6. Iveson TJ, Kerr RS, Saunders MP, et al. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018. PMID 29611518.
7. Jongeneel G, Greuter MJE, van Erning FN, et al. Model-based evaluation of the cost effectiveness of 3 <i>versus</i> 6 months' adjuvant chemotherapy in high-risk stage II colon cancer patients. Ther Adv Gastroenterol. 2020. PMID 32994804.
8. Kidwell KM, Yothers G, Ganz PA, et al. Long-term neurotoxicity effects of oxaliplatin added to fluorouracil and leucovorin as adjuvant therapy for colon cancer: results from National Surgical Adjuvant Breast and Bowel Project trials C-07 and LTS-01. Cancer. 2012. PMID 22569841.
9. Kotaka M, Yamanaka T, Yoshino T, et al. Safety data from the phase III Japanese ACHIEVE trial: part of an international, prospective, planned pooled analysis of six phase III trials comparing 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer. ESMO Open. 2018. PMID 29713499.
10. Yoshino T, Yamanaka T, Oki E, et al. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019. PMID 31513248.
11. Zhang L, Deng Y, Liu S, et al. Lymphovascular invasion represents a superior prognostic and predictive pathological factor of the duration of adjuvant chemotherapy for stage III colon cancer patients. BMC Cancer. 2023. PMID 36593480.