Advanced rectal cancer: total neoadjuvant therapy

A 52-year-old bus driver sought care for bleeding when passing stool. Colonoscopy showed an adenocarcinoma 5 centimeters from the anal verge. Pelvic MRI classified the tumor as cT3, with extramural venous invasion and 4 suspicious lymph nodes in the mesorectum, and CT showed no metastases. Mismatch repair is preserved. At the consultation, he wants to know whether he will need a colostomy bag and whether it is true that some patients do not need surgery. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The question comes from Dr. Alexei's list for the oncology series: what changes when all chemotherapy is given before surgery in locally advanced rectal cancer, and when is organ preservation an option? The reference trials are RAPIDO, PRODIGE 23 and OPRA. 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: the treatment sequence changes what can be offered afterward.

Key points

• Total neoadjuvant therapy places systemic chemotherapy and radiotherapy before surgery.
• RAPIDO, with short-course radiotherapy followed by chemotherapy, reduced disease-related failure and distant metastases at 3 years.
• PRODIGE 23, with FOLFIRINOX before chemoradiotherapy, improved disease-free survival at 3 years.
• Both trials roughly doubled the pathological complete response rate.
• In the RAPIDO follow-up, locoregional recurrence was higher in the experimental group.
• OPRA showed rectal preservation in about half of the patients, with more preservation when chemotherapy comes after chemoradiotherapy.

Why this is a reasoning scenario

For years, the standard treatment for locally advanced rectal cancer was chemoradiotherapy with a fluoropyrimidine, total mesorectal excision and adjuvant chemotherapy. This sequence controls disease in the pelvis well, but chemotherapy after surgery is often delayed, reduced or abandoned, and distant metastases remain the main cause of death. Total neoadjuvant therapy emerged to give chemotherapy when the patient is in better condition to receive it.

The driver in the scenario has a high-risk tumor on MRI, with extramural venous invasion and several suspicious lymph nodes. He also has a concrete concern about a colostomy, which could affect his work. The two things are connected: a treatment that produces more complete responses opens the possibility of preserving the rectum, but that possibility brings its own rules.

The post on why the multidisciplinary team differs in the colon and the rectum shows that the radiologist and the radiation oncologist play a central role in the rectum. Here the focus is on the sequence and what it allows.

The mistake the scenario wants to avoid

The most common mistake is treating total neoadjuvant therapy as a single protocol, when the trials used different regimens, sequences and populations. Another mistake is promising the patient that he will not need surgery before knowing the response. A third mistake is indicating the watch and wait strategy without a rigorous follow-up program.

What total neoadjuvant therapy is

Total neoadjuvant therapy is the name given to strategies that place all or nearly all systemic chemotherapy before surgery, together with radiotherapy. A 2023 guide for surgeons summarizes that it promises better control of systemic disease, better treatment adherence and less time with a stoma (Johnson et al., 2023). The same guide notes that the name covers different options in the order of chemotherapy, the drugs and the radiotherapy fractionation (Johnson et al., 2023).

The main variations

The strategies tested in the trials fall into a few variations:

• Short-course radiotherapy, 5 fractions of 5 Gy, followed by consolidation chemotherapy, as in RAPIDO.
• Induction chemotherapy followed by long-course chemoradiotherapy, as in PRODIGE 23.
• Long-course chemoradiotherapy followed by consolidation chemotherapy, as in one of the OPRA groups.
• Induction chemotherapy followed by chemoradiotherapy, as in the other OPRA group.

Each variation has advantages. The short course is faster and cheaper. Induction treats systemic disease early. Consolidation gives more time between radiotherapy and response assessment, which favors complete responses.

RAPIDO: short course and chemotherapy

RAPIDO included only high-risk patients, with at least one of these findings: T4, extramural venous invasion, N2, mesorectal fascia involvement or enlarged lateral lymph nodes (Johnson et al., 2023). The experimental group received radiotherapy of 5 by 5 Gy over 8 days, followed by 6 cycles of CAPOX or 9 of FOLFOX before surgery (Johnson et al., 2023). In the protocol, CAPOX used capecitabine 1,000 mg per square meter twice a day on days 1 to 14 and oxaliplatin 130 mg per square meter every 3 weeks, starting 11 to 18 days after radiotherapy (Nilsson et al., 2013).

What the study showed

At 3 years, total neoadjuvant therapy reduced disease-related failure, with a hazard ratio of 0.75, and distant metastases, with a hazard ratio of 0.69 (Johnson et al., 2023). Pathological complete response was 28.4 in 100 with the experimental strategy and 14.3 in 100 with standard treatment (Johnson et al., 2023). Chemotherapy was completed by 85 in 100 patients in the experimental group and 67 in 100 in the standard group (Johnson et al., 2023).

The local recurrence warning

At a median follow-up of 5.6 years, locoregional recurrence was detected in 10 in 100 operated patients in the experimental group, 44 of 431, and in 6 in 100 in the standard group, 26 of 428 (Dijkstra et al., 2023). Among the recurrences, a mesorectum torn during surgery was more frequent in the experimental group (Dijkstra et al., 2023). The authors concluded that the reduction in distant metastases held, but that the strategy needs to be refined (Dijkstra et al., 2023).

This finding shows that total neoadjuvant therapy is not only a gain. Replacing long-course chemoradiotherapy with the short course followed by chemotherapy may have a cost in local control for some patients.

PRODIGE 23: FOLFIRINOX before chemoradiotherapy

PRODIGE 23 started with 6 cycles of FOLFIRINOX, a combination of leucovorin, 5-fluorouracil, irinotecan and oxaliplatin, followed by long-course chemoradiotherapy with 50 Gy over 5 weeks (Johnson et al., 2023). The population included patients with T3 or T4, broader than in RAPIDO, and the primary outcome was disease-free survival (Johnson et al., 2023).

What the study showed

Disease-free survival at 3 years was higher with total neoadjuvant therapy, with a hazard ratio of 0.69 (Johnson et al., 2023). Pathological complete response was 27.8 in 100 with FOLFIRINOX before chemoradiotherapy and 12.1 in 100 with standard treatment (Johnson et al., 2023). Chemotherapy was completed by 81 in 100 patients in the experimental group (Johnson et al., 2023).

Study	Experimental sequence	Pathological complete response	Main finding
RAPIDO	5 by 5 Gy, then CAPOX or FOLFOX, then surgery	28.4 versus 14.3 in 100	Less disease-related failure and fewer metastases, with more local recurrence in long-term follow-up
PRODIGE 23	FOLFIRINOX, then chemoradiotherapy, then surgery	27.8 versus 12.1 in 100	Better disease-free survival at 3 years
OPRA	Chemotherapy and chemoradiotherapy in randomized order, then surgery or observation	Not applicable, due to observation	Rectum preservation in about half

Source of the table numbers: Johnson et al., 2023, and Verheij et al., 2024 (Johnson et al., 2023) (Verheij et al., 2024).

Why comparing the two is difficult

The 2023 guide notes that the order of chemotherapy, the drugs, the fractionation and the radiotherapy doses differed between the two studies, and that the primary outcomes were also different (Johnson et al., 2023). RAPIDO used disease-related failure, which includes locoregional recurrence, distant metastasis, a new primary tumor or treatment-related death (Johnson et al., 2023). A direct comparison between the two is therefore not possible, and the choice depends on the patient and on the service.

How to choose the sequence

With no direct comparison between RAPIDO and PRODIGE 23, the choice of sequence weighs the characteristics of the tumor, the patient and the service. A few points help organize the discussion:

• An involved mesorectal fascia or enlarged lateral lymph nodes calls for special attention to local control.
• Extramural venous invasion and N2 indicate high systemic risk and favor giving chemotherapy early.
• A wish to preserve the rectum favors sequences with consolidation, which produced more complete responses.
• Age, comorbidities and kidney function weigh on the choice between FOLFIRINOX, FOLFOX and CAPOX.
• Distance from home to the service and access to transport weigh on the long course, with 5 weeks of daily radiotherapy.

The 2024 network meta-analysis notes that the choice involves trade-offs: the short course with consolidation increased the response and disease-free survival, but also locoregional recurrence at 5 years (Turri et al., 2024). Long follow-up of RAPIDO confirmed this signal, with locoregional recurrences associated with enlarged lateral lymph nodes, an involved circumferential margin, tumor deposits and positive lymph nodes in the specimen (Dijkstra et al., 2023). For the driver in the scenario, with extramural venous invasion and 4 suspicious lymph nodes, the discussion should include the systemic risk and the preference to avoid a colostomy, and the team should explain why it chose one sequence and not another.

It is also worth recalling what changes in routine practice. Total neoadjuvant therapy postpones surgery by several months, and the patient needs to understand that this interval is part of the plan and is not a delay. During this period, the visits serve to monitor toxicity, adjust doses and keep the patient motivated to complete the treatment.

What the meta-analyses show

A 2020 meta-analysis of 7 studies and 2,416 patients found a higher pathologic complete response rate and longer disease-free survival with total neoadjuvant therapy, with no difference in sphincter-preserving surgery or in the need for an ileostomy (Kasi et al., 2020). Another 2020 meta-analysis concluded that the strategy improves disease-free survival and 3-year overall survival, without a major increase in serious adverse events (Riesco-Martinez et al., 2020).

The 2024 network meta-analysis

A network meta-analysis of 27 randomized studies and 13,413 patients compared the variations (Turri et al., 2024). For pathologic complete response, long-course chemoradiotherapy followed by consolidation had a relative risk of 1.96, the short course followed by consolidation, 1.76, and induction followed by chemoradiotherapy, 1.57, all compared with standard chemoradiotherapy (Turri et al., 2024). For 3-year disease-free survival, the short course with consolidation and induction with chemoradiotherapy were superior, but the short course with consolidation had more locoregional recurrence at 5 years, with a relative risk of 1.65 (Turri et al., 2024).

The meta-analyses confirm the pattern of the individual studies: more complete responses, better systemic control and a signal of worse local control with the short course followed by consolidation.

OPRA and rectum preservation

OPRA randomized 324 patients with stage II or III rectal cancer to induction chemotherapy followed by chemoradiotherapy or to chemoradiotherapy followed by consolidation chemotherapy (Garcia-Aguilar et al., 2022). Both groups received 4 months of FOLFOX or CAPOX and 50 to 56 Gy of radiotherapy with a fluoropyrimidine (Garcia-Aguilar et al., 2022). Those with a complete or near-complete response were offered watch and wait, and those with an incomplete response were referred for total mesorectal excision (Verheij et al., 2024).

What the study showed

At 3 years, disease-free survival was 76 out of 100 in both groups, similar to the historical figure of 75 out of 100 (Garcia-Aguilar et al., 2022). Mesorectal excision-free survival at 3 years was 41 out of 100 with induction and 53 out of 100 with consolidation (Garcia-Aguilar et al., 2022). In the 5-year update, disease-free survival was 71 and 69 out of 100, and mesorectal excision-free survival was 39 and 54 out of 100, in favor of consolidation (Verheij et al., 2024).

When the tumor grows back

Among the 81 patients with tumor regrowth in OPRA, 94 out of 100 regrew in the first 2 years and 99 out of 100 in the first 3 years (Verheij et al., 2024). Disease-free survival was 64 out of 100 both in those who had surgery right after reassessment and in those who had surgery after regrowth (Verheij et al., 2024). A secondary analysis showed that the probability of preserving the rectum at 3 years was 77 out of 100 with a complete clinical response and 40 out of 100 with a near-complete response (Thompson et al., 2024).

For the driver in the scenario, these numbers show that rectum preservation is possible, but not guaranteed. The conversation should explain that the final decision depends on the response, assessed by examination, endoscopy and MRI.

Watching and waiting safely

The watch-and-wait strategy requires a follow-up program with digital examination, endoscopy and MRI at short intervals, especially in the first 2 years. It is not a way to avoid treatment, but to delay or skip surgery in those who had a complete response.

What the cohort data show

In a matched Chinese cohort, patients under observation had more local recurrence, 14.9 versus 1.1 out of 100, but 85.7 out of 100 of these recurrences were salvaged (Wang et al., 2021). Sphincter preservation was much higher with observation in tumors up to 3 centimeters from the anal verge, 89.7 versus 41.2 out of 100 (Wang et al., 2021). In the international watch-and-wait registry, with 1,010 patients, organ preservation at 2 years was similar between those with a complete response at the first reassessment, 77.8 out of 100, and those with a complete response later, 79.3 out of 100 (Temmink et al., 2023).

Patient preferences

A review of the lessons from OPRA cites a study in which 83 out of 100 patients would choose watch and wait if they had a complete response, even with more local regrowth (Goffredo et al., 2022). The same review notes that the strategy should also be discussed with younger patients, and not only with older ones (Goffredo et al., 2022).

Practical criteria for considering watch and wait include:

• Complete clinical response on digital examination and endoscopy.
• MRI with no residual tumor and no suspicious lymph nodes.
• A patient willing to undergo frequent tests in the first years.
• A service with radiology, endoscopy and surgery teams experienced in follow-up.
• Agreement that surgery will be performed if there is regrowth.

The post about diagnostic uncertainty helps with conversations about decisions in which the outcome depends on the response.

And repair deficiency

A small share of rectal tumors has mismatch repair deficiency. In this group, immunotherapy changed the conversation, as the post about dostarlimab in rectal cancer with repair deficiency shows. The driver in the scenario has preserved repair, and total neoadjuvant therapy remains the foundation.

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 finding the ICD-10 code. Rectal cancer is a good exercise because the decisive clue is in the MRI, such as extramural venous invasion, and in what the patient wants, such as avoiding a colostomy. The post on differential diagnosis with clues shows how to train with progressive clues.

Three exercises with cases

Change the MRI. Say what changes if the tumor involves the mesorectal fascia.

Change the response. Say what to do if, after consolidation, endoscopy shows a flat scar and the MRI shows a small residual signal.

Change the repair. Say what changes if the biopsy shows mismatch repair deficiency.

The post on clinical decision making covers tests that change management. The limits on using the game are on the NEXO Economy page. If you research the teaching of clinical reasoning, the page for Researchers explains how to get in touch.

Frequently asked questions

Does total neoadjuvant therapy improve survival?

The studies showed better systemic control and better disease-free survival, and a meta-analysis found a gain in 3-year overall survival (Johnson et al., 2023) (Riesco-Martinez et al., 2020).

Is the short course of radiotherapy safe for local control?

In the long-term follow-up of RAPIDO, locoregional recurrence was higher in the experimental group, 10 versus 6 per 100 (Dijkstra et al., 2023).

How many patients preserve the rectum in OPRA?

About half of the randomized patients, with 5-year mesorectal excision-free survival of 54 per 100 in the consolidation group (Verheij et al., 2024).

Does surgery after regrowth worsen the outcome?

In OPRA, disease-free survival was similar in those who had surgery after reassessment and in those who had surgery after regrowth (Verheij et al., 2024).

What is the CAPOX dose in RAPIDO?

Capecitabine 1,000 mg per square meter twice a day on days 1 to 14 and oxaliplatin 130 mg per square meter every 3 weeks, for 6 cycles (Nilsson et al., 2013). Check your service's protocol and the package insert before prescribing, and adjust capecitabine for renal function.

Final checklist

• I reviewed the MRI: T, extramural venous invasion, mesorectal fascia and lymph nodes.
• I confirmed the absence of metastases and the mismatch repair status.
• I discussed the variations of total neoadjuvant therapy with the team.
• I explained to the patient the chance of a complete response without promising to preserve the rectum.
• I planned the reassessment with digital examination, endoscopy and MRI.
• I defined the follow-up program if the option is watch and wait.
• I recorded the patient's preferences about surgery and stoma.

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

References

1. Dijkstra EA, Nilsson PJ, Nilsson PJ, et al. Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery: A 5-Year Follow-up of the RAPIDO Trial. Ann Surg. 2023. PMID 36661037.
2. Garcia-Aguilar J, Patil S, Gollub MJ, et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J Clin Oncol. 2022. PMID 35483010.
3. Goffredo P, Quezada-Diaz FF, Garcia-Aguilar J, et al. Non-Operative Management of Patients with Rectal Cancer: Lessons Learnt from the OPRA Trial. Cancers (Basel). 2022. PMID 35804975.
4. Johnson GGRJ, Park J, Helewa RM, et al. Total neoadjuvant therapy for rectal cancer: a guide for surgeons. Can J Surg. 2023. PMID 37085291.
5. Kasi A, Abbasi S, Handa S, et al. Total Neoadjuvant Therapy vs Standard Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020. PMID 33326026.
6. Nilsson PJ, van Etten B, Hospers GA, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer--the RAPIDO trial. BMC Cancer. 2013. PMID 23742033.
7. Riesco-Martinez MC, Fernandez-Martos C, Gravalos-Castro C, et al. Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials. Cancers (Basel). 2020. PMID 33291454.
8. Temmink SJD, Peeters KCMJ, Bahadoer RR, et al. Watch and wait after neoadjuvant treatment in rectal cancer: comparison of outcomes in patients with and without a complete response at first reassessment in the International Watch & Wait Database (IWWD). Br J Surg. 2023. PMID 36972213.
9. Thompson HM, Omer DM, Lin S, et al. Organ Preservation and Survival by Clinical Response Grade in Patients With Rectal Cancer Treated With Total Neoadjuvant Therapy: A Secondary Analysis of the OPRA Randomized Clinical Trial. JAMA Netw Open. 2024. PMID 38194231.
10. Turri G, Ostuzzi G, Vita G, et al. Treatment of Locally Advanced Rectal Cancer in the Era of Total Neoadjuvant Therapy: A Systematic Review and Network Meta-Analysis. JAMA Netw Open. 2024. PMID 38833249.
11. Verheij FS, Omer DM, Williams H, et al. Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial. J Clin Oncol. 2024. PMID 37883738.
12. Wang QX, Zhang R, Xiao WW, et al. The watch-and-wait strategy versus surgical resection for rectal cancer patients with a clinical complete response after neoadjuvant chemoradiotherapy. Radiat Oncol. 2021. PMID 33468176.