Im sich stetig weiterentwickelnden Fortschritt haben sich die letzten Jahre als ein entscheidendes Kapitel im Bereich der Rektumkarzinombehandlung erwiesen. Dieses Update soll die bahnbrechenden Entwicklungen und transformativen Ansätze beleuchten, die in jüngster Zeit die Landschaft der lokalisierten Rektumkarzinom-Therapie neugestaltet haben und erkundet ihre Auswirkungen auf den Horizont der täglichen klinischen Routine.

In the ever-evolving landscape of advancements, the last few years have emerged as a pivotal chapter in the realm of rectal cancer treatment. This update aims to shed light on the groundbreaking developments and transformative approaches that recently have reshaped the landscape of localized rectal cancer therapy, offering new and exploring their implications on the horizon of daily clinical routine.
Key Words: rectal cancer treatment, rectal cancer therapy, daily clinical routine

Total neoadjuvant treatment: updated results from RAPIDO, PRDIGE-23 and OPRA trial

In recent decades, there has been a notable shift in the approach to enhance patient survival in the treatment of locally advanced rectal cancer, and the proposal to administer chemotherapy prior to surgery, aimed at addressing occult micro metastasis at an early stage and improving treatment compliance, has gained traction. Multiple trials examining diverse strategies for integrating both chemotherapy and chemoradiotherapy (CRT) in the neoadjuvant setting, collectively referred to as “total neoadjuvant therapy (TNT),” have yielded encouraging results. However, it is worth highlighting that three specific trials have emerged as game changers in reshaping the landscape of locally advanced rectal cancer treatment: RAPIDO; PRODIGE and OPRA (1, 2, 3). These trials explore the sequential administration of oxaliplatin-based chemotherapy and chemo-radiotherapy before surgery, marking a significant advancement in the field.

RAPIDO trial randomized 920 patients with rectal adenocarcinoma, less than 16 cm from the anal verge at endoscopy and with high-risk features (cT4a/b, cN2, enlarged lateral lymph nodes, extramural vascular invasion or involved mesorectal fascia). The results demonstrated that preoperative short-course radiotherapy followed by systemic chemotherapy resulted in a decreased disease-related treatment failure rate and distant metastasis, compared with standard CRT, at 3 years of follow-up. No benefit in OS was seen at the primary analysis, neither at the updated results with a longer follow-up (4). Nonetheless, a significantly higher incidence of local relapse was detected in the experimental arm at the 5 years follow-up (10% versus 6% p=0.027). Rationally explaining this finding proves to be challenging, but the possibility has been raised that it might be attributed to the disparity in the intensity of the locoregional treatment administered in both arms of the study (5). In the standard arm, the protocol involved standard-dose CRT, followed by surgery performed within the conventional timeframe. Conversely, the experimental arm utilized a short-course radiotherapy but introduced a delay of 40 weeks before surgery. The short-course radiotherapy delivered a biological dose equivalent ranging from 31.3 to 35.7 Gy. This was notably lower than the standard arm’s dosage. While this reduced biological dose equivalent might not pose an issue in the immediate preoperative phase, where complete surgery is feasible, it likely accounts for the inferior locoregional control results observed in this trial, given the staggered nature of the surgeries. Glynne-Jones et al have also proposed additional factors contributing to increased local recurrence rates, such as potential treatment-induced tumor fragmentation and the operational challenges associated with delayed surgery (6).

The second game changer trial exploring a TNT strategy, PRODIGE-23, involving 461 patients, featured two arms: the standard-of-care arm comprised CRT, TME (total mesorectal excision) surgery seven weeks later, and adjuvant mFOLFOX6 for 1q 2 cycles or capecitabine for eight cycles, whilst the experimental arm involved induction chemo with mFOLFIRINOX, excluding bolus 5FU, for six cycles, followed by CRT and TME seven weeks later. Subsequently, patients received six cycles of mFOLFOX6 or four cycles of capecitabine.

Eligible participants were under 76 years old, diagnosed with MRI stage T3 or T4 rectal cancer with or without nodal involvement. The primary endpoint was disease-free survival (DFS), and, at the primary analysis, the superiority of the experimental arm was deomosntrated, but, also in this case, no benefit in OS was shown (2).

The seven-year results from the trial have been presented at ASCO 2023 and demonstrated a statistically significant improvement in OS with the TNT approach (81.9% versus 76.1%, p=0.033) (7).

In conclusion, induction chemo with mFOLFIRINOX before chemo-RT enhances overall survival (OS) in locally advanced rectal cancer. The durability of DFS and metastases-free survival is noteworthy, and the quality of life remains comparable or improved with this approach. This presents an additional viable option for patients grappling with locally advanced rectal cancer.

In the Phase 2 OPRA trial, patients with stage II/III rectal cancer underwent randomization into two arms: the induction chemotherapy arm, receiving chemotherapy first followed by CRT, and the consolidation arm, undergoing CRT first followed by chemotherapy. Following this phase, all patients underwent restaging, and those achieving a complete or near-complete response (indicating significant tumor reduction with treatment) were given the option of watchful waiting or non-operative management. Under non-operative management, patients could defer surgery until local regrowth occurred. If an incomplete response was observed, surgery was offered at that time to remove the rectum along with the tumor (3). The trial was not planned to do a formal comparison between the two arms, and the primary endpoint was 3-year DFS in comparison to the historical data, versus an investigational 85%. Formally, this is a negative trial, not reaching the primary endpoint of superiority, resulting in a 3-years DFS of 76%. However, the consolidation chemo arm demonstrated a significantly higher rate of organ preservation, and these results have driven us to consider that an organ preservation strategy for those patients achieving complete remission is not disadvantageous in terms of oncological outcomes.

Recently, the updated results at a longer follow-up have beeen published (8). At the median follow-up of 5.1 years, 75% of trial participants were offered non-operative management, with similar rates in both arms. Local regrowth occurred in 36% of patients, with 44% in the induction arm and 29% in the consolidation arm. The 5-year organ preservation rates were 54% in the consolidation arm and 39% in the induction arm. In cases of local regrowth, TME was performed. Notably, there was no disparity in five-year DFS between TME at restaging (surgery upfront) and TME at regrowth (salvage surgery later), both standing at 64%. This indicates that delaying surgery until local regrowth did not impact the likelihood of being disease-free at five years. Therefore, for individuals opting for non-operative management, subsequent surgery after local regrowth did not compromise their five-year disease-free outcomes when compared to those who underwent upfront surgery.

Commentary: in my clinical practice, I usually contemplate a TNT strategy when dealing with patients diagnosed with locally advanced rectal carcinoma at high risk (cT4, cN2, enlarged lateral lymph nodes, extramural vascular invasion or involved mesorectal fascia), preferably if they are under the age of 70 or are otherwise able to tolerate a combination chemotherapy regimen, keeping in mind that the average age of patients included in these studies was approximately 60 years. Another scenario in which I consider TNT is when patients present with locally advanced stage tumors, but the treatment goal is organ preservation (for instance, in the case of patients not suitable or who refuse surgery). This approach allows us to achieve a 30% rate of complete response, making it a valuable consideration in such cases.

Regarding the regimen, my preference leans towards the consolidation arm of OPRA trial. I do not regard PRODIGE-23 as standard, as FOLFIRINOX is an intensive regimen for a selected population, not applicable to the average patient with rectal carcinoma. However, it can be an excellent strategy in the case of younger patients with a significant burden of symptomatic disease for achieving rapid cytoreduction, or for those with aggressive histotypes less responsive to treatments (e.g. mucinous histology).

Personally, I am not familiar with the RAPIDO regimen because I have never chosen it for my patients in neoadjuvant setting, as the higher local recurrence rate raises concerns in a curative context, especially with other available options. In patients with “ugly” rectal cancer, short-course radiation may be a problem in terms of local recurrence. Some selected cases can be represented by people who travel long-distance and convenience is an issue, short-course radiation per RAPIDO may be best, but I might be a little bit more comfortable with using RAPIDO in slightly lower-risk patients. Of course, this short-course radiotherapy followed by chemotherapy remains a highly valid option in case of distant metastasis, if the goal is also the local control.

Early efficacy of dostarlimab in mismatch repair – deficient locally advanced rectal cancer

Another of the most noteworthy recent developments in the field of rectal cancer revolves around a single arm phase 2 trial (NCT04165772) investigating the efficacy of single-agent dostarlimab in a limited cohort of individuals with stage II/III dMMR locally advanced rectal cancer.
Data presented at the 2022 ASCO Annual Meeting and detailed in the New England Journal of Medicine (9) revealed that among the 12 patients who completed 6 months of dostarlimab treatment, the complete response rate stood at 100%, with subsequent imaging indicating no signs of tumor. As of the data cutoff point, none of the patients had undergone chemoradiotherapy or surgery, and there were no signs of progression or recurrence during the follow-up period. Moreover, there were no reports of adverse effects of grade 3 or higher.

While dMMR accounts for only 5% to 10% of rectal tumors, this subgroup has historically shown poor responses to chemotherapy, including neoadjuvant chemotherapy for locally advanced rectal cancer. Given the promising outcomes observed with dostarlimab and the absence of a necessity for surgery in this small subset of patients, these findings represent a positive development in the realm of rectal cancer research.
Commentary: in my clinical practice, I routinely test the microsatellite status, and I would consider an immune checkpoint inhibitor in the case of a patient with MSI-H locally advanced rectal carcinoma. However, I have not yet encountered this scenario, but, certainly, immunotherapy would be a topic for discussion in the multidisciplinary team, as an alternative to chemo and RT, and such patients must be discussed in a specialized center with an interdisciplinary tumor board.

Radiation may be safely omitted in selected patients with locally advanced rectal cancer

During the Plenary Session of ASCO 2023, the final results from the randomized phase 3 PROSPECT trial were presented, comparing neoadjuvant FOLFOX to chemoradiotherapy in patients with locally advanced mid- or high-rectal cancer, clinically staged as T2N1 or T3N0–1, and deemed suitable for sphincter-sparing surgery. Of note, immediately after the presentation, these data were published in the New England Journal of Medicine, highlighting the impact of this research (10).

PROSPECT was a large international trial, looking at over 1,100 patients from US and Canada, and Switzerland was also participating in this trial over SAKK. This study aimed to try to answer the question “can we get away with not giving radiation in certain types of rectal cancer?”
This trial was initiated in 2012, when locally advanced rectal cancer was treated using the “classical” approach of CRT, then surgery. The enrolled patients had intermediate risk, high or mid rectal tumors, which were cT1-T3 and node positive or negative, and were eligible for radiation treatment and sphincter-sparing surgery. The aim was to de-escalate treatment and skip radiation without compromising outcomes. Patients were assigned either standard preoperative CRT and surgery, or induction chemotherapy with six cycles of FOLFOX followed by tumor response assessment. Patients with a 20% or greater tumor reduction proceeded to surgery without radiotherapy, while those with nonresponsive tumors underwent CRT, followed by surgery.

Out of 1128 patients, with a median age of 57 and predominantly male, 91% had T3N0–1 cancers, 53% had T3N1 cancers, and 64% had cancers 5 to 10 cm from the anal verge. The primary endpoint of noninferior DFS at 5 years was achieved for induction FOLFOX compared with chemoradiotherapy (80.8% and 78.6%; hazard ratio, 0.92; P=0.005). Both FOLFOX and chemoradiotherapy groups exhibited comparable OS (89.5% and 90.2%; HR, 1.04) and rates of local recurrence (1.6% and 1.8%; HR, 1.18). Notably, only 9.1% of patients in the FOLFOX arm necessitated CRT, with an additional 1.4% receiving It postoperatively. Pathologic complete response rates to FOLFOX and chemoradiotherapy were also comparable (21.9% and 24.3%). Interestingly, in this trial, side effects were captured by both clinicians and patients, and toxicity and Quality of life represented the secondary endpoints of the study. The extent of side effects captured by clinicians and patients both showed side effects in each arm to vary before and after surgery, as expected according to the different toxicity profile of FOLFOX in comparison to capecitabine in association to radiotherapy. What has truly made an impact and garnered significant attention are the Quality-of-life data at 12 months post-treatment, demonstrating a significantly better bowel and sexual function in the FOLFOX group.

These results have been streghten by other two trials: FOWARC (11) and CONVERT (12), which found no significant difference in survival omitting radiotherapy in patients with intermediate-risk rectal cancer.

Nonetheless, when considering the treatment path for a specific subgroup of patients, the exclusion of radiotherapy necessitates an amplification of the chemotherapy aspect. However, this heightened chemotherapy approach introduces its own challenges, notably arising from oxaliplatin and its associated adverse effects. The outcomes of the PROSPECT trial are substantiated by patient-reported data, revealing a heightened incidence of oxaliplatin-related adverse events – such as neuropathy, nausea, and vomiting – in the group abstaining from chemoradiotherapy compared to the control group (13).

Commentary: These results suggest that patients with clinical stage T2N1 or T3N0–1 mid- or high-rectal cancers can forego radiation therapy when provided with induction therapy using FOLFOX before surgery. This has transformative implications for clinical practice and expands on the idea of personalized treatment strategies for locally advanced rectal cancer employing chemo, chemo-RT, and surgery as needed to get to the outcomes that are desired and clinically appropriate for each patient. In case of an elderly patient with comorbidities and a locally advanced mid-rectal tumor, without high risk features, we might opt for radiotherapy with capecitabine to avoid toxicities associated with combination chemotherapy (neutropenia, peripheral neuropathy). For the same tumor but in a 50-year-old patient prioritizing the preservation of bowel and sexual function, we may choose a radiation-free option. With the increase in young-onset colorectal cancer, having women of childbearing age who have a relatively favorable tumor, then PROSPECT is the perfect treatment to avoid radiation and have a chance of maintaining fertility.
We need to remember that the study was initiated in 2012, and, in the meantime, surgical techniques have advanced, sometimes obviating the need for preoperative treatments. Additionally, new treatment paradigms have emerged in the management of locally advanced stage rectal carcinoma: the organ-preserving strategy, the concept of TNT, and immunotherapy in MSI-H tumors. If organ preservation is a priority for a 50-year-old patient as mentioned earlier, a TNT approach should be considered. In a non-operative management strategy, patients may need both chemotherapy and CRT as neoadjuvant treatment to reduce the tumor size, potentially leading to complete disappearance and allowing them to forego surgery.

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