Rectal Cancer: Open Questions in 2022 Current Standards of Clinical Practice and Ongoing Trials

Background: Rectal cancer remains a complex disease and a relevant global health issue, increasingly affecting also younger patients. This update review summarizes the current standard of care and discusses the individualized treatment approaches taking into consideration individual tumor characteristics and patients preferences. Summary: Remaining “gray zones” of rectal cancer therapy warranting further prospective studies are identified including surgical approaches for rectal cancer, e.g., minimally invasive surgical techniques and lateral lymph node dissection for low rectal cancers. The emerging concept of a watch-and-wait strategy upon clinical complete response after chemoradiotherapy is discussed, also considering the still limited evidence and the clinical challenges arising from individualized patient management. Key Messages: Finally, currently conducted clinical trials of the German Rectal Cancer Study Group are described, aiming to further individualize multimodal treatment according to risk profiles and strict MRI criteria.

© 2022 S. Karger AG, Basel

Key Points

The current therapy of rectal cancer patients has diversified toward risk-adapted approaches according to precise pretreatment diagnostics.

Several “grey zones” in rectal cancer management require further investigation such as the role of lateral lymph node dissection.

Watch and wait upon clinical complete response is an increasingly relevant concept which needs further evaluation within clinical trials.

Currently initiated clinical trials of the German Rectal Cancer Study Group investigate the risk-adapted personalized application of treatment modalities.

Molecular markers for treatment stratification are well established for palliative chemotherapy but still needed for response prediction of preoperative therapy.

Introduction: Rectal Cancer Treatment in 2022

Rectal cancer treatment has become a multidisciplinary challenge with divergent and personalized approaches according to individual patients’ characteristics [1]. While treatment outcomes could be improved over the last decades, rectal cancer remains a relevant health issue worldwide and occurs increasingly in younger patients [2]. With a worldwide perspective, the incidence and mortality rates of rectal cancer do not correlate but seem to depend on the availability of centers with high-volume expertise and a multidisciplinary team of clinicians guiding the course of treatment. In experienced centers, superior outcomes can be achieved shifting the focus of interdisciplinary treatment efforts toward quality-of-life and functional outcomes [3].

The development of high-resolution MRI imaging over the past decade has diversified treatment recommendations from using the same schedule of neoadjuvant chemoradiotherapy (nCRT) followed by TME surgery and adjuvant chemotherapy (CT) for all locally advanced tumors (cT3-4 or N+ M0) toward a variety of more individualized options [4, 5]. Based on MRI criteria, the recommended standard of care (Fig. 1) for limited tumors (cT1 without clearly suspicious lymph nodes [LNs]) is a local resection. For cT3a/b (<5 mm infiltration in the perirectal fat tissue) of the middle third without suspicious LNs or extramural vascular invasion, primary high-quality TME surgery can be performed, whereas cT3c/d-cT4 or cT3 tumors in the lower rectum should be treated by nCRT according to current guidelines. Tumors of the upper third of the rectum without risk factors for local recurrence (LR) should be treated by primary surgery, while tumors at risk for LR (cT4, mrCRM+, and cN++) may undergo nCRT [5].

Fig. 1.

Flowchart of the current treatment standard.

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The distance of the tumor to the mesorectal fascia should, according to the current German S3 guidelines, not be taken as criterion for therapy stratification outside clinical trials. The concept of total neoadjuvant treatment (TNT), applying induction or consolidation CT before or after CRT, was tested as an innovative treatment approach for high-risk tumors in the CAO/ARO/AIO-12 trial. The results showed a better pathological complete response rate (25% vs. 17%) and better compliance with CRT in up-front CRT followed by CT and TME. While the long-term outcome results did not show significant differences in oncological endpoints, toxicity, or quality of life, it was concluded that up-front CRT followed by consolidation CT should be the preferred TNT regimen when prioritizing organ preservation [6, 7]. With applying the established therapeutic options in a more tailored approach and TNT as a novel and more and more accepted concept, treatment recommendations have become more complex and should be advised within multidisciplinary teams.

Remaining “Grey Zones” in Treatment of Rectal Cancer Patients

While risk-adapted therapy according to patient characteristics and MRI criteria allows a more individualized treatment, several grey zones in current rectal cancer treatment still exist and need further investigation within prospective clinical trials. The most relevant remaining “grey zones” have been identified by an international expert meeting (2017 Assisi Think Tank Meeting on rectal cancer) [8]. The expert panel identified cT2 tumors as a group of tumors needing further investigation and suggested to evaluate CRT concepts with the intention to achieve organ preservation especially for low-lying tumors otherwise requiring abdominoperineal resection with a permanent colostomy. For cT3 low-risk tumors, the evaluation of nCRT followed by TME surgery versus TME surgery alone was suggested. For cT4 tumors, the international expert meeting proposed the evaluation of TNT concepts.

In respect to the surgical approach, an important open question remains the role of lateral LN dissection in low rectal cancers. While standard of care in Japan, the dissection of lateral LNs in patients with lateral LNs of >7 mm on pretreatment MRI recently showed a significant reduction of LR (5.7% vs. 19.5%; p = 0.42) in a large retrospective multicenter pooled analysis of 1.216 patients but requires further prospective validation [9-11]. Furthermore, the surgical approach reaching favorable oncological outcomes together with best functional results still warrants generation of further clinical evidence. While the ACOSOG Z6051 and the ALaCaRT trial showed no differences for oncological long-term results compared to open TME, robotic surgery was introduced to overcome technical and visual limitations of laparoscopy [12-14]. The randomized controlled ROLARR trial comparing robotic versus laproscopic TME found comparable oncological outcomes but higher costs and longer operative times for the robotic approach [15]. A recent systematic review and meta-analysis of 5,565 patients found a significantly better recovery of anorectal function after robotic TME in comparison to laparoscopic TME (p = 0.006) versus open TME (p = 0.002) [16]. With increasing experience in robotic surgery approaches, surgery times and costs are expected to decrease, and future trials should focus on the potential to further improve functional outcomes.

Watch and Wait for Clinical Complete Response after CRT

For patients treated with nCRT, clinical complete response (cCR) of the disease presents a particularly challenging clinical situation [17]. Since cCR is observed more frequently with intensified CRT protocols, including TNT, there has been an increasing interest in organ preservation and watch-and-wait strategies [18]. While this concept is being evaluated by different expert centers worldwide, robust data on the oncological long-term outcome are still limited. The largest series has been reported within the International Watch & Wait database, comprising data of more than 1,000 patients [19]. Their oncological outcome is reported to be similar to standard therapy including TME surgery; however, up to 25% of initial cCR patients will develop a local regrowth within the first 2 years of follow-up. Since most of these recurrences are endoluminal, many patients can be directed to salvage surgery, and it is speculated that this would not compromise the oncological outcome due to delayed surgical resection [20]. However, long-term data from randomized trials are lacking for this situation. One reason for the development of tumor regrowth after initial cCR may be explained by the response pattern induced by CRT. Histopathologically, response has been described in concepts of shrinkage versus fragmentation, where destruction of the tumor mass occurs with the formation of small groups of remaining tumor cell clusters. These cases might account for local regrowths after cCR and support the hypothesis that the initial tumor infiltration and expansion need to be taken into account for a watch-and-wait concept [21, 22]. Furthermore, the underlying tumor characteristics leading to shrinkage rather than fragmentation should be studied on a molecular level to identify patients suitable for a watch-and-wait concept together with improved imaging technologies such as delta radiomics to identify patients with sustained cCR [23, 24]. Preliminary data on MRI imaging after nCRT suggest that diffusion-weighted imaging can predict cCR with a higher accuracy than morphology-based MR assessment alone; however, further prediction optimization is needed [25].

Current Clinical Trials Generating Evidence for Remaining Open Questions

The German Rectal Cancer Study Group (GRCSG) has initiated the ACO/ARO/AIO-18.1 study (https://acoaroaio-rektumstudie.de/aco-aro-aio-181-rektumstudie), a phase III study for tumors in the lower two-thirds of the rectum with an experimental arm consisting of preoperative oxaliplatin-based radiochemotherapy and subsequent consolidation CT versus 5-fluorouracil-based standard radiochemotherapy alone. With the current standard regimen according to recent guideline recommendations, pathological complete response rates are in the range of 10%, 3-year local failure rates in the range of 5%, distant recurrences occur in 25–30% of patients, and 3-year disease-free survival amounts to 70%. The ACO/ARO/AIO-18.1 randomized trial aims to improve standard treatment by incorporating several novel and innovative aspects, which were previously established within the CAO/ARO/AIO-04 and CAO/ARO/AIO-12 randomized trials [26, 27]. Patients will be enrolled and randomized based on strict MRI features of intermediate and high-risk characteristics. The CRT and CT regimens incorporate 5-FU/oxaliplatin with doses and intensities shown to be effective and well-tolerated without compromising treatment compliance in the CAO/ARO/AIO-04 trial. The sequence and interval of CRT, CT, and surgery adopts the innovative TNT approach which was established in the randomized phase II CAO/ARO/AIO-12 trial. Surgical stratification allows for watch-and-wait management for strictly selected patients following close follow-up visits.

In patients with low risk for local failure in the middle-third of the rectum (cT3a/b, cN0) as determined with quality controlled MRI, the German S3 guidelines and the ESMO clinical practice guidelines state that neoadjuvant radiotherapy may be omitted [5, 28]. However, the distant failure rate is still substantial with a range of 20–25% in these patients, highlighting the need for more effective systemic treatment.

Therefore, the GRCSG has initiated for these low-risk patients the ACO/ARO/AIO-18.2 randomized trial incorporating three novel aspects: (i) patient selection relies on strict and quality controlled MRI features and therefore identifies a cohort without imminent need for radiotherapy; (ii) the sequence of CT and surgery is reversed in a way that CT is administered preoperatively to increase the rate of patients treated with CT, and (iii) 3 months of neoadjuvant FOLFOX or XELOX (instead of up to 6 months adjuvant CT) are applied as a sole perioperative treatment in order to administer effective doses at an early time point in order to increase compliance. Thus, patients with rectal cancer but low risk for local failure (i.e., cT1/2 N+ in all thirds of the rectum, cT3a/b N0 in the middle-third, and cT3-4 Nany in the upper-third) will be included and randomized between 3 months of neoadjuvant FOLFOX/XELOX versus primary resection of the tumor followed by risk (i.e., stage)-adapted adjuvant CT. Currently recruiting phase 3 clinical trials for patients with locally advanced rectal cancer according to the ClinicalTrials.gov (https://clinicaltrials.gov, visited last on December 12, 2021) which will shed light on remaining “grey zones” are summarized in Table 1.

Table 1.

Currently recruiting phase 3 clinical trials for locally advanced rectal cancer

/WebMaterial/ShowPic/1417868Role of Molecular Markers in Rectal Cancer Treatment

Molecular markers are firmly established for stratification of specific systemic therapy approaches for metastastic rectal cancer, e.g., the RAS and BRAF status. Latest therapy approaches used as monotherapy or in combination enable targeted interventions at the immunological level, e.g., by means of checkpoint inhibition or targeted therapy, in case of HER-2 amplification or NTRK fusions, establishing further individualized treatment [29, 30]. However, molecular markers for targeted or immunotherapy approaches have currently no therapeutic role for perioperative (radio-)CT in nonmetastatic rectal cancer.

Conclusion

Rectal cancer remains a relevant global health issue, increasingly affecting younger patients. This update review summarizes the current standard of care and discusses the diversified treatment approaches taking into consideration individual tumor characteristics and reflects open questions which currently require further clinical evidence. Academic centers should be encouraged to set up further studies, aiming to reduce the remaining “grey zones” in the management of rectal cancer patients such as the role of adjuvant CT after nCRT, the value of systemic CT prior to standard nCRT, or surgical questions like the role of lateral LN dissection or the identification and management of patients with cCR. International collaborative initiatives such as the Lateral Node Study Consortium [31] and the International Watch & Wait Database Consortium [19] can be taken as examples of synergistic international efforts to increase clinical evidence in order to align future clinical guidelines and provide the best clinical care for rectal cancer patients in an individualized manner.

Acknowledgments

This review article is based on contributions by none than the authors listed in the author list.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding source is to be acknowledged for this review.

Author Contributions

L.-C.C., C.R., and M.G. contributed to the conception of the work, drafted the article, and gave final approval of the version to be published and are accountable for all aspects of the work.

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