By the ESTRO lower gastrointestinal (GI) focus group 

ESTRO 2025 Congress Report I Clinical Track

V. Rectal Cancer Is the New Anal Cancer: Organ Preservation in Focus
Panel Discussion I Sunday, 4 May 2025

This early morning session brought together leading experts to discuss the evolving role of organ preservation in rectal cancer. They drew parallels to treatment strategies in anal cancer. Professor Emmanouil Fokas  (Germany) opened the session with a state-of-the-art lecture highlighting the shift in rectal cancer management toward organ preservation. This transition underscores the urgent need for new, adapted clinical guidelines and the development of nationwide expertise to support safe and effective implementation in routine practice.

Building on this shift, Prof Fokas outlined several key requirements for successfully implementing organ preservation strategies. Take-home messages included the importance of high-quality baseline MRI for accurate risk-based stratification, precise assessment of tumour response, and the need for structured, intensive surveillance programmes. He emphasised that the integration of radiotherapy into multidisciplinary treatment had significantly raised the bar for organ preservation rates, reaching 60-80% in early or intermediate-stage disease (e.g., the OPERA and STAR-TREC trials) and around 50% even in more advanced cases (OPRA). Given the growing complexity of therapeutic options and care pathways, he stressed that shared decision-making would be essential to ensure personalised, patient-centred treatment planning.

The lecture was followed by three clinical case discussions led by Professors Cihan Gani (Germany), Alexandra Gilbert (UK), and Maria Antonietta Gambacorta (Italy). They illustrated practical challenges and opportunities in applying organ-sparing strategies. The session concluded with a lively panel discussion that explored whether organ preservation would remain limited to selected patients or become a broader standard in rectal cancer management.

 

5. Plenary – Joint Green Journal & The Lancet Oncology: Top Clinical Trials

This special plenary session marked a new collaboration between Radiotherapy & Oncology (the Green Journal), The Lancet Oncology, and ESTRO. This joint initiative aims to spotlight the most impactful clinical trials in radiation oncology, with selected studies published in parallel with their presentation at the Congress. The session featured top-rated abstracts from each track, highlighting research that showed the potential to change clinical practice or current paradigms in the field.

This year’s programme was focused on five high-impact clinical trials in rectal and anal cancer: PLATO ACT 4, STAR-TREC, PRIME-RT, STELLAR, and STELLAR II.
Together, these studies represent a major step forward in the individualisation of treatment for rectal and anal cancer—whether through dose de-escalation, organ preservation, or the integration of immunotherapy—and set the stage for ongoing refinement of modern radiotherapy-based strategies.

Prof David Sebag-Montefiore (UK) presented long-term results of the PLATO ACT 4 trial. These results demonstrated that reduced-dose chemoradiotherapy (41.4Gy vs. standard 50.4Gy) was oncologically safe in selected patients with early-stage anal cancer (T1–2≤4 cm, N0), with similar efficacy and toxicity outcomes, thus supporting dose de-escalation in this group.

Prof Corrie Marijnen (Netherlands) followed with 12-month results from STAR-TREC, an international phase II/III trial in which organ preservation strategies were evaluated in early/intermediate-stage rectal cancer. Patients were randomised to receive either long-course chemoradiotherapy (CRT) or short-course radiotherapy (SCRT), with response-adapted management including watch-and-wait or local excision. CRT yielded higher rates of organ preservation (57%) than did SCRT (27%), with both arms showing excellent safety, laying the groundwork for the application of less invasive treatment strategies in selected patients.

Prof Maria Antonietta Gambacorta (Italy) provided expert commentary on both the PLATO ACT 4 and STAR-TREC trials, placing their findings within the broader context of organ preservation strategies in lower gastrointestinal cancers.

Reflecting on PLATO ACT 4, she situated the trial within the continuum of over three decades of clinical research in anal cancer, and highlighted the specific knowledge gaps it addressed—particularly the safety and feasibility of radiotherapy dose de-escalation in small, early-stage tumours. She drew attention to the reduced treatment compliance that was observed in the standard-dose arm, which may have impacted efficacy outcomes, especially considering that prolonged treatment times and interruptions exceeding two days are known to increase local failure rates and worsen survival in anal cancer. Despite the use of a lower dose in one arm, late toxicity rates were comparable between groups. Prof Gambacorta suggested that irradiated volume—rather than dose alone—might be a key driver of long-term side effects. In this context, she emphasised the potential of advanced technologies, such as improved imaging and MR-guided radiotherapy, to reduce treatment volumes and thus toxicity. She concluded that the trial supported a change in clinical practice by endorsing reduced-dose radiotherapy for patients with ≤4cm intrasphincteric tumours, while underlining the importance of meticulous treatment planning.

In her discussion of STAR-TREC, Prof Gambacorta emphasised that the trial had targeted a distinct subset of rectal cancer patients—those with early-to-intermediate-stage disease (up to cT3ab N0 without high-risk features), representing approximately 25% of rectal cancer cases. These patients are typically cured with surgery alone, and the primary aim of the study was organ preservation. She noted that while the data were not yet mature, they were in line with those published in the current literature. She considered that long-course CRT was more effective than SCRT for tumours smaller than 3cm, and that these findings supported the hypothesis of a tumour volume effect and a potential benefit from treatment intensification through higher radiation doses and concurrent chemotherapy. She also stressed the importance of accurate patient selection, noting that the trial was conducted in expert centres on carefully selected patients, and that imaging may fail to accurately stage disease in more than 20% of cases.

In the second part of the session, immunotherapy entered the spotlight.

Prof Campbell Roxburgh (UK) presented the phase II PRIME-RT trial, in which the feasibility of adding durvalumab to both short- and long-course total neoadjuvant therapy (TNT) in mismatch repair-proficient locally advanced rectal cancer was assessed. At the end of the treatment, 52% of patients had achieved clinical or pathological complete response (57% in the SCRT arm vs. 48% in the LCRT arm), meeting the predefined threshold for clinical efficacy in both groups. Higher response rates in the SCRT arm support further exploration of immunoradiotherapy combinations.

Prof Yuan Tang (China) shared five-year outcomes of the phase III STELLAR trial in which SCRT-based TNT was compared with standard long-course CRT in locally advanced rectal cancer. TNT proved non-inferior in terms of disease-free survival and demonstrated a sustained overall survival benefit, with comparable toxicity and quality of life at long-term follow-up.

Finally, Prof Jing Jin (China) presented phase II data from STELLAR II, a randomised trial in which researchers evaluated whether the addition of sintilimab (a PD-1 inhibitor) to SCRT-based TNT could enhance response in mismatch repair-proficient/microsatellite-stable rectal cancer. The study showed a significantly higher complete response rate in the immunotherapy arm (45.6% vs. 24.7%), with manageable toxicity, offering early evidence that immune checkpoint blockade may enhance tumour response even in microsatellite-stable rectal cancers.

Prof Claus Rödel (Germany) provided a comprehensive commentary on the STELLAR I, STELLAR II, and PRIME-RT trials, highlighting their relevance to three major themes in rectal cancer management: TNT targeting of distant metastases; organ preservation to improve function and quality of life; and the emerging role of immunotherapy in microsatellite-stable tumours.

Discussing STELLAR I, he reviewed the differing outcomes of trials that used SCRT TNT schedules (Polish II, RAPIDO, STELLAR), and questioned the choice of disease-free survival non-inferiority as the primary endpoint, the broad inclusion criteria, and the absence of clear benefit in disease control or quality of life despite higher toxicity. While an improvement in overall survival was observed, he noted that similar rates of disease-free survival, locoregional recurrence, and distant metastasis between arms raise doubts about the durability of this benefit. He stressed that although TNT was listed as a preferred approach in guidelines, this was mainly based on distant metastasis reduction in RAPIDO and PRODIGE 23, while Polish II was negative and STELLAR showed only non-inferiority. Several open questions remain, including optimal chemotherapy duration, sequencing, and radiotherapy modality (SCRT vs. CRT).

Turning to STELLAR II and PRIME-RT, Prof Rödel addressed the integration of immune checkpoint inhibitors into TNT for microsatellite-stable rectal cancer. He questioned the timing of the delivery of immune checkpoint inhibitors in PRIME-RT, in which durvalumab was given before and during CRT, noting that evidence from trials such as POLARSTAR and PACIFIC suggested that sequential administration might be more effective.

He underscored several strengths of STELLAR II: it is the largest randomised trial in 100% microsatellite-stable patients, with adequate statistical power, a clear design, SCRT as the backbone, sequential use of sintilimab, and response assessment at 20 weeks to allow for tumour regression.

In closing, he offered a synthesis of current evidence:

• when total mesorectal excision (TME) is mandatory in advanced tumours, both SCRT and CRT are viable (e.g., Polish I, Trans-Tasman);
• for organ preservation, CRT appears superior to SCRT (as shown in STAR-TREC);
• when neoadjuvant chemotherapy is added to SCRT with planned TME, this approach is more effective than CRT + TME (e.g., RAPIDO, STELLAR, Polish II); and
• for combination with immunotherapy, SCRT may be the preferred radiotherapy platform.

 

5. Top Clinical Trials – ESTRO 2025

At the Top Clinical Trials session on 5 May, two lower gastrointestinal (GI) studies were presented.

Prof David Sebag-Montefiore (UK) presented the mature results of the phase III ARISTOTLE trial, the largest randomised study to date in which researchers have assessed the addition of concurrent irinotecan to capecitabine chemoradiation in MRI-defined locally advanced rectal cancer. The addition of irinotecan led to lower compliance with radiotherapy and chemotherapy and was associated with a higher incidence of grade ≥3 adverse events, particularly diarrhoea, leucopenia, and neutropenia. No significant improvement was observed in rates of disease-free survival or other oncologic endpoints. These findings do not support the addition of irinotecan to standard CRT in high-risk rectal cancer.

Prof Sebag-Montefiore highlighted the high quality of multidisciplinary care, as reflected by the very low (5%) rate of loco-regional failure. Further translational research is planned to identify predictive biomarkers of response to irinotecan-based chemoradiation.

Prof Cihan Gani (Germany) presented the results of the CAO/ARO/AIO-16 study on organ preservation and functional outcomes after TNT for locally advanced rectal cancer. In this multicentre phase II trial, 91 patients received chemoradiotherapy followed by three cycles of FOLFOX. Clinical complete response was achieved in 37% of patients, who were managed with a watch-and-wait approach. Three-year TME-free survival was 21%. Patients who avoided surgery had better bowel function, lower low anterior resection syndrome and Wexner scores, and less late toxicity. This study addresses key evidence gaps in TNT—specifically long-term data on organ preservation, quality of life, and anorectal function—and offers important insights for future trials regarding the timing of response assessment, chemotherapy duration, and possibly radiotherapy dose.

In his commentary on the two trials, Prof Panagiotis Balermpas (Switzerland) emphasised that irinotecan should no longer be used concomitantly with chemoradiotherapy, given the lack of efficacy and increased toxicity that was observed in the ARISTOTLE trial. He stressed the importance of maintaining high-quality, standardised neoadjuvant CRT as the backbone of rectal cancer treatment and pointed to oxaliplatin-based TNT as a promising strategy for achieving organ preservation. He also noted that ongoing advancements in imaging, radiotherapy techniques, and personalised treatment planning were likely to strengthen the role of TNT in rectal cancer, with the potential to improve both long-term oncologic outcomes and quality of life.

Joanna Socha, MD, PhD,

Associate Professor at Faculty of Medicine, Jan Dlugosz University, Czestochowa, Poland;

Senior consultant in radiation oncology at the Department of Radiotherapy, Regional Oncology Center, Czestochowa, Poland

e-mail: sochajoanna@wp.pl
Member of the ESTRO Lower GI focus group