*Wiktor Krawczyk, Zbigniew Lorenc, Jakub Wantulok, Michał Święch
What about radiotherapy for rectal cancer?
Co z tą radioterapią w leczeniu raka odbytnicy?
Department of General, Colorectal and Multiorgan Trauma Clinical Surgery, Medical University of Silesia in Katowice
Streszczenie
Rak odbytnicy stanowi jedno z najtrudniejszych wyzwań w onkologii ze względu na wysokie ryzyko nawrotów oraz liczne powikłania związane z leczeniem. W ostatnich dziesięcioleciach nastąpił znaczący postęp w leczeniu tego nowotworu, głównie dzięki wprowadzeniu techniki całkowitego wycięcia mezorektum (TME) oraz zastosowaniu okołooperacyjnej radioterapii i chemioterapii. Technika TME, rozwinięta w latach 80. XX wieku, zrewolucjonizowała chirurgię raka odbytnicy, znacząco redukując częstość nawrotów miejscowych i poprawiając wyniki leczenia. Dodatkowo, wdrożenie radioterapii okołooperacyjnej, zarówno w formie terapii neoadiuwantowej, jak i adiuwantowej, przyczyniło się do dalszej redukcji ryzyka wznowy nowotworu i poprawy przeżywalności pacjentów. Całkowita terapia neoadiuwantowa (TNT) zyskuje na znaczeniu jako podejście w leczeniu raka odbytnicy w stadium II-III. TNT łączy chemioradioterapię (ChRT) z chemioterapią przed operacją i pokazuje obiecujące wyniki. Badania fazy II i III, takie jak RAPIDO i UNICANCER-PRODIGE 23, wykazały, że TNT prowadzi do wyższych wskaźników całkowitej odpowiedzi patologicznej, poprawia długoterminowe przeżycie (DFS), obniża wczesne powikłania oraz zmniejsza ryzyko nawrotów miejscowych. Nie ustalono jednak, czy lepsze wyniki daje wcześniejsze podanie chemioterapii czy ChRT. Badania także porównywały TNT z konwencjonalnymi terapiami, wskazując na korzyści w kontekście skuteczności leczenia i mniejszej toksyczności. W artykule omówiono różne podejścia do leczenia okołooperacyjnego ze szczególnym uwzględnieniem radioterapii. Przedstawione zostały także najnowsze badania kliniczne, które wskazują na dalsze możliwości poprawy wyników leczenia poprzez optymalizację terapii skojarzonej.
Summary
Rectal cancer represents one of the most difficult oncological challenges due to its high risk of recurrence and multiple treatment complications. Recent decades have witnessed significant advances in the treatment of this malignancy, mainly due to the introduction of Total Mesorectal Excision and the use of perioperative radiation therapy and chemotherapy. Total mesorectal excision, developed in the 1980s, revolutionised rectal cancer surgery, significantly reducing local recurrence rates and improving treatment outcomes. Additionally, the implementation of both neoadjuvant and adjuvant perioperative radiation therapy has further reduced the risk of recurrence and improved patient survival. Complete neoadjuvant therapy (CNT) is gaining importance as an approach in the treatment of stage II-III rectal cancer. CNT combines chemoradiotherapy (ChRT) with chemotherapy before surgery and shows promising results. Phase II and III studies, such as RAPIDO and UNICANCER-PRODIGE 23, have shown that CNT leads to higher rates of complete pathological response, improves long-term survival (DFS), reduces early complications, and reduces the risk of local recurrence. However, it is not clear whether earlier chemotherapy or ChRT provides better results. Studies have also compared CNT with conventional therapies, indicating benefits in terms of treatment efficacy and lower toxicity. The paper discusses various approaches to perioperative management with a special focus on radiation therapy. It also presents recent clinical trials suggesting the possibility of further improvement of treatment outcomes by optimising combination therapy.
Rectal cancer (RC) is one of the most common gastrointestinal malignancies, posing a significant clinical challenge due to its complexity and tendency to recur. Although recent advances in cancer diagnosis and therapies have significantly improved treatment outcomes, RC remains a difficult clinical problem, requiring a multidirectional therapeutic approach.
Historically, RC treatment approaches were based mainly on surgical interventions, which at the time, however, had many limitations. Surgeries were characterised by a high risk of complications, and local recurrence rates were alarmingly high. Low surgical precision and the lack of advanced supportive techniques meant that many patients experienced serious complications, such as faecal incontinence, significantly impacting their quality of life. The introduction of Total Mesorectal Excision (TME) by Dutch surgeon Richard J. Heald in the 1980s was a breakthrough in the surgical treatment of rectal cancer.
Treatment outcomes with TME have been impressive. Multiple studies have shown that TME significantly reduced the risk of local recurrence to < 10%, which was a considerable improvement over previous surgical techniques. Additionally, precise resection of the mesorectum reduced the number of gastrointestinal (GI) complications, resulting in a better quality of life for patients.
Perioperative radiation therapy (RT), which plays an important role in reducing the risk of tumour recurrence and improving patient survival rates, is one of the key elements of modern rectal cancer treatment. The aim of this paper was to discuss in detail the role of perioperative RT in the treatment of rectal cancer, with particular emphasis on its use as part of neoadjuvant and adjuvant approaches. Recent clinical trials highlighting the importance of this modality will also be presented, along with its potential benefits and challenges in clinical practice. Neoadjuvant/adjuvant therapy for stage II (T3-4, no lymph node involvement with invasion through the muscular wall) or stage III (lymph node involvement, but no distant metastasis) rectal cancer usually includes locoregional treatment due to the relatively high risk of local recurrence. This risk is related to the close proximity of the rectum to pelvic structures and organs, the lack of surrounding rectal serosa, and the technical difficulties associated with obtaining wide surgical margins during resection. In contrast, adjuvant treatment of colon cancer (CC) focuses more on preventing distant metastasis, and the rate of local recurrence is lower.
Although RT is associated with reduced RC recurrence rates, it also involves a higher risk of radiation-induced reactions (e.g., radiation-induced trauma, haematologic disease) compared to surgery alone (1). Some patients with a lower risk of local recurrence (e.g., T3 N0 M0 proximal rectal cancer with negative radiographic margins and favourable prognostic factors) can be adequately treated with surgery and adjuvant chemotherapy (ACT). However, one retrospective study has shown that 22% of 188 patients with T3 N0 M0 rectal cancer who were clinically diagnosed by EUS or MRI and subsequently received preoperative chemoradiotherapy (CRT) presented with lymph node involvement on histopathology. These findings suggest that many patients are under-staged and would benefit from preoperative CRT. Therefore, the guidelines recommend preoperative treatment for patients with T3 N0 disease (2).
Combination therapy, consisting of surgery, fluoropyrimidine-based CT with pelvic RT, is recommended for most patients with stage II or III rectal cancer. Perioperative pelvic RT regimens for stage II/III patients are still under investigation. Current guidelines recommend several possible sequences of therapy, depending on a variety of factors and response to initial treatment.
Total neoadjuvant therapy
A therapeutic approach for stage II or III rectal cancer including courses of CRT, including preoperative neoadjuvant chemotherapy, is gaining attention. This approach, referred to as total neoadjuvant therapy (TNT), was first assessed in several small phase II trials, but has recently been supported by phase III trials (3).
In the Spanish GCR-3 randomised phase II trial (4), patients were randomly assigned to receive induction CT before CRT or postoperatively. Similar levels of pathological complete response (pCR) and 5-year DFS and OS were observed, and induction CT appeared to be less toxic and better tolerated. The GCR-3 trial provided the basis for the RAPIDO trial and showed that TNT reduced early post-radiation reaction and produced similar outcomes compared to the conventional approach. A pooled analysis of two phase II trials, EXPERT and EXPERT-C (5), assessed the safety and efficacy of neoadjuvant chemotherapy (NCT) followed by CRT and surgery. Of the 269 patients who were included, 91.1% completed CT, 88.1% completed CRT, and 89.2% underwent surgery. The 5-year PFS and OS rates were 66.4 and 73.3%, respectively. Another phase II trial comparing response rates in patients with stage II-III RC treated with CRT alone or CRT + preoperative FOLFOX showed that FOLFOX was independently associated with higher pCR rates, with the highest and lowest pCR rate (38 and 18%, respectively) after 6 cycles of neoadjuvant FOLFOX and CRT alone, respectively (6). However, it is difficult to determine whether the higher pCR with FOLFOX was due to its longer duration, the longer interval between CRT and surgery, or a combination of these two factors.
The TNT approach was recently assessed in a phase III study. RAPIDO, a randomised phase III trial, compared the standard therapeutic approach (CRT followed by TME and then optional adjuvant chemotherapy) with the experimental TNT approach (short-course RT followed by CT before TME) in 912 patients with locally advanced RC. Three years after randomisation, the disease-related treatment failure rate was 23.7% with TNT vs. 30.4% with standard treatment. There were no differences in the secondary endpoint of OS. Serious adverse events (SAEs) occurred in 38% of the TNT group and 34% of the standard therapy group (7). Another randomised phase III study, UNICANCER-PRODIGE 23, compared a neoadjuvant approach including both FOLFIRINOX and CRT before TME with the standard approach of neoadjuvant CRT prior to TME in 461 patients with locally advanced RC. Both groups received adjuvant FOLFOX after TME, although it was shorter in the group receiving NCT. After a median follow-up of 46.5 months, the 3-year DFS was 76% in the TNT vs. 69% in the standard therapy group. Throughout the entire treatment period, AEs occurred in 11% of patients in the NCT group and in 23% in the standard therapy group. There were no deaths within postoperative 30 days in the TNT group, and five deaths in the standard therapy group (8).
These findings were also supported by systematic reviews and meta-analyses showing a higher rate of pCR with TNT. A retrospective cohort analysis conducted in patients with T3-4 rectal cancer or lymph node involvement showed that patients in the TNT group received a higher percentage of the planned chemotherapy dose than those in the ACT group. Complete response rates were 36 and 21% in the TNT and ACT groups, respectively (9).
It has not been determined whether it is better for TNT to start with CT and then proceed to CRT, or the other way round. Phase II Organ Preservation in Rectal Adenocarcinoma (OPRA) trial suggested that starting treatment with CRT may improve DFS. The CAO/ARO/AIO-12 randomised phase II trial also compared the TNT approach of induction CT vs. FOLFOX followed by CRT with 5-FU/oxaliplatin or CRT followed by CT. This study showed that starting with CRT led to higher CRT completion rates, but lower CT completion rates compared to chemotherapy first. Pathological complete response occurred in 17% of patients who received CT first and in 25% of patients who received CRT first. A secondary analysis of long-term outcomes (median 43 months) from the CAO/ARO/AIO-12 trial showed similar results between the two groups, including 3-year DFS (73% for both groups), a 3-year rate of local recurrence (6 vs. 5%) and distant metastasis (18 vs. 16%). Chronic post-radiation reactions occurred in 11.8% of patients who first received CT vs. 9.9% of patients who first received CRT. Collectively, these data suggest that the TNT approach using CRT followed by CT results in a higher rate of pCR, with no significant differences in DFS, local recurrence, distant metastasis or toxicity (10).
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