Authors:

Jean Pierre Gerard

Syrine Ben Dhia

David Baron

Diana Mitrea

Jerome Doyen

Arthur Sun Myint

Abstract

Surgery and radiotherapy for rectal cancer emerged in Europe at the dawn of the 20th century, marking the foundation of modern treatment strategies. Over the decades, Europe has led the way in conducting pivotal randomized trials, shaping and optimizing the multidisciplinary management of rectal cancer. These trials have progressively refined surgical techniques, radiation protocols, and chemotherapy integration, resulting in significant advancements in patient outcomes. This chapter provides a comprehensive overview of these historical and scientific milestones, highlighting the continuous evolution of treatment paradigms. It underscores the current frontier in rectal cancer care: the challenge of organ preservation. This innovative approach aims to minimize invasive procedures, improve quality of life, and maintain oncological safety, reflecting a major shift toward more personalized and less morbid therapeutic strategies.

Introduction

From magical thinking to anatomical-clinical approach: Dawn of rectal cancer management

After centuries of magical approaches and inefficient practice, scientific knowledge progressively evolved in the field of rectal cancer treatments and opened the doors to modern medical management. Using cadaver dissection, rectal anatomy was well known since the 18th century. Rectal cancer, was identified in the early eighteenth century by autopsy carried out on patients. R Laennec (Paris, 1781-1826) introduced the stethoscope’s use and also pioneered the clinical methods of examination, which led to the first digital rectal examination (DRE) of the rectum shortly after 1850. With introduction of the microscope by A Van leewenhoek (1632-1723), R Virchow (1821-1902) was able to identify cancer cells and to demonstrate that cancer was due to the development of abnormal cells ^[1]. Rigid rectoscopy designed by Raoul Bensaude (1866-1938) was first performed in the knee-chest position. Rectoscopy was later introduced into clinical practice by F Trendelenburg (1844-1924) which enable biopsies to be taken from the rectal cancer. Histopathological classification of tumors, separating sarcoma and epithelial cancer, was in routine use at the end of 19th century.

Until the discovery and use of ether, the general anesthetic agent in 1846 at Boston (W Morton; 1819-1868) surgery for treating cancer was difficult and painful. With the discovery of microbes by L Pasteur (1822-1895), the use of asepsis promoted by I Semmelweis (1818-1865) and J Lister (1827-1912) reduce septic complications and the outcomes from surgery improved significantly (and continues to be) the cornerstone of solid tumor cancer treatment. It is in 1948, to test the efficacy of streptomycin against tuberculosis ^[2] the first randomized trial was carried out (R Fisher, 1890-1962) which opened the door to evidence based medicine which is the present gold standard to validate new treatments for change in clinical practices.

The standard of care for rectal adenocarcinoma initially was surgery, however, it is now a multidisciplinary approach. This chapter aims to describe the main developments occurring in Europe since the first abdominoperineal resection (APR) performed by Miles in 1908 which was the only curative treatment available over one hundred years ago. After the discovery of X rays (Roentgen 1895), radiotherapy played an important role for inoperable rectal cancers and later chemotherapy (and medical treatments) was used as neo adjuvant and adjuvant treatment to improve local control and survival. Most importantly, following randomized trials, we were able to provide evidence to evaluate the best strategy for treating individual patients with rectal cancer.

For 120 years, depending on progress achieved during this timeline, different clinical end points were used. First, local control following surgery (and survival), local control being a prerequisite for cure. When APR was validated, attempt at sphincter preservation to avoid permanent colostomy became a new challenge. After the Second World War, high energy radiotherapy machines were used post operatively initially then preoperatively aimed to reduce local recurrences. In the sixties with the advent of chemotherapy (5-flurourocil [5-FU]), the aim was first to treat metastases and then later used as adjuvant treatment (efficient in colon cancer) to prevent metastases, mainly in the liver or in the lung. Later randomized trial also showed adjuvant chemotherapy to possibly increase overall survival. The present challenge, with modern conformal radiotherapy and endocavitary irradiation (with or without radio chemotherapy), is to achieve a complete clinical response (cCR) of the primary to improve organ preservation and reserving surgery as a salvage treatment for local failures.

1. History of rectal cancer treatment: 1908-1990

1.1 Milestones in developments for surgery

The first surgeon to amputate rectum for cancer was Jacques Lisfranc (1790-1857), a surgeon at La Pitiѐ Hospital in Paris in 1826. Later followed by Theodor Kocher (1841-1917) from Bern who attempted primary closure of anus following resection of cancer in the rectum. With advantage of aseptic technique and anaesthesia, W E Miles (1869-1947) tried the first curative attempt for rectal cancer using abdomino-perineal resection or rectum (APR) in 1908, at the Royal Cancer Hospital (now renamed as Royal Marsden, London. The results of his operation in the early 1900s were far from optimal with a very high post-operative mortality rate close to 50%, a high rate of local relapses close to 40% and only very few long-term survivors (less than 10%). APR, sometimes performed through a posterior sacral approach (Kraske - Vienna- Austria), became the standard surgery for rectal cancer. However, to reduce the trauma of permanent colostomy, anterior resection (AR) with colorectal anastomosis was proposed in the mid1920s (MJE Villard 1868-1953- France). In the 1950s the results of APR for distal- middle cancer and AR for upper rectal tumor achieved cure with 5 years and overall survival rate around 45% ^[3]. In 1980 to reduce the rate of local recurrence R J Heald (UK) introduced the concept of total mesorectal excision (TME). This very skilled dissection technique along the mesorectal fascia (holy plane) under direct vision control was able to achieve more R0 resections and functional dissections to spare the hypogastric nerves. TME resulted in fewer local relapse (below 10%) and better bladder and sexual function were achieved ^[4]. In most surgical departments the TME approach was progressively adopted and it was the merit of the Dutch TME trial to evaluate the benefit, if any, of preoperative radiotherapy with TME, to reduces local recurrence rate further ^[5]. In the 1990s, G Buess (1940-2010) from Tubingen in Germany developed a new local excision technique using a dedicated endoscope and microsurgery (TEMS : trans-anal endoscopic micro surgery) to increase the chance of organ preservation for early cancers ^[6]. With the widespread use of colorectal cancer screening the gastroenterologists are treating, routinely in expert centers, small borderline rectal polyps (often in latero-spreading tumors) using Endoscopic Mucosal Resection (EMR) often complemented with radiotherapy if any infiltrating tumor (pT1sm3 or more advanced stage) is observed on the pathologic specimen ^[7].

1.2 Milestones in developments for radiotherapy

Until the 1960s rectal adenocarcinoma was considered as a very radio-resistant cancer. This is mainly because of the poor tolerance of the organ at risk (OAR)when using the orthovoltage machines.Low energy x-rays restricted the delivery radiation dose high enough to cure rectal tumor without damaging the normal surrounding tissues. At the turn of twentieth century endocavitary radium implants demonstrated some gratifying responses in rectal cancer. It was the merit of J. Papillon in the 1960s (1914-1993) to establishthe use of Contact X-Ray Brachytherapy (CXB) 50 kVp which allows delivery of high radiation dose (90 Gy/3fraction/4 weeks) through an endocavitary approach. As the radiation dose is targeted directly on to the tumor,it was possible to deliver high enough radiation dose to achieve cCR and long term local control for early adenocarcinoma in 80% of cases ^[8]. Later, inthe 1960 -70s, telecobalt and high energy Linac made it possible to deliver higher doses of 45 to 50 Gy to the rectal tumor. External beam radiotherapy given either before or after surgery was able to reduce the rate of local relapse significantly ^[5]. Hence, surgery combined with radiotherapy became the standard of care for rectal cancer up to our present era ^[9].

1.3 Milestones in developments for chemotherapy

In 1957, Charles Heidelberger discovered 5-Fluorouracil (5-FU) at Wisconsin University in the USA. Its use was rapidly spread to Europe and other parts of the world. 5-FU showed efficacy in achieving partial response in liver metastases of colorectal adenocarcinoma ^[10]. In the 1960s, cisplatin was developed and found to be effective as an antimitotic drug (testicular tumors) but has limited role for colorectal cancers. Oxaliplatin was first synthesized in 1978 at Nagoya City University by Yoshinori Kidani.[24] It was later developed in Europe as a less toxic and more effective alternative to cisplatin. It gained European Drug and Medicine Control authorities’ approval in 1996. It was in the 1990s that oxaliplatin was shown to achieve high response rate in colorectal adenocarcinoma and led to the use of the FOLFOX combination with a 50% partial response rate and some clinical complete response (cCR) in liver metastases ^[11]. It was the merit of André De Gramont in Paris, who applied the concept of adjuvant chemotherapy first pioneered for breast cancer by G Bonadonna (Milan 1934-2015). De Gramont demonstrated within a randomized trial, the efficacy of FOLFOX to improve overall survival, after surgery for advanced colon cancer, ^[12].

1.4 Timeline of randomized trials in medicine and rectal cancer. Testing hypotheses to bring strong evidence and change the practice (1990-2024)

It is now widely accepted that high level of evidence can be obtained from the results of well-controlled randomized trials. Medical science, like all sciences, starts with observation and then hypothesis. Experimental medicine promoted by C Bernard (1813-1878) was a method for testing these hypotheses. Analysis of well measured data and relevant endpoints leads to conclusions and usually new hypothesis.

The ultimate (ideal) hypothesis for rectal cancer treatment is: can we cure these cancers without any toxicity (and at an affordable financial cost)? We will see in the next paragraphs what has been achieved in Europe and what problems we face in the road ahead.

• 1990- 2000: A 40% rate of local relapse after surgery is too high. Can we reduce this by using radiotherapy?

In 1997, The Swedish rectal trial (1168 pts) using a preoperative short course RT (SCRT) :25 Gy/5 fractions/5days demonstrated reduced local recurrence (11% vs 27%) and also overall 5-year survival (58% vs 48%) ^[13]. The North Western UK trial also using SCRT but into a small pelvic volume (< 1liter) reduced local recurrence from 36% to 12% with fewer toxicity than the Swedish trial and 10/16 of the local relapses occurred within the small irradiated volume ^[14].

• Do we still need radiotherapy with TME surgery?

The Duch TME trial in 2001 showed that with TME alone at 2 years the rate of local recurrence was 8% and it was reduced to 2% with pre-operative SCRT ^[5]. At 10 Years the rate was 18% vs 10% and 90% of the local recurrences were located below the S2/S3 junction ^[15]. This trial with the North western UK trial demonstrated that only a small posterior and lower pelvis should be irradiated to achieve a good therapeutic (efficacy/toxicity) ratio.

• Radiotherapy is efficient for local control. Is chemoradiotherapy (CRT) more efficient?

The FFCD 9203 and EORTC 22921 trials (15,16) enrolled 1820 patients and compared neoadjuvant radiotherapy (nRT) delivering 45 Gy over 5 weeks with the same nRT with concomitant chemotherapy (5FU). Both trials achieved a significant reduced local 5-year relapse rate (8% vs 16%) with CRT with an acceptable toxicity. In the EORTC trial an adjuvant chemotherapy was also given with no impact on overall survival with may be (in subgroup analysis) a possible survival benefit for tumors of the upper rectum ^[16].

• In North America until 2000 postoperative CRT was still the standard. Europe was using mainly preoperative. Which approach is better?

The answer came from the German CAO-ARO trial (1995-2002): a total of 799 patients were randomised and preoperative nCRT was superior to postoperative with fewer 5-year local relapse (5% vs 10%) and lower toxicity grade 3-4 (14% vs 24%). These superior results were maintained at 10 years and preoperative (nCRT) became the standard of care, worldwide ^[17].

• Is Short course RT as efficient as long course CRT?

Many trials have tried to answer this important question (^[18],^[19]). In summary nCRT (45-50 Gy/5 weeks) gives more ypCR (15-20% vs 6-9%) in LARC, fewer local relapse, more early toxicity but no improvement of overall survival. SCRT can be a well-adapted regimen, especially for elderly, frail patient.

• Can we improve the efficacy of CRT by adding more drugs to 5FU?

Here also many trials have tested this hypothesis. The Italian Star trial in 2011 showed increase toxicity with oxaliplatin and no benefit for ypCR, local control or survival ^[20]. Most other trials came to a similar conclusion. Later, oral drug Capecitabine replaces the intravenous 5FU. Patients can be treated as out patients which is more convenient for the patients ^[21]. Folfirnox is still under discussion but in France is considered as standard induction and adjuvant chemotherapy since the Prodige 23 Trial ^[22]. In USA the ongoing JANUS trial is comparing Folfox with Folfirnox in a TNT setting ^[23].

• Can we improve overall survival with medical treatment in 2024?

All preoperative chemoradiation therapy trials between 2000-2015 were negative(24). Recently: Prospect, Prodige 23, FOWARC, Rapido (^[19], ^[22], ^[24], ^[25]) have tested this hypothesis without clearer convincing results. The spectacular difference which occurred within the past 50 years is that in the 1970s in LARC (cM0) the 5-year overall survival was 50-55% and in 2024 this improved to 85-90%(^[22], ^[24]). This improvement is probably due to better detection at the base line of small metastases. ‘Will Rogers’ phenomenon with stage migration is partly responsible for this. However, this improvement can be either be due to better initial treatment at baseline with local control close to 95% and also better second line treatment at time of metastasis development. Only larger phase III trials with 1000 patients or more will be able to demonstrate in the future a gain in survival (85-90 to 90-95%!). One important treatment revolution which came recently is the use of immunotherapy with Dostarlimab in MSI rectal cancer. Such immunotherapy is achieving close to 95% of local control in MSI tumours without any surgery or radiotherapy. Unfortunately, MSI rectal cancer accounts for only 1% of all rectal cancer cases ^[26].

2. The most important challenge in 2024: Rectal preservation

With improvement of 85-90% overall survival in cM0 rectal cancer it will be difficult in the near future to demonstrate further significant survival improvement (with acceptable toxicity). The US ongoing Janus trial comparing Folfox with Folfirnox will answer the question of the best neoadjuvant chemotherapy hopefully in 2025. Anterior Resection is and will remain the standard treatment for upper rectum tumors treated like recto-sigmoid tumors. However, anterior resection surgery does not provide a fully satisfactory bowel function (LARS syndrome) and the road ahead appears to be Rectal Preservation with a good bowel function. At present, quality of life seems to be the main challenge to improve the outcome for rectal cancer patients. Therefore, the question for lower-mid rectum is: can we improve Quality of Life (QoL)? Only randomized trials can provide evidence and it is important to remember that rectal adenocarcinoma is a radioresistant tumor and that radiation dose of greater than 92 EQD2 must be delivered when using EBRT to achieve 50% T3 tumor sterilization ^[27].

Papillon in the early 1970s in Lyon was the first researcher to report a high rate of clinical complete response (cCR) using CXB in selected early rectal cancer ^[8]. CXB is a unique technique able to deliver with high precision under direct eye control a very high dose (30 Gy/fraction) to a small volume (3 cm diameter, 5 cc volume). To perform this technique, with presently the Papillon+TM machine emitting 50 kVp X-rays, the radiation oncologist should be able to use rigid rectoscopy. A Brazilian surgeon, Angelita Habr Gama has historically played an important role for rectal preservation because she was the first to convince her surgeon colleagues not to operate when, after nCRT a cCR was achieved ^[28]. She very wisely called this strategy ‘Watch and Wait’(W&W) because the best method to select the suitable patient is to first assess the tumor response after external beam radiotherapy using rectoscopy (Watch!) and palpation. It is important to wait and delay the assessment after the nCRT to allow enough time to observe a cCR, in those who are going to achieve this, so as to avoid performing a TME (too early) with a pathological report showing no residual cancer (ypT0N0). Since 2010 an International Watch and Wait data base (IWWD) ^[29] was set up to collect the data from all the international expert centres who are adopting watch and wait approach for patients who have achieved cCR following external beam radiotherapy with or without chemotherapy. The outcome of more than 1000 patients in the IWWD showed that, using nCRT and a W&W strategy many patients suitable for surgery could avoid extirpative surgery and a stoma. However, in those patients who achieved cCR in the IWWD database there was local regrowth in nearly 25% who end up having salvage surgery. This resulted in reduction of organ preservation rate close to 30-40% at 5 years.

R J Heald the pioneer of TME was the first to recommend ‘not to operate’ in case of cCR ^[30]. This non operative modality was strongly supported in New York by combining neo adjuvant chemotherapy (given prior to surgery) and CRT in a TNT (Total Neoadjuvant Treatment) strategy ^[31] which achieved 50% of OP in LARC ^[32].

• Is it possible to increase the rate of OP by using local excision in early cT1-T3, N0 tumor?

The French GRECCAR group conducted two phase III trials. Greccar2 ^[33] included 120 pts (2000-2012) staged cT2 N0 < 4cm diameter treated with nCRT (Cap45) and when a partial response (PR: T< 2cm) or cCR was observed the subsequent treatment was randomized between local excision (experimental arm) or a TME surgery (standard arm). At 5 years there was no difference in survival and an OP rate of 50% was achieved demonstrating that OP was not detrimental for survival. The second trial GRECCAR 12 (V. Vendrely et al. ESTRO congress 2024), using TNT in the same early tumors ≤ 4cm diameter: nCRT (Cap 50) with or without neoadjuvant Folfirinox (4 cycles), achieved close to 70% OP at one year in the group with induction Folfirinox. The Spanish TAU-TEM trial included (2010-2021) early (superficial) cT2-T3a/b with nCRT and TME as control group and the same nCRT followed by local excision in the experimental group. At 1 year the rate of OP was 81% using nCRT and Local excision, the rate of ypCR in the TME group was 44% and 21% of the operative specimen showed a ypN1-2 ^[34].

• Is it possible to increase the rate of OP using the CXB technique?

The European OPERA trial ^[35] included cT2-T3a/b, cN0 tumors < 5cm diameter, the Habr Gama approach (nCRT 45 Gy) in all patients and randomized the boost between EBRT 9 Gy/1 week(Arm A-standard of care arm) and CXB 90 Gy/ 3 fraction/4 weeks (Arm B- experimental arm). Between 2015-2020, 141 patients were randomized. At 3 years the OP rate was 59% in the EBRT boost group (Arm A) and 81% in the CXB group (Arm B) (p: 0.003). At 5 -year the difference of OP in favor of CXB was still 79% vs 53%. In a stratified subgroup of tumors < 3 cm diameter at baseline, where CXB was given before the nCRT(Arm B1) the rate of cCR was 97% and OP at 5 years was 93% with only 2/33 patients needing a salvage TME for PR or local recurrence. This trial has been a practice changing in France (and UK) and for tumors staged cT2T3a/b ≤ 3cm diameter. It is recommended that patients who are keen to avoid extirpative surgery and a stoma should be offered a planned rectal preservation plan starting treatment with CXB (90 Gy/3 fr/4 weeks) immediately combined with CRT (Cap 45). With such a protocol a rectal preservation (with good bowel function) is expected, for this selected group of patients of any age (operable or not), in over 90% of cases.

Conclusion

Europe has played a very important role in the history of rectal cancer management. Surgery which remains the main curative treatment of rectal cancer was initiated by Jacques Lisfranc (1790-1857), a surgeon at La Pitiѐ Hospital in Paris in 1826 and improved by R J Heald in the 1990s using the TME technique. Robotic surgery will be used increasingly and even liver transplantation has been offered for highly selected patients with liver metastases and may achieve 50% 5-year disease free survival ^[36].

Adjuvant treatment with chemotherapy, pioneered in Italy by Bonadonna for breast cancer (1980) was first demonstrated to improve survival of colon cancer by De Gramont using the Folfox regimen (2009). For Low and mid rectum benefit of adjuvant chemotherapy with currently available agents to increase survival is still debatable. Using the experimental randomized trial methodology, implemented for medical treatment by Fisher (1933), it was possible to show that nCRT was superior to nRT alone (EORTC and FFCD trials) in 2004 and the German CAO-ARO study was a pivotal trial to demonstrate the benefit of preoperative CRT vs post operative (2004). The Swedish trials and Dutch TME trials have shown the important place of SCRT even for patients who had good quality TME surgery. The French Greccar, Spanish Tautem and European OPERA trials have shown that rectal preservation can become a standard treatment for patients with tumours T2-T3a/b ≤ 4 cm diameter in expert centers with no detrimental effect on survival and good bowel function. The role of radiotherapy and probably of CXB first for early (≤ 3 cm) tumors should be considered when a planned organ preservation is recommended after MDT discussion for well-informed patients wishing to avoid extirpative surgery and a stoma. CXB imposes a learning curve for the radiation oncologists to master the technique. The role of CXB in LARC is presently evaluated by phase III trials.

Presently patients with non-metastatic rectal cancer can achieve 5-year overall survival rate approaching 90% using nCRT and some form of surgery (or organ preservation in early tumor stages). Immunotherapy according to molecular tumor profile appears promising to predict patients who will benefit to avoid radiotherapy and surgery in those who respond. Tailored treatment according to tumor stage/molecular profile and patient characteristics will be our challenge for the future. Further progress in treatments to improve outcomes in patients with metastatic disease is highly desirable.

Since last century Europe has played a major role in the step-by-step improvement of cures and quality of life in rectal cancer. North America, with its large population, has also played a pivotal role in clinical, translational and fundamental research in the world. In Asia, Chinese oncologists are also increasingly active in these large Phase III trials ^[37] and with 1.2 billion inhabitants are able to run large randomized trials. In Europe, with its very large diversity (more than 28 different languages among 500 million people!), it has been very creative during the past century in the management of rectal cancer. It is important for all researchers with their innovations to maintain efficient deliveries for science and clinical studies. Large, randomized trials are necessary as evidence to change clinic practice. However, we must be aware that the world population is ageing, and the management of rectal cancer should reflect this. Any innovative treatment approach should aim to minimize invasive procedures, improve patients’ quality of life, and maintain oncological safety. With the accumulation of knowledge over centuries and advances in science, it is gratifying to know that the current management of rectal cancer has reflected a major shift toward more personalized and less morbid therapeutic strategies for the patients.

Acknowledgment

If I have gained some original experience in the treatment of rectal cancer, it exclusively because I had the unique chance to be trained by Jean Papillon in Lyon between 1970 until his death in 1993. No word can express how this prestigious mentor was pivotal to developing the first radiotherapy (Contact X ray brachytherapy) able to cure in 80% of cases early rectal adenocarcinoma, considered until his work initiated in the 1950s, as fully radioresistant. I am also grateful to the visionary Jean Claude Horiot who in the 1970s, when back to Houston in Dijon, introduced me to modern radiotherapy and to ESTRO. Randomized trials being the cornerstone of evidence-based medicine, I have a special thought to my old friend the late Jean Faivre, also in Dijon, who allowed me to join the FFCD (Fédération Francophone de cancérologie Digestive) and to prove through the FFCD 9203 trial that chemoradiotherapy was superior to radiotherapy alone. OPERA being my last contribution to the medical science of rectal cancer, it is my great pleasure to thanks my forever good friends Nicolas Barbet and Arthur Sun Myint whose participation was crucial to the success of this practice changing trial.

References

1. Etziony M. The Process of Discovery. Can Med Assoc J. 11 août 1962;87(6):296‑8.

2. Long ER, Ferebee SH. A Controlled Investigation of Streptomycin Treatment in Pulmonary Tuberculosis. Public Health Rep 1896-1970. 1950;65(44):1421.

3. Galler AS, Petrelli NJ, Shakamuri SP. Rectal cancer surgery: A brief history. Surg Oncol. déc 2011;20(4):223‑30.

4. Heald RJ, Ryall RDH. RECURRENCE AND SURVIVAL AFTER TOTAL MESORECTAL EXCISION FOR RECTAL CANCER. The Lancet. juin 1986;327(8496):1479‑82.

5. Kapiteijn E, Marijnen CAM, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative Radiotherapy Combined with Total Mesorectal Excision for Resectable Rectal Cancer. N Engl J Med. 30 août 2001;345(9):638‑46.

6. Buess G, Mentges B, Manncke K, Starlinger M, Becker HD. Technique and results of transanal endoscopic microsurgery in early rectal cancer. Am J Surg. janv 1992;163(1):63‑70.

7. Jones HJS, Cunningham C. Adjuvant radiotherapy after local excision of rectal cancer. Acta Oncol. 1 avr 2019;58(sup1):S60‑4.

8. Papillon J. Intracavitary irradiation of early rectal cancer for cureA series of 186 cases. Cancer. août 1975;36(S2):696‑701.

9. Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rödel C, Cervantes A, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. juill 2017;28:iv22‑40.

10. Shirasaka T. Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas. Jpn J Clin Oncol. janv 2009;39(1):2‑15.

11. Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, et al. A Review of the Evolution of Systemic Chemotherapy in the Management of Colorectal Cancer. Clin Colorectal Cancer. mars 2015;14(1):1‑10.

12. De Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. févr 1997;15(2):808‑15.

13. Improved Survival with Preoperative Radiotherapy in Resectable Rectal Cancer. N Engl J Med. 3 avr 1997;336(14):980‑7.

14. Marsh PJ, James RD, Schofield PF. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma: Results of a prospective, randomized trial. Dis Colon Rectum. déc 1994;37(12):1205‑14.

15. Detering R, Karthaus EG, Borstlap WAA, Marijnen CAM, Van De Velde CJH, Bemelman WA, et al. Treatment and survival of locally recurrent rectal cancer: A cross-sectional population study 15 years after the Dutch TME trial. Eur J Surg Oncol. nov 2019;45(11):2059‑69.

16. Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. févr 2014;15(2):184‑90.

17. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative Versus Postoperative Chemoradiotherapy for Locally Advanced Rectal Cancer: Results of the German CAO/ARO/AIO-94 Randomized Phase III Trial After a Median Follow-Up of 11 Years. J Clin Oncol. 1 juin 2012;30(16):1926‑33.

18. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 19 sept 2006;93(10):1215‑23.

19. Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, et al. Randomized Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of Local Recurrence in Patients With T3 Rectal Cancer: Trans-Tasman Radiation Oncology Group Trial 01.04. J Clin Oncol. 1 nov 2012;30(31):3827‑33.

20. Aschele C, Lonardi S, Cionini L, Pinto C, Cordio SS, Rosati G, et al. Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer. J Clin Oncol. 20 mai 2016;34(15_suppl):3521‑3521.

21. Alzahrani S, Al Doghaither H, Al‑ghafari A, Pushparaj P. 5‑Fluorouracil and capecitabine therapies for the treatment of colorectal cancer (Review). Oncol Rep. 7 août 2023;50(4):175.

22. Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. mai 2021;22(5):702‑15.

23. Alvarez J, Shi Q, Dasari A, Garcia-Aguilar J, Sanoff H, George T, et al. ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer [Internet]. Surgery; 2024 [cité 1 déc 2024]. Disponible sur: http://medrxiv.org/lookup/doi/10.1101/2024.04.25.24306396

24. Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 27 juill 2023;389(4):322‑34.

25. Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, et al. Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial. J Clin Oncol. 1 déc2019;37(34):3223‑33.

26. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 23 juin 2022;386(25):2363‑76.

27. Appelt AL, Pløen J, Harling H, Jensen FS, Jensen LH, Jørgensen JCR, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. août 2015;16(8):919‑27.

28. Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U, Silva E Sousa AH, et al. Operative Versus Nonoperative Treatment for Stage 0 Distal Rectal Cancer Following Chemoradiation Therapy: Long-term Results. Ann Surg. oct 2004;240(4):711‑8.

29. Valk MVD, International Watch and Wait Database Consortium. The International Watch & Wait database (IWWD) for rectal cancer: An update. J Clin Oncol. 1 févr 2017;35(4_suppl):521‑521.

30. Heald R. When Not to Operate. Clin Oncol. févr 2023;35(2):80‑1.

31. Petrelli F, Trevisan F, Cabiddu M, Sgroi G, Bruschieri L, Rausa E, et al. Total Neoadjuvant Therapy in Rectal Cancer: A Systematic Review and Meta-analysis of Treatment Outcomes. Ann Surg. mars 2020;271(3):440‑8.

32. Garcia-Aguilar J, Patil S, Gollub MJ, Kim JK, Yuval JB, Thompson HM, et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J Clin Oncol. 10 août 2022;40(23):2546‑56.

33. Rullier E, Rouanet P, Tuech JJ, Valverde A, Lelong B, Rivoire M, et al. Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial. The Lancet. juill 2017;390(10093):469‑79.

34. Serra-Aracil X, Pericay C, Badia-Closa J, Golda T, Biondo S, Hernández P, et al. Short-term outcomes of chemoradiotherapy and local excision versus total mesorectal excision in T2-T3ab,N0,M0 rectal cancer: a multicentrerandomised, controlled, phase III trial (the TAU-TEM study). Ann Oncol. janv 2023;34(1):78‑90.

35. Baron D, Loscos TP, Schiappa R, Barbet N, Dost E, Ben Dhia S, et al. A phase III randomized trial on the addition of a contact x-ray brachytherapy boost to standard neoadjuvant chemo-radiotherapy for organ preservation in early rectal adenocarcinoma: 5 year results of the OPERA trial. Ann Oncol. nov2024;S0923753424049044.

36. Heinemann V, Stintzing S. Liver transplantation in metastatic colorectal cancer: a new standard of care? The Lancet. sept 2024;404(10458):1078‑9.

37. Kang L, Zeng Z, Luo S, Zhang H, Wang Q, Ren M, et al. Transanal vs laparoscopic total mesorectal excision for rectal cancer: a multicenter randomized phase III clinical trial (TaLaR trial) protocol. Gastroenterol Rep. 16 mars 2021;9(1):71‑6.

Reference Research Centres: St Mark’s Hospital, London, United Kingdom; Centre Antoine Lacassagne, Nice, France