What is the future of CRC treatment?

Atualizado: 4 de mai. de 2023

Colorectal cancer (CRC) is responsible for 1 million deaths a year. Surgical and oncological treatments have evolved a lot through the years, but morbidity and mortality are still significant. Adenocarcinoma is the most frequent subtype of CRC, but squamous cell carcinoma, carcinoid tumor, sarcoma, and lymphoma are also possible subtypes. The incidence is influenced by genetics and environmental factors, being higher in high-income countries (possibly associated with lifestyle). Those countries are also associated with an increasing incidence in younger patients. On the other hand, CRC associated with inflammatory bowel disease (Crohn’s and ulcerative colitis) is decreasing due to the improved treatment of these diseases.

Because CRC symptoms are usually non-specific, diagnosis is often made at advanced stages. Fecal immunochemical tests to identify blood in the stool (there are tests able to confirm the colorectal origin of the blood) are being used to triage symptomatic patients and to reduce the burden of colonoscopy. Although some authors say virtual colonoscopy may indicate surgery without the need for a colonoscopy, visual identification, and biopsy is crucial for treatment planning, I think.

According to Niclas Dohrn et al. from the Department of Surgery of Copenhagen University Hospital (Denmark), surgical resection is still the cornerstone of treatment. About 25% of patients have distant metastasis, but resection of the primary tumor may give a survival advantage, some would say. A CRC staged as ≤T1 can be managed with local excision by endoscopic mucosal resection or submucosal dissection. The authors state that a traditional resection surgery means a complete mesocolic resection following the embryological planes, with central ligation of vessels and lymph nodes, with at least a 10 cm margin from the tumor to the colon section line. In the rectum, the margin is much lower with a minimum of 2 cm distal margin for lower rectal cancer. That is why anterior resection is possible only if a tumor is at least 5 cm away from the anal verge (to preserve at least 3 cm of sphincter).

In fact, rectal cancer should be considered separately from colonic cancer because it is partially extraperitoneal, has differences in metastatic behavior, close relationship with the anal sphincter, and autonomous nerve plexus. The authors say that the principle of total mesorectal excision was introduced by Heald R et al in 1986. However, I remember reading a sentence by Goligher saying that “if a patient was not incontinent after rectal resection, that is because he was not well operated”. This idea is extreme and outdated, but the idea of complete resection of the rectum and surrounding tissues (mesorectum) was already there. Although minimally invasive surgery (laparoscopic and robotic) gives patients and surgeons a lot of advantages, doubts about the oncological outcomes of laparoscopic rectal cancer surgery are still a matter of debate.

Disease control or even curative treatment can be achieved with resection of multiple sites of disease in the presence of metachronous or synchronous metastatic disease, the authors say. Of course, a multidisciplinary approach is mandatory.

I believe the constant improvements in non-surgical treatment are responsible for better outcomes. A watchful waiting strategy is possible after a clinical complete response (cCR) to neoadjuvant therapy in a patient with a strong motivation for organ preservation. Niclas Dohrn et al. say that this strategy (chemoradiation and watchful waiting) can be offered to patients with smaller tumors if a cCR is achieved. I confess I still have some doubts about this topic. Will the recurrence be more aggressive? Will salvage surgery be more debilitating? Should cCR be only used to allow surgeons to perform a safer resection?

Neoadjuvant immunotherapy has demonstrated great results in tumors (locally advanced or metastatic) with a deficient MMR (dMMR) system. Immunotherapy uses the recognition of the cancer by the immune response of the patient. However, cancers with a dMMR are only 15%, decreasing from the right colon to the rectum.

Adjuvant chemotherapy can reduce recurrence and is usually recommended for:

≥ Stage III disease
Stage II patients in case of emergency presentation, T4, anastomotic leakage, lymphovascular and perineural invasion, < 12 nodes, poorly differentiated histology

For metastatic disease, personalized treatments are now included in daily clinical practice (e.g., RAS and BRAF mutation).

New non-surgical treatments can promote organ-preserving strategies (local resections or chemoradiation/immunotherapy). Oncological precision therapy based on the tumor genome can be of great help. According to the authors, immunotherapy, which is already indicated as the first-line treatment in dMMR metastatic CRC, will revolutionize CRC treatment in the near future, as more studies are evaluating its utility in tumors with a normal MMR system.

In sum, the future is coming as new non-surgical oncological treatment options are developed. Apart from the minimally invasive approaches, the surgical technique is basically unchanged.