Rectal cancer: the treatment pathway

By Cristiano Antonino On Mar 4, 2023

Rectal cancers account for about 30% of all new cases of large bowel cancer (23% in women and 32% in men)

In Italy, cancers (carcinomas) of the large intestine are among the most frequent (13% of new cancers diagnosed per year in both sexes); in particular, they rank third in men (after prostate and lung cancer) and second in women (after breast cancer).

It is estimated that there are more than 40,000 new cases of large bowel cancer per year.

Survival at 5 years after diagnosis in Italy is about 65% in men and 66% in women.

Unfortunately, even today overall large bowel cancer is the second leading cause of death from malignancy in both sexes.

Anatomy and physiology of rectal tumours

Tumours of the rectum differ from colon tumours in their anatomical location (last part of the digestive tract upstream of the anal canal), within the pelvis, where they are located in the mesorectal fat below the peritoneal reflection and in contact with the structures of the pelvis (which are bladder, uterus and vagina in women; bladder, prostate and seminal vesicles in men).

The rectum is divided into three portions: the lower rectum, extending from 0 to 5 cm, the middle rectum from 5 to 10 cm and the upper rectum from 10 to 15 cm from the external anal margin measured with a rigid rectoscope.

The vascularisation is peculiar because the haemorrhoidal venous plexus acts as a link between the mesenteric-portal venous circle and the systemic venous circle, allowing any metastases that propagate via the bloodstream to skip the hepatic filter and reach the lung directly: this is why in rectal tumours it is not uncommon to identify lung metastases even without other localisations.

The rectum has a very important anatomical and physiological function as a stool reservoir and ensures faecal continence by means of the rectal sling, which is an anatomical complex formed by the elevator muscles of the anus and the muscles of the pelvis, which allows the voluntary release of faeces. The tumour alters these physiological functions.

Cancer of the rectum, the risk factors

They are similar to those for colon cancer and are represented by:

– excessive consumption of red meat and sausages, refined flours and sugars

– overweight and reduced physical activity

– smoking and excessive alcohol

– Crohn’s disease and ulcerative rectocolitis.

Conversely, protective factors are represented by:

– consumption of fruit and vegetables and unrefined carbohydrates

– vitamin D and calcium

There are hereditary susceptibilities attributable to syndromes in which genetic mutations have been identified, which are:

familial adenomatous polyposis (FAP)
Lynch syndrome,

The symptoms of rectal cancer are generally late and related to the growth of the tumour mass and functional obstruction of defecation.

These symptoms may be:

– rectal bleeding

– blood in the stool (haematochezia)

– ribbon-like stools/difficulty in evacuation

– tenesmus (painful spasm in the anal region/at evacuation)

– sense of incomplete evacuation

– mucus in stools (mucorrhoea)

– in rare and severe cases, low bowel obstruction

Diagnosis of rectal cancer

The diagnosis of rectal cancer is usually made following the onset of symptoms with digital rectal exploration (about 50% are palpable on rectal exploration alone), rectoscopy and biopsy for histological examination; this test must always be followed by a complete colonoscopy to check for further colon cancer.

Standard oncological staging involves rectal echendoscopy, CT scan of the thorax and abdomen with contrast medium (to exclude distant metastases) and MRI of the pelvis with contrast medium to define anatomical relationships (extent of tumour in the pelvis) and lymph node involvement.

Treatment of locally advanced rectal cancer

For localised (non-metastatic) tumours the treatment of choice is surgery (anterior resection of the rectum with complete excision of the mesorectum), which must occur after treatment with medical oncological therapy and radiotherapy.

These therapies (surgery and radiotherapy) may cause some functional sequelae that may persist even after healing.

In selected cases, modern approaches (also within clinical trials) try to avoid demolitive surgical treatment by boosting chemotherapy and radiotherapy to achieve complete clinical remission of the tumour (TNT strategy, Total Neoadjuvant Treatment, followed by close clinical and instrumental follow-up, without surgery, the so-called Non Operative Management or NOM).

Moreover, in cases with molecular features of microsatellite instability, so-called MSI-H or dMMR, treatment with immunotherapy (instead of chemo-radiotherapy) is now possible and has proven to avoid surgery in almost all cases.

In metastatic tumours (stage IV) the therapeutic approach follows the consolidated one for colon tumours in general: for the choice of therapy molecular characterisation of the surgical specimen or biopsy is required in order to assess the mutational status of RAS (KRAS, NRAS), BRAF, MMR (to identify tumours with microsatellite instability, dMRR or MSI-H), and HER2.

The different types of drugs, administered orally and/or intravenously, are selected on the basis of the outcome of the molecular profile and also taking into account the general condition and copathology.

Oncological therapies are administered in ordinary inpatient settings or through periodic Day Hospital/MAC visits, in order to adequately monitor any therapy-related toxicities.

Studies and clinical trials for rectal cancer

At the Niguarda Cancer Center experimental studies are active for the treatment of non-metastatic rectal adenocarcinoma involving the TNT (Total Neoadjuvant Treatment) / NOM (Non Operative Management) approach, without surgery, within the NO-CUT programme for tumours that are candidates for chemo-radiotherapy and the iNOCUT programme with immunotherapy for tumours with dMRR.

In metastatic disease there are studies involving the search for tumour-specific targets to achieve regression/stabilisation of metastases not amenable to surgery. \1

New and more promising approaches include treatment programmes with immunotherapy and next-generation immunotherapeutic drugs, as well as inhibitors of specific tumour proteins or genes (HER2, NTRK, BRAF, KRAS G12C, TP53 Y220C, PIK3CA).

The molecular profile of genetic mutations observed in rectal cancers differs from that of the remaining colon cancers by a higher incidence of molecular targets such as Her2, and a lower incidence of anti-EGFR drug resistance alterations such as BRAF mutations.

The most recent data in the literature report a low incidence of dMRR rectal cancers, i.e. 5-10% of cases, but the active search for this genetic alteration has become increasingly important in the light of new potential treatment options with immunotherapy, and therefore these alterations should be sought in all cases.

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