Multimodal Rectal Cancer Treatment: New challenges

Histology: some variants, such as signet ring and mucinous, are associated with a worse prognosis, and also with a poor response to neoadjuvant treatment. Peritoneal involvement: associated with a decreased overall survival. Molecular markers: any genetic and epigenetic alterations that negatively affect the process of regulation, control of cell proliferation and differentiation, apoptosis, and angiogenesis.

Neoadjuvant chemoradiotherapy (nCRT) + total mesorectal excision (TME) is considered nowadays the standard treatment for locally advanced rectal cancer. Since TME was described by Heald in the 80s, local recurrence has decreased from 30% to 10-5%, but still some advanced tumors had an adverse prognosis. That’s why some therapies like CRT are implemented. When we refer to neoadjuvant therapy (NAT), we’re practically talking about radiotherapy and chemo is administered as a radiosensitizer.

Some countries advocate for classifying rectal tumors in categories (GOOD, BAD and UGLY), according to some characteristics which confer good or bad prognosis. According to this, patients are enrolled into 3 possible treatments: primary surgery, short course RT, long course RT.

Summarizing, neoadjuvant therapy indications are: T4 tumors, N positive or with some adverse prognostic factors:

• Presence of extramural vascular invasion (EMVI)

• Suspicious mesorectal lymph nodes

• Circumferential resection margin <1mm

• Tumor height - Tumor in the anterior quadrant

We deliver neoadjuvant therapy for the following reasons:

• Increasing downstaging

• Increasing the sphincter preserving procedures

• Increasing R0 resections

• Increasing the pathological complete response rate

Increasing the pathological complete response rate:

• Short course radiotherapy, with immediate or delayed surgery

• Long course radiotherapy with conconcurrent chemotherapy

• and Total neoadjuvant treatment with both

There’s currently an ongoing debate regarding the appropriate interval from the end of NAT and surgery that allows to achieve higher rates of pathological complete response (pCR). 8 weeks is considered standard, but interestingly some questions are yet to be answered: Do longer intervals increase the pCR? Is there any difference in DFS, OS or morbidity?

The GRECCAR-6 study demonstrated that waiting for extended intervals does not increase the pathological complete response rate but increases technical difficulties during surgery and is associated with a higher complication rate.

Probst et al on the contrary reflects that the key for obtaining a higher pathological complete response rate is increasing the interval from the end of NAT to surgery, without increasing the complications rate.

It’s important to be aware of two concepts:

• Clinical complete response (cCR): no evidence of tumour when assessed by digital rectal examination (DRE), endoscopy-biopsy and MRI.

• Near Complete Response (nearCR): minor or equivocal findings during clinical examination which cannot be defined as cCR nor clinical bad response.

We have several tools to evaluate the response to NAT:

• Endoscopy with a poor sensitivity of 50% and a negative predictive value of 11%, which can be explained by geographic misses when doing the biopsy.

• Digital rectal exam.

• MRI: has a special role, based on the tumor regression grade.

• PET TC: for the assessment of the metabolic response. Shows an accuracy of 91% which could be increased by a combination with clinical assessment.

• CEA levels.

Endoscopy findings suggesting a pCR:

• Normal mucosa

• Whitening of the mucosa

• Telagiectasia

• Absence of tumor

In reference to the MRI role, TRG referring to a classification of cancer response to preoperative treatment, can predict a prognosis of survival. It depends on what the radiologist sees in the images. It has its equivalent in the pathology report. TRG 1 and 2 are considered good response.

Keon Jang et al in their meta-analysis evaluate the role of TRG. mrTRG1 for detecting pCR: Sensitivity: 32%. Specificity: 93%. They recommend using it as just ONE of the parameters for deciding to perform a less radical excision. Still more studies are needed, but the fact is that mrTRG is q0 times more likely to detect a pCR than proctoscopy/biopsy.

Even though NAT is important for obtaining better oncological outcomes, it’s not harmless. This is demonstrated by the high rates of bowel dysfunction evidenced in patients treated by preoperative chemoRT, with various symptoms ranging from incontinence to anal blood or mucus loss, compared with those patients treated by surgery alone. Also they are more likely to develop some wound complications, hernias or bowel obstruction.

Radical excision of the rectum entails a heavy burden for the patient: 28-40% of associated morbidity, 2% of mortality and also bowel, anorectal and sexual dysfunction.

LARS or Low Anterior Resection Syndrome is defined as a disordered bowel function after rectal resection, leading to a detriment in quality of life. Comprises a bunch of symptoms like clustering of stools or fecal incontinence. Patients should expect some improvement over the first year, particularly in the first 6 months. The greater improvement in bowel function is in the first year and will never return to baseline. It’s worrying that 87% of patients are aware of their survival data, but only 53% were aware of functional alterations. POLARS, or the Pre-Operative Low Anterior Resection Syndrome score take into account 6 items for determining the risk of developing LARS: Age (older patients might have some functional bowel alterations that make them more likely to perceive the symptoms as minor), gender (more likely in women), Type of surgery (frequent in total mesorectal excision), Tumor Height (more in low and ultralow rectal tumors), Stoma (after reconstruction), and preop RADIOTHERAPY. The POLARS could help us to better inform patients and to decide the best treatment option for them.

So, how to avoid morbidity? By selective use of radiation AND/OR increased adoption of nonoperative management and Watch & Wait. Pathological complete response (pCR) is seen in up to 20% after NAT. These patients could benefit from organ sparing management.

There are a lot of studies trying to demonstrate the role of non-operative management in rectal cancer. Habr-Gamma, Garcia-Aguilar, Brown are obtaining great results with this strategy. Reported in the literature, watch and wait could obtain a 6% of local recurrence, 93% of disease free survival, 85% overall survival.

There’s an international W&W database. The most striking result is the 24% local recurrence, knowing that these recurrences are mostly early recurrences (first 2 years), 97% endoluminal recurrences, and 88% of regrowths were treated with salvage surgery. On the other hand they reported 94% 5 year DSS.

The follow up proposal during W&W is:

• 1rs/2nd year: DRE, Proctoscopy, CEA every 1-2 months + MRI/CT every 6 months.

• 3er-5th year: DRE, Proctoscopy, CEA every 6 months + MRI/CT annually.

• And if detection of relapse at any time, you should perform salvage surgery.

The other way to avoid morbidity is the better selection of patients who received NAT. MERCURY and OCCUM are two studies that aim to demonstrate that delivery of Nat could be reduced so that we can reduce organ injury:

• MERCURY: evaluate primary surgery alone in MRI-predicted stage II or less and in MRI “good prognosis” stage III. 33% surgery alone, overall survival: 68%, Disease free survival: 85%, local recurrence: 3%..

• OCCUM: reduce patients receiving NAT to 39.5%, found a Circumferential Resection Margin positive in 2.5% (surgery), 8.6% (NAT). R0: 99.2% (surgery), 96.8% (NAT). 5y-LRR and OS: awaited.

Patients with locally advanced rectal cancer currently have a 30-35% risk of distant metastatic recurrence, which is the most frequent cause of cancer related death in this population. For solving this problem, the concept of TOTAL NEOADJUVANT THERAPY emerged. Consist in deliver chemotherapy as induction or consolidation concomitant with the conventional chemoRT. It has the following advantages:

• Improved delivery of planned therapy

• Increased downstaging

• Earlier introduction of optimal systemic chemotherapy

• Delivery of all chemotherapy preoperatively

• Reduce duration with a diverting ileostomy

Based on two types of local recurrence, pelvic and in the lateral lymph nodes of the pelvis: the first associated with residual tumor cells in the pelvis and the second to lymph drainage. Pelvic recurrence is related to CRM & Histology and LPLN with CEA & swelling. Lateral pelvic lymph node dissection is perform in some Eastern countries like Japan. They demonstrated a 5-year relapse free survival similar in TME alone and TME plus LPLND (73.4% vs. 73.3%), explaining why they perform this procedure systematically. On the other hand it carries the risk of longer operation time and more complications. nCRT is recommended for avoiding pelvic recurrence and LPLND for LPLN recurrence.