Advanced/Metastatic CRC

1. DIAGNOSTIC WORK UP FOR ADVANCED/METASTATIC DISEASE

·   A complete work-up should be carried out to achieve an accurate histological diagnosis of the primary tumor, assess the baseline characteristics of the patient and determine the extent of the disease

        Strong recommendation, High grade evidence (5)

·   Besides a comprehensive physical examination, request blood tests including complete blood count and chemistry profile.

Strong recommendation, High grade evidence (5).

· In addition, serum levels of CEA should be evaluated and monitored during the follow-up period to help evaluate response to treatment.

       Strong recommendation, Low grade evidence (6-8)

·  CT of the thoracic, abdominal and pelvic cavities with i.v. contrast administration is the preferred radiological method for the evaluation of the extent of CRC.

       Strong recommendation, High grade evidence (9,10)

·  .A  Triphasic CT or Dynamic liver MRI is recommended to characterise non-typical liver lesions on CT scans or when liver metastases seem resectable or potentially resectable.

        Strong recommendation, High grade evidence ( 11).

·  FDG-PET/CT scan can be useful, particularly in patients with increased tumour markers without evidence of metastatic disease, or to define the extent of metastatic disease on potentially resectable metastases.

        Conditional recommendation, High grade evidence (8,12).

·  FDG-PET/CT is NOT USEFULL in mucinous and sigent ring differentiation

        Strong recommendation, High grade evidence (8,12).

·   .Testing for KRAS, NRAS exon 2, 3 and 4 and BRAF mutations is recommended in all patients at the time of mCRC diagnosis.

        Strong recommendation, High grade evidence (13-15).

·   RAS testing is mandatory before treatment with antiEGFR monoclonal antibodies and can be carried out on either the primary tumour or other metastatic sites.

        Strong recommendation, High grade evidence  (13-15).

·  BRAF mutation status should be assessed simultaneously with the evaluation of RAS, for prognostic assessment and for the option of treatment with antiEGFR mAbs.

        Strong recommendation, Low grade evidence (16,17).

· Identification of HER2 amplification by IHC or FISH is recommended in RAS-wt patients to detect those who may benefit from HER2 blockade

        Strong recommendation, Low grade evidence (18).

1.  TREATMENT OF POTENTIALLY RESECTABLE ADVANCED AND METASTATIC DISEASE

-  In patients with resectable metastases ,  favorable prognostic criteria and a feasible surgical approach, preoperative / post-operative systemic treatment may not be needed.

Conditional recommendation, low grade evidence (19).

-  In patients with resectable metastases, the use of perioperative oxaliplatin-based chemotherapy is recommended where the prognostic situation is unclear.

Strong recommendation, high grade evidence (20).

-  Anti-EGFR monoclonal antibodies in left-sided RAS-wt patients should be used as conversion therapy, when complete resection is the aim.

Strong recommendation, high grade evidence(21).

-  In patients with right-sided and RAS-mutant disease, FOLFOXIRI-bevacizumab and, to a lesser extent, a cytotoxic doublet-bevacizumab should be considered the best choice depending on patients’ ability to tolerate triplet chemotherapy.

Strong recommendation, high grade evidence (21).

-  Patients unresponsive to first-line chemotherapy should not be denied resection or ablation of metastases since the outcome of resected patients after second-line treatment could be also favorable.

Conditional recommendation, low grade evidence (22).

-  In case of peritoneal metastasis only, complete cytoreductive surgery may be carried out.

Conditional recommendation, high grade evidence (23).

Intent and choice of local treatment

-  Local treatment can be used primarily as a metastasis-directed  treatment to halt local failure , further dissemination, and/or following systemic therapy as a consolidation treatment, to delay or pause further treatment

Conditional recommendation, low grade evidence (24,25).

-  Frequent radiological reevaluations of the potential applicability of surgery or other local treatment techniques should be carried out, generally every 8-12 weeks. 

Strong recommendation, very low grade evidence(26).

Local ablation treatment

- In patients with unresectable CRLMs only, or OMD in the liver, Thermal Ablation can be considered for small metastases.

Conditional  recommendation, low grade evidence (27-29).

-  Thermal Ablation is a valid treatment option for recurrent disease after surgical resection for small CRLMs

Strong recommendation, high grade evidence (30).

-  In patients with lung-only metastases or OMD including lung lesions, thermal ablation may be considered along with resection, according to tumor size, number, location, the extent of lung parenchyma loss, or other comorbidities.

Conditional recommendation, low grade evidence (27-29).

-  SBRT may be considered as a local treatment option

Conditional recommendation, low grade evidence (31).

2.     MANAGEMENT OF ADVANCED AND METASTATIC DISEASE WITHOUT POTENTIAL CONVERSION

First-line therapy

l   Determining the RAS mutational status on a tumour biopsy is mandatory to guide the best treatment decision.

Strong recommendation, high grade evidence (32).

 

l  Delivering a biological therapy in combination with chemotherapy in the first-line setting is recommended, unless contraindicated.

Strong recommendation, high grade evidence (33).

-  First-line treatment will consist of doublet of chemotherapy (FOLFOX, FOLFIRI, CAPOX)  combined with an anti-VEGF or anti-EGFR mAbs unless contraindicated .

Strong recommendation, high grade evidence (34).

-  In RAS-wt and BRAF-wt left-sided tumors, doublet chemotherapy  plus an anti-EGFR mAbs is the preferred option.

Strong recommendation, high grade evidence (34).

- In RAS-wt right-sided tumors, chemotherapy +  bevacizumab is the recommended treatment unless contraindicated ,

Strong  recommendation, high grade evidence (35).

-  Anti-EGFR mAbs should be combined with the doublets FOLFOX or FOLFIRI.

Strong recommendation, high grade evidence (33,36).

-  Bevacizumab should  be combined with single fluoropyrimidines, irinotecan or oxaliplatin-based doublet of ChT (FOLFOX, CAPOX, FOLFIRI) or triplets (FOLOXIRI)

Strong recommendation, high grade evidence (37-39).

-  A triplet with FOLFOXIRI plus bevacizumab could also be an option for selective patients with good PS and without comorbidities

Conditional recommendation, high grade evidence (37-39).

-  Triplets including FOLFOXIRI should not be used in patients >75 years old, with PS2 or in patients with significant comorbidities.

Strong recommendation, very low grade evidence (40).

-  In patients with comorbidities, older age or with metastatic disease not amenable to a curative treatment strategy and no significant disease-related symptoms, monotherapy with a fluoropyrimidine  bevacizumab is recommended

Strong recommendation, high grade evidence (41).

-  In frail or elderly patients unable to tolerate chemotherapy, whose tumours are left-sided and RAS-wt, monotherapy with anti-EGFR mAbs can be considered

Conditional recommendation, very low grade evidence (42).

Maintenance and subsequent therapy

- After first-line therapy with ChT based on oxaliplatin and  bevacizumab, maintenance therapy with a fluoropyrimidine  is recommended in nonprogressive patients after at least 6 months of treatment.

Strong recommendation, high grade evidence (43).

- Reintroduction of an initial successful induction therapy may be done after progressive disease while on maintenance therapy

.Conditional  recommendation, high grade evidence (37).

-  After failure of  first-line oxaliplatin-based therapy, second-line treatment with irinotecan-based or monotherapy is recommended unless contraindicated

Strong recommendation, high grade evidence (44, 45).

-  After failure of  first-line Irinotican-based therapy, second-line treatment with Oxaloplatin-based therapy (FOLFOX or CAPOX)  is recommended unless contraindicated

Strong recommendation, high grade evidence (22).

- In RAS-wt patients not previously treated with an anti- EGFR moAb, treatment with chemotherapy (FOLFIRI or irinotecan) and cetuximab or panitumumab is recommended  for left-sided colon tumours.

Strong recommendation, high grade evidence (46).

-  In patients previously treated with chemotherapy alone, a combination of doublet chemotherapy + bevacizumab or anti EGFR (Left side) is recommended.

Strong recommendation, high grade evidence (46).

-  Bevacizumab can be combined with a fluoropyrimidine doublet with oxaliplatin or irinotecan, depending on the first-line chemotherapy backbone delivered.

Conditional  recommendation, high grade evidence (46).

-  Reintroduction of the initial induction therapy can be considered after second-line therapy, as long as the patient did not progress during the induction course of first-line chemotherapy. Treatment should be based upon previous treatment lines, AEs, and PS.

Conditional recommendation, low grade evidence.

➡️ Follow up and monitoring (47-53)

· History and physical examination and CEA level determination are recommended every 3-6 months for 3 years and every 6-12 months at years 4 and 5 after surgery.

Strong recommendation, high grade evidence.

·  Colonoscopy must be carried out at year 1 and every 3-5 years thereafter, looking for metachronous adenomas and cancers.

Strong recommendation, moderate grade evidence.

·  CT scan of chest , abdomen and pelvis  every 6-12 months for the first 3 years are recommended  in patients who are at higher risk of recurrence according to the TNM classification.

Stroncommendation, high grade evidence.

·   Long-term follow-up, rehabilitation and survivorship care programmes should be implemented, aiming at detection of recurrent or new cancers, assessment and management of late and psychosocial effects and implementation of healocal treatmenth promotion measures.

Strong recommendation, low grade evidence.