ST GALLEN EORTC TREATMENT FOR PRIMARY RECTAL CANCER: RECOMMENDATIONS ON CONTROVERSIAL ISSUE

Parag Roy Senior resident

Lok Nayak Hospital

Staging – MRI based

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situ: intraepithelial or invasion of lamina

propriaT1 Tumor invades submucosaT2 Tumor invades muscularis propriaT3 Tumor invades through the muscularis propria into

pericolorectal tissuesT3a: tumour extends <1 mm beyond muscularis propria T3b: tumour extends 1-5 mm beyond muscularis propria T3c: tumour extends 5-15 mm beyond muscularis propria T3d: tumour extends 15 mm beyond muscularis propria

T4a Tumor penetrates to the surface of the visceral peritoneum

T4b Tumor directly invades or is adherent to other organs or structures

REGIONAL LYMPH NODES (N)

Nx Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in 1 to 3 regional lymph nodesN1a Metastasis in 1 regional lymph nodeN1b Metastasis in 2-3 regional lymph nodesN1c Tumor deposit(s) in the subserosa, mesentery, or non-

peritonealizedpericolic or perirectal tissues without regional nodal metastasis

N2 Metastasis in 4 or more regional lymph nodesN2a Metastasis in 4 to 6 regional lymph nodesN2b Metastasis in 7 or more regional lymph nodes

DISTANT METASTASIS (M)

M0 No distant metastasis

M1 Distant metastasis

M1a Metastasis confined to one organ or site (e.g., liver, lung, ovary, non-regional node).

M1b Metastases in more than one organ/site or the peritoneum.

Aim

■ EORTC Gastrointestinal Cancer Conference 2014 focused on the primary treatment of rectal cancer

■ Main interests were controversial issues which could not be easily answered through study of published evidence and guidelines

■ Treatment strategy for localized rectal cancer is based European Society for Medical Oncology (ESMO) or the National Comprehensive Cancer Network (NCCN)

■ Aim the prevention of recurrent disease with maintained bowel, sexual and genitourinary function.

Cont..

■ Debate is on the ideal modality and sequence of combination treatment for intermediate stages.

■ T3b or less tumours in the upper or middle rectum have low risk of local failure, if the tumor is > 1 mm from the mesorectal fascia (MRF)

■ ESMO guidelines consider primary surgery followed by adjuvant treatment

■ NCCN guidelines favor preoperative chemotherapy or preoperative combined radiochemotherapy and recommend adjuvant

Methods

■ Preparatory panel discussion 8th March 2014 with 27 experts

■ 100 question were proposed■ Of them 42 were retained for the joint discussion.

Pretherapeutic local staging

■ Local imaging of the tumour - MRI (91% of the panelists) or even MRI & EUS (33% of panelists)

■ No role for EUS or computed tomography (CT) scans alone.■ Exceptions are T1 tumours- EUS by 88% of the panelists with 38%

opting for EUS & MRI.■ EUS was preferred - because of its excellent resolution and its superior

definition of the infiltration depth mainly in T1 tumor■ For lymph node involvement’, MRI was also considered to be the best

imaging tool (92% for MRI alone, 8% together with EUS).

Sensitivities and specificities of imaging

Minimum technical requirements for MRI■ 1.5 or 3 Tesla system with phase array coil■ Standard T2 fast-spin echo for initial localization/planning■ High-resolution T2-weighed images: minimal voxel density of 1.1

mm3, e.g. 3-mm sections with in-plane resolution of 0.5-0.8 mm

Scanning protocol: MRI

■ Sagittal T2-weighted fast-spin echo to identify the tumor■ Large field-view axial sections of the whole pelvis■ High-resolution axial images of the tumor and adjacent tissues

(perpendicular to the rectum long axis at the tumor level)■ Lymph node assessment: high-resolution axial imaging of the upper

tumor border up to L5/S1■ Low tumors: high-resolution coronal imaging of levator muscles,

sphincter complex and their relation to the rectal wall

Interpretation and reporting :MRI■ Technique, resolution, quality■ Height of the tumor (from the anal verge)■ Tumor description– Size– Circumferential location– T-stage– Infiltration depth beyond muscularis propria (mm)■ Nodal spread– Location (perirectal, pelvic)– Number– Description (size, signal intensity, irregular border)– Distance from tumor and MRF■ Extramural vascular invasion■ circumferential resection margin status (distance to MRF < 1 mm)

Risk stratification for cancer of the mid rectum■ Low risk ■ Intermediate risk – Low risk– Moderate risk – High risk■ High risk

■ All these are based on MRI and clinical findings

Low risk and High risk Low risk High risk

Low-risk local recurrence/low-risk metastases

High-risk local recurrence/high-risk metastases

MRI cT2/T3a/T3b, <4 mm extension into muscularis propria, CRM not threatened (predicted >2 mm), cN0, CT M0

MRI cTany, extension into muscularis propria, T4b, CRM breached or threatened (predicted <1 mm), CT M0 Possibly Mucinous

No requirement for preop radiotherapyImmediate surgery

Requires RCT

UK NICE Guidelines and Recommendations

Low risk + (but does not include T3b < 4 mm)

Threatened (<1 mm) or breached resection margin or low tumors encroaching onto intersphincteric plane or levator involvemen

Do not give RT RCT recommended

Intermediate riskIntermediate risk

Low-risk local recurrence/ moderate-risk metastases

Moderate-risk of local recurrence/ high-risk

metastases

Moderate-risk of local recurrence/ high-risk

metastasesMRI cT3b, >4 mm extension into muscularis propria, CRM not threatened (predicted >2 mm), cN1, CT M0

MRI cT3b, >4 mm cT3c, cN2, EMVI, CRM not threatened (predicted >2 mm), CT M0

MRI cT3d, T4a (resectable), CRM not threatened (predicted >2 mm), CT M0

If surgeon convinced able to perform R0 resection and good quality in mesorectal plane could omit RT

SCRT depending on whether shrinkage of tumour required or neoadjuvant chemotherapy alone

SCRT or RCT depending on whether shrinkage of tumour required or neoadjuvantchemotherapy alone

UK NICE Guidelines and RecommendationsAny cT3b or greater, in which the potential surgical margin is not threatened or Any suspicious lymph node not threatening the surgical resection margin or The presence of extramural vascular invasion

SCRT or RCT

Clinical risk factors

■ Obesity■ Male/with anterior tumors■ Narrow pelvis■ Previous pelvic surgery■ Large bulky tumor■ Sepsis/fistula/perforation

T3 rectal cancers always need Pre- OP RCT or radiotherapy?■ Preoperative chemoradiation (RCT) or short-course preoperative

radiotherapy (SCRT) are considered standard of care for patients with clinical stage II and III

■ Because surgery alone- increased local recurrence and lower chance of sphincter preservation

■ Benefit of omitting RCT of SCRT– improved wound healing,– less frequent anastomotic leaks– avoidance of long-term radiation toxicity, – smaller risk of secondary malignancies

Cont..

■ For easily resectable cancers of the mid-rectum with no detectable lymph node metastases (cT3 cN0), 71% of panelists did not feel combination therapy

■ RCT the best option for treating easily resectable rectal cancer of the mid-rectum with lymph node metastases (cT3 cN+ ).

■ SCRT is also an alternative in T3N+ (75% panelist says)■ But in low rectal T3N0 needs RCT or SCRT (by 66% panelist)■ ‘easily resectable’ defined as tumours with less than 5 mm infiltration depth

into the mesorectal fat and at least 1 mm distance from the mesorectal fascia■ Upper third cancer not discussed as treated by analogy of colon cancer

When RCT modality of choice

■ Clinically unresectable disease to downstage disease■ Clinical stages suggests cN+■ MRI shows threatened or breached Circumferential Resection Margin■ Cancer which requires surgical resection beyond conventional TME

■ Dutch TME trial and MRC CR07 trail showed reduction of LR using SCRT without improving OS ( no use of modern MRI technique)

■ low rates of local recurrence for patients with pathological findings of a clear CRM > 3 mm and pN0

SCRT vs RCT

Adjuvant chemotherapy

■ Cancer-related deaths due to distant metastasis■ ACT reduces the incidence of distant relapse and improves overall

survival.■ Most panelists (83%) recommended against ACT for cN0/ypN0 tumors■ cN+ /ypN0 the panelists opinion on ACT was divided (pro 41%, con

59%)■ Histologically confirmed positive lymph nodes after neoadjuvant RCT

(ypN+ ), the majority of panelists (77%) voted in favour of ACT.

Adjuvant Chemotherapy

Rectal cancer with synchronous liver metastases■ Incidence of synchronous liver metastases in patients with primary

rectal cancer is approximately 15%■ Goal is complete resection of all primary and metastatic lesions■ Divided into initially resectable and potentially resectable disease

after conversion therapy■ Not to start classical 5FU based Chemoradiotherapy■ Preoperative short-course radiotherapy with systemic combination

chemotherapy or alternatively a liver-first resection approach in resectable metastases,

EORTC 22921- Long term results

Cont..

■ Pre-op. RT, pre-op. CRT, preoperative RT and post-op. chemotherapy, or pre-op. CRT and post-op. chemotherapy in 1,011 cT3 or cT4 resectable rectal cancer

■ In 2006 (NEJM) the result showed chemotherapy confers a significant benefit in local control, regardless of whether it is administered before or after surgery

■ In Lancet oncol- 10-year overall survival was 49·4% for the preoperative RT group and 50·7% for the preoperative CTRT group (p=0·91).

■ 10-year overall survival was 51·8% for the adjuvant CT group and 48·4% for the surveillance group (p=0·32)

■ Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival.

■ This trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy.

Adjuvant Chemotherapy

Cont..

■ Data taken from 1196 patients with (y) pTNM stage II or III disease, who had an R0 resection

■ No significant differences in OS between who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0·97, 95% CI 0·81–1·17; p=0·775)

■ Overall, adjuvant chemotherapy did not significantly improve DFS. (HR 0·91, 95% CI 0·77–1·07; p=0·230) or distant recurrences (0·94, 0·78–1·14; p=0·523) compared with observation.

■ Thus adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences.

Conclusion from St Gallen

■ Panel recommended MRI or MRI + EUS as mandatory staging modalities, except for early T1 cancers with an option for local excision

■ Primary surgery with total mesorectal excision was recommended for early tumours with limited risk of recurrence (i.e. cT1-2 or cT3a N0 with clear mesorectal fascia and above the levator muscles), whereas all other stages were considered for multimodal treatment

■ Recommendation of long-course RCT over short-course radiotherapy for most clinical situations where neoadjuvant treatment is indicated, with the exception of T3a/b N0 tumours where short-course radiotherapy or even no neoadjuvant therapy were regarded to be an option

■ In resectable tumours and synchronous liver metastases, no indication to start with classical fluoropyrimidine-based RCT but start preoperative short-course radiotherapy with combination chemotherapy or alternatively a liver-first resection approach in resectable metastases

Thank you

Neoadjuvant long-course RCT versus SCRT■ decrease the risk of locoregional relapse and to downsize/downstage

tumors that threaten the mesorectal fascia or to facilitate sphincter preservation.

■ Dutch and the MRC trials show a significant decrease of LR in node positive

■ CR07 trial has also shown that pelvic recurrence rates were 20% for poor grade TME compared with only 6% for good-quality CRM-negative TME node-positive

■ neoadjuvant approach seems indicated in node-positive disease if the quality of the TME surgery is in doubt and preoperative assessment of the MRI-validated prognostic factors linked to local recurrence