Evolving concepts in clinical complete response to neoadjuvant therapy for rectal cancer

The Royal Marsden

How do we find the patients with a complete response?

Gina BrownSvetlana Balyasnikova (Royal

Marsden BRC fellow)

The Royal Marsden Hospital, NHS Fountation Trust

1

The Royal Marsden

Funding and support from the NIHR Biomedical Research Centre, Pelican Cancer Foundation and Imperial College London.

The Royal Marsden Hospital, NHS Fountation Trust2

3RD INTERNATIONALCOLORECTAL CANCER SYMPOSIUM

Royal Society of Medicine, London

Wednesday 3rd May 2017

TRIGGER IMPRESSSERENADE MERCURY IIMINSTREL 6 vs 12Beyond TME ctDNADeferral of Surgery SOPRANO

Confirmed SpeakersProf Angelita Habr-Gama, University of Sao Paolo, Brazil

Prof Cathy Eng, MD Anderson, Texas, USA

Prof Iris Nagtegaal, RUMCA, Netherlands

Dr Rodrigo of Sao Paolo, Brazil

Mr Graham Branagan, Salisbury, UK

A chance for collaborators, investigators and their teams to meet and exchange ideas

SESSIONSNew Trials UpdatePrognostic Stratification TrialsCompleted Trials Update

TRIALS

https://colorectalcancersymposium2017.wordpress.com/

Background The Royal Marsden Hospital, NHS Fountation Trust3

• Clinical assessment, including DRE and colonoscopy remains the method of choice for tumour response assessment

• a significant discrepancy between rates of clinical and pathological complete responders has been reported with 8-61% of pCR patients being missed on clinical examination even in the experienced hands

(Hiotis SP et al. J Am Coll Surg. 2002; Smith FM et al. Br J Surg. 2012).

TIMING AFTER CRT? WHEN IS MAXIMUM RESPONSE REACHED?

6 weeksymrT3b

12 weeksymrT2

BaselinemrT4 invading

Bladder and peritoneum Final Pathology: ypT2N0

Patients undergoing surgery with a delay of at least 8 weeks after completion of radiotherapy are 3 times more likely to undergo T downstaging (OR, 3.79; CI: 1.10 –12.99; P<0.03) than patients undergoing surgery at less than 8 weeks. A greater delay to surgery following the completion of pre-operative therapy is associated with an increased likelihood of achieving a pathological complete response. This is being prospectively tested in a randomised trial evaluating the timing of response assessment and surgery (the 6 vs. 12 trial)

Evans J, et al. Timing of surgery following preoperative therapy in rectal cancer: the need for a prospective randomized trial? Dis Colon Rectum 2011;54:1251–9.Published with permission from Wolters Kluwer Health

RMH EXPERIENCE 2003 -2009: SELECTIVE PREOPERATIVE CRT

Analysis– Good response – defined as ypT0-

ypT2 – 218 patients treated between 2003-

2009– 57% of patients had been enrolled

into EXPERT trial – 12 weeks of capecitabine and oxaliplatin neoadjuvant chemotherapy prior to CRT

– 118/218 showed good response – 40%

Criteria for preoperative CRT Tumours within 1 mm of mesorectal

fascia (ie, potential circumferential resection margin involvement)

T3c (extramural spread 5-15 mm) and T3d (extramural spread >15 mm), regardless of N stage

MRI T4a or T4b disease regardless of N stage

Low rectal cancer with tumour bordering the intersphincteric/ distal TME plane on MRI

Tumours with MRI extramural venous invasion (mrEMVI)

Yu SK, et al. Int J Radiat Oncol Biol Phys 2013;87:505–11.

Can imaging help?The Royal Marsden Hospital, NHS Fountation Trust6

• DWI has been proposed as a tool to increase specificity for detecting complete responders, published results suggested that MRI tends to miss a number of complete responders and clinical assessment to be more accurate modality and prevails over imaging in finding complete responders

• (Maas, M., et al.,. Ann Surg Oncol, 2015. 22(12); Smith, J.J., et al. BMC Cancer, 2015);

• A number of other imaging techniques have been suggested for rectal cancer response assessment, these include mrVolumetric analysis and mrRECIST analysis which draw similar conclusions;

POST TREATMENT YMRTN STAGE VS. PATHOLOGY TN STAGE

Overall accuracy for response assessment was 72% PPV for mrT0-2 for good response on pathology was 80% (95% CI 68%-88%) PPV for node negative status on MRI was 84% (95% CI 78%-89%) Overall accuracy for path nodal assessment was 75%


DISEASE FREE SURVIVAL GOOD VS. POOR RESPONDERS: PATHOLOGY AND MRI

ypT0-2

ypT3-4

79%

63%

ymrT0-T2

ymrT3-T4

80%

67%

Despite a lack of 100% agreement between pathology and MRI, assessment of T stage by either MRI or pathology show equal performance in the prediction of survival


HOW ARE THE PATIENTS IDENTIFIED?

mrTRG PET

Clinically - DRE+/- biopsy

ENROLMENTmrTRG1-2 @ 4-6 weeks post CRT no viable disease

– (low signal intensity fibrotic scar tissue only)confirmed by MRI @ 8-12 weeks

mrTRG3 @ 4-6 weeks post CRT a good partial response– Continued incremental response on MRI @ 8-12 weeks

NOT INITIALLY EXCLUDED EVEN IF:DRE – Thickening of rectal wall or clinically palpable tumourEndoscopically – Mucosal abnormalityPathology – Biopsy positive

Clinical trial : Avoiding Surgery in Rectal Cancer After Pre-Operative Therapy, ClinicalTrials.gov Identifier: NCT01047969

ROYAL MARSDEN CRITERIA

MRI defined complete response: mrTRG1-2: low signal intensity fibrotic scar tissue only seen at MRI performed 4 weeks after long-course CRT, confirmed at 8-12 week MRI

– Biopsy positive disease not an initial exclusion criterion– Thickening of rectal wall – not an exclusion– Abnormality on endoscopy – not an exclusion– Clinically palpable tumour – not an exclusion– PET-CT positivity not an initial exclusion– Persistent DWI signal – not an initial exclusion


PATIENTS DEFERRING SURGERYFollow-up schedule

Clinical follow-up 1M, 2M, 3Mly – 1-2 yrs, 6Mly – 3-4 yrs, then annually

MRI 1M, 2M, 3Mly – 1st yr, 6Mly – 2nd yr, annually

PET 2M, 4M, 1 yr

Sigmoidoscopy 3Mly – Yr 1, 6Mly – Yr 2, annually

CT & colonoscopy As per current NICE guidelines


2006 2007 2008 2009 2010 2011 2012 2013 20140

10

20

30

40

50

60

70

PATIENT ACCRUAL

FICARE 2007

Trial Protocol

Proforma reporting

mrTRGdriven


PROFORMA REPORTING

Ref: http://www.slideshare.net/GinaBrown3/reporting-proforma-templates-for-colon-and-rectal-cancer

TRG 2

Good response : dense fibrosis; no obvious residual tumour, signifying microscopic residual disease only and on continued surveillance may become TRG1 no viable tumour

Courtesy of The Royal Marsden Hospital

Magnetic tumor regression gradeidentified 10 times more patients with a pathologicalcomplete response (diagnostic OR = 10.2 (95% CI, 1.30–73.73)) compared with clinical assessment with RMA.17 detected using mrTRG 1-330-40% patients with mrTRG 1-3 than pCR – what would have happened if we had deferred surgery for those….?

How does clinical assessment, DWI, RECIST or mrVolumetry compare against mrTRG


• clinical assessment • additional preoperative imaging techniques (DWI,

mrRECIST or mrVolumetric analyses) • Versus the current RMH practice in finding patients with sustained (for at least 12 month) response

Inclusion criteriaThe Royal Marsden Hospital, NHS Fountation Trust18

• Patients >18 years old with locally advanced rectal adenocarcinoma (T3c-T4 N any, CRM+ M0) treated with neoadjuvant chemoradiotherapy who had a good response (i.e. mrTRG 1-3 on post treatment MRI scan) and were followed up for at least 18 months;

• Baseline and post treatment scans required for each patient;

• DRE, flexi and DWI findings are needed for each patient

Methods and materialsThe Royal Marsden Hospital, NHS Fountation Trust19

• Overall 69 patients with mrTRG1-3 identified

The Royal Marsden

mr RECIST

Reduction of cranio-caudal length >50% was considered as good response


The Royal Marsden

mr Volumetric analysis

Reduction of tumour volume >80% was considered as good response


Patient before CRT


Patient after CRT


Patient before CRT


Patient after CRT


Records of clinical assessmentThe Royal Marsden Hospital, NHS Fountation Trust26

• Digital rectal examination findings were recorded from the deferral of surgery CRFs

• Appearances of macroscopic residual tumour at endoscopy, polypoidal tissue, ulcer with irregular borders, wall thickening, or palpable mass at DRE were considered clinically as non complete responders

ResultsThe Royal Marsden Hospital, NHS Fountation Trust27

A. Number of patients eligible

(rate of regrowth)

B. Number of patients ineligible (rate of regrowth)

A vs B Difference (95% Cl, p value <0.05)

Clinical assessment

(DRE, colonoscopy) 14/69 (21%) 55/69 (27%) 0.06 (-0.1967 - 0.3167,

P= 0.6468)

mr RECIST Reduction of cranio-caudal length > 50%

26/69 (19%%) 43/69 (30%) 0.11 (-0.1032 - 0.3232, p= 0.3119)

mr Volumetric analysis

Volume reduction >

80% 29/69 (20%) 40/69 (30%) 0.1 (-0.1091 - 0.3091,

p= 0.3487)

DWI Hypointense

signal (no tumour)

25/69 (24)% 44/69 (27%) 0.03 (-0.1851 - 0.2451, p= 0.7846)

Clinical and T2+DWI

Meet all of the above

criteria 6/69 (33%) 63/69 (23%) 0 (-0.3938 - 0.3938,

p=1)

mrTRG TRG1 21

Overall – 26% (18/69)

TRG2 37

TRG3 11

• Any of the evaluated methods (clinical examination or additional MR techniques, such as DWI, mrVolumetric or mrRECIST analyses) reduce number of patients who could potentially avoid surgical treatment - with no improvement in specificity.

Results (2-sample z-test to compare sample proportion; Newcombe 10 for unpaired difference)


• No statistically significant difference was found in rates of early regrowth (within the first 12 months after CRT) between mrTRG1-3 group and other groups;

• Combined clinical and T2+DWI assessment did not improve identification of patient with sustained response (for at least 12 months).

RESPONSE METHODS COMPARED

Method Prospectively validated against DFS outcomes

MRI DWI No – many retrospective quantitative cut-offs and qualitative assessments – none prospectively validated

DCE-MRI No – many retrospective values proposed – none validated

PET-CT No – but retrospective SUV cut-offs proposed – unverified prospectively

mrVolume assessment Yes: >80% volume reduction

mrTRG Yes: TRG1-5 validated prospectively and against outcomesmrT and mrN stage Validated prospectively and against outcomes

TRG AND SURVIVAL In independently validated series, mrTRG identifies prognostically distinct groups. mrTRG can distinguish between ‘good’ and ‘poor’ responders to CRT. This shows good interobserver agreement amongst radiologists who can undertake this scoring on high resolution T2 weighted scans Patients with mrTRG 4 & 5 have relatively little response to preoperative therapy. As expected this group has a significantly higher risk of CRM involvement, distant failure and poor OS compared with patients that have mrTRG 1-3. On the other hand, mrTRG1&2 is strongly associated with complete response

p=0.001HR 3.28 (95%CI; 1.22–8.80)

MRI TRG 4-5

Patel UB, et al. J Clin Oncol. 2011;29:3753–3760

MRI assessment

Royal Marsden n=208 patients

Yu et al , ESMO World GI Congress, Barcelona 2015

• Philosophy of avoiding APE surgery if patient has had a good response to treatment

• mrTRG 1-3 - used to identify patients suitable for deferral (many are falsely positive on biopsy, DWI and PET-CT)

• Serial imaging – decision for deferral is not based on a single scan – uses the advantage of high resolution MRI monitoring

• Employing serial MRI monitoring - gives opportunity to delay surgery until there is evidence of tumour regrowth rather than biopsy of tumour cells which are of uncertain viability

MRI reassessment after CRT

MRTRG IS A PROGNOSTIC (AND PREDICTIVE) BIOMARKER

Shows good interobserver radiology agreement and reproducibility

– MERCURY trial (JCO 2011 – multiple radiologists) (1)– EXPERT-C trial (2)– GEMCAD study (17 radiologists) (3)– CORE study (interobserver agreement) (4)

Identified 40% of patients with mrTRG1/2 – 89.8% overall survival Compared with only 8.8% patients with pathologic CR Therefore mrTRG could be justified as a more clinically relevant endpoint

MRTRG AS A RESPONSE BIOMARKER

– mrTRG 1-2 has similar DFS and OS as pCR but seen more frequently than pCR

– Tumours continue to show regression with 75% of patients reaching maximum response at 6months

– mrTRG status at the time of surgery predicts outcome which is independent of baseline tumour stage

– mrTRG 1-2 at end of treatment for advanced T3/T4 is associated with >80% DFS

ROLLING THIS OUT TO OTHER CENTRES VIA THE INTERNATIONAL TRIGGER TRIAL

Eligbility – all patients who are planned to receive CRT for advanced rectal cancerConsented to randomise to control arm of surgery versus mrTRG driven armmrTRG 1-2 – patients offered deferral of surgerymrTRG 3-5- patients offered consolidation chemotherapy and reassessed, if mrTRG1-2 after chemotherapy – offered deferral of surgery

THE TRIGGER TRIAL: MAGNETIC RESONANCE TUMOUR REGRESSION GRADE AS BIOMARKER FOR STRATIFIED MANAGEMENT OF RECTAL CANCER

PATIENTS

Clinical trial: ClinicalTrials.gov Identifier: NCT02704520

MRI REASSESSMENT AFTER CRT

– mrTRG 1-3 - used to identify patients suitable for deferral (many are positive on biopsy, DWI or PET-CT)

– Serial imaging – decision for deferral is not based on a single scan

– Employing serial MRI monitoring = greater rate of recruitment of initially advanced cancers

The Royal Marsden

ConclusionThe Royal Marsden Hospital, NHS Fountation Trust40

• mrTRG 1-3 identifies at least 4 times (than the current standards) more patient eligible for watch and wait approach with no increase of regrowth rates;

• Other MRI techniques, such as DWI, mrVolumetric regression analysis or mrRECIST analysis does not better identification of patients with sustained comlete response

• Combined clinical and imaging (T2+DWI MRI) approach reduces the number of patients who could potentially be followed up more than 80% of eligible patients would have been deprived of entering deferral trial with no improvement in outcomes of early regrowth rates

ACKNOWLEDGEMENTS

Svetlana Balyasnikova, Jemma Bhoday, Uday Patel, Stanley Yu: Research FellowsAngelita Habr Gama, Rodrigo Perez, TRIGGER co-investigatorsDeferral of Surgery Trial.

– RJ Heald, P. Tekkis, D Cunningham, D Tait, A Wotherspoon, G Stamp, I Chau. MERCURY trial investigators, Pelican Cancer FoundationEXPERT-C trial:

– A Dewdney, D. Cunningham, J Tabernero, J Capdevila, B Glimelius, A Cervantes, D Tait, A Wotherspoon, Y Chua, R Wong and I Chau

CORE Trial investigators:– Rutten H, Rullier E, Quirke P,West N, Sebag-Montefiore D, Peeters M, Van Cutsem

E , Ricci S , Van de Velde C, Glynne-Jones R.

Health & Medicine

Evolving concepts in clinical complete response to neoadjuvant therapy for rectal cancer