2021 Master Class Virtual Series AN UPDATE ON COLORECTAL ...

1

2021 Master Class Virtual SeriesAN UPDATE ON COLORECTAL CANCERRobert J. Mayer, MDFaculty Vice President for Academic AffairsDana-Farber Cancer Institute

Stephen B. Kay Family Professor of MedicineHarvard Medical School

2

Faculty Disclosure

• None

Faculty of this CE activity may include discussions of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off label or investigational uses (any uses not approved by the FDA) of products or devices.

3

PROGRESS

4CA Cancer J Clin 2020;70:7-30

6

INCREASING APPEARANCE OF COLORECTAL CANCER (CRC) IN INDIVIDUALS UNDER AGE 50

• since 1994, incidence of CRC in individuals < age 50 has been increasing by 2% each year

• increase not appreciated until about 10 years ago• unrelated to a family history or the presence of a

genetic syndrome

7

INCREASING APPEARANCE OF COLORECTAL CANCER (CRC) IN INDIVIDUALS UNDER AGE 50

• clinically similar in location and presenting symptoms to CRC’s found in older people− i.e. no unique molecular biomarkers in tumors from younger

patients• likely related to lifestyle changes (diet, obesity, etc.)

− possibly involving a carcinogenic effect of bowel bacteria (microflora/microbiome)

• implications− begin screening at an earlier age− conduct additional research

9

PROGNOSTIC POTENTIAL OF CIRCULATING TUMOR DNA (ctDNA) MEASUREMENT IN POST-OPERATIVE SURVEILLANCE OF NON-

METASTATIC COLORECTAL CANCERPreliminary Data

• Denmark (130 patient)− negative prognostic significance of detectable ctDNA

at post-operative day 30 and at completion of adjuvant therapy Reinert, et. al. JAMA Oncol 2019;5:1124-1131

• Johns Hopkins (58 Swedish patients)− positive ctDNA levels 77% recurrence rate (10/13)− negative ctDNA levels 0% recurrence rate (0/45)

Wang, et. al. JAMA Oncol 2019;5:1118-1123

10

ADVANCED DISEASE

11

WHICH IS BETTER IN ADVANCED COLON CANCER?

5-FU/LEUCOVORIN COMBINED WITH:

OXALIPLATINOR

IRINOTECAN

12

CHEMOTHERAPY REGIMENS FOR METASTATIC COLORECTAL CANCER

response rate

median survival

FOLFOX5-FU/leucovorin/oxaliplatin 50% 16 months

FOLFIRI5-FU/leucovorin/irinotecan 40-50% 17 months

13

HR for PFS

Author Study HR (95% CI) Weight, % YearGiantonio E3200 0.61 (0.51-0.73) 22.4 2007Hurwitz AVF2107 0.66 (0.57-0.75) 24.8 2004Kabbinavar Phase II 0.45 (0.28-0.72) 8.9 2003Kabbinavar AVF2192 0.61 (0.48-0.78) 18.1 2005Saltz NO16966 0.83 (0.74-0.94) 25.8 2008

Overall 0.66 (0.56-0.77) 100.0

HR for OSAuthor Study HR (95% CI) Weight, % YearGiantonio E3200 0.75 (0.63-0.89) 28.1 2007Hurwitz AVF2107 0.66 (0.54-0.80) 25.1 2004Kabbinavar AVF2192 0.79 (0.56-1.11) 13.1 2005Saltz NO16966 0.89 (0.78-1.02) 33.7 2008Overall 0.77 (0.67-0.89) 100.0

Cao, et. al. Int J Colorectal Dis. 2009;24:677-685

A META-ANALYSIS COMPARING CHEMOTHERAPY + BEVACIZUMABWITH CHEMOTHERAPY ALONE IN MCRC: HR FOR PFS AND OS

14

VALUE OF FOLFOXIRI/BEVACIZUMAB IN METASTATIC COLORECTAL CANCER

• combing 5-fluorouracil/leucovorin/irinotecan/oxaliplatin• randomized trials

• meta-analysis (J Clin Oncol 2020;38:3314)− prolonged survival but enhanced toxicity− no increased benefit in b-raf mutant tumors

“TRIBE” “OLIVIA”FOLFOXIRI/bevacizumab FOLFOXIRI/bevacizumab

FOLFIRI/bevacizumab FOLFOX/bevacizumab

NEJM 2014;371:1609Lancet Oncol 2015;16:1306

Ann Oncol 2015;26:702

15Cremolini C, et. al.; J Clin Oncol 2020 383314-3324

16

proliferationangiogenesis

cell survival

metastatic spread

EGFr activation tumor

tumor

bloodvessel

bloodvessel

spread of cancer cellsEGF TGF-a

THE ROLE OF EGFr IN TUMOR GROWTH AND CANCER

17

CRYSTAL TRIAL: STUDY DESIGN

FOLFIRI

irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus +

2400 mg/m2 as 46-hr continuous infusion)

+ FA every 2 weeks

Cetuximab + FOLFIRI

Cetuximab IV 400 mg/m2 on day 1,then 250 mg/m2 weekly

+ irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus +

2400 mg/m2 as 46-hr continuous infusion)

+ FA every 2 weeks

REGFR-expressing

Metastatic CRC

Van Cutsem E, et. al. J Clin Oncol 2007;25(18S):4000

Stratification factors: • Regions• ECOG PS

Populations• Randomized patients: n = 1217• Safety population: n = 1202• ITT population: n = 1198

18Van Cutsem E, et. al. N Engl J Med 2009;360(14):1408-1417

P = 0.048

19

CRYSTAL STUDYFOLFIRI-CETUXIMAB VS. FOLFIRI

Progression Free Survival

p value hazard function

all patients + 0.048 0.85

k-ras codon 12/13 wild typeº 0.0012 0.70

ras wild type * 0.0002 0.56

+Van Cutsem E, et. al. N Engl J Med 2009;360(14):1408-1417ºVan Cutsem E, et al. J Clin Oncol 2011;29:2011-9*Van Cutsem E, et. al. J Clin Oncol 2015;33:692-700

20

IN PATIENTS WITH UNTREATED K-RAS WILD-TYPE METASTATIC COLORECTAL CANCER:

Is chemotherapy with a VEGF inhibitor better, equivalent, or inferior to chemotherapy with an EGFR inhibitor?

21Venook, et. al. JAMA 2017;317:2392-2401

22

80405: Overall Survival by Sidedness

23

80405: OS by Sidedness (Cetuximab)<br />

24

RIGHT VERSUS LEFT COLON CANCER

J Natl Compr Canc Netw 2017;15:411-419

LEFT-SIDED CRC• superior outcomes

with cetuximab• better prognosis

• tubular adenoma• CMS2 and CMS4• higher EREGIAREG

expression• hindgut

RIGHT-SIDED CRC• inferior outcomes

with cetuximab• poorer prognosis

• sessile serrated polyps

• CMS1 and CMS3• CIMP-high• midgut• BRAF mutant• MSI-high• bile acid exposure• invasive bacteria

biofilms

25

QUESTION 1Which one of the following is true in regards to a potentially resectable mismatch repair deficient colorectal cancer in a 62-year-old man?

1. there is a greater than 50% probability that the patient has Lynch Syndrome.

2. if the patient were found to have metastatic disease at the time of surgery, he would more likely benefit from FOLFIRI than from FOLFOX.

3. the presence of mismatch repair deficiency eliminates the possibility of the tumor also having a b-raf mutation.

4. if the patient were found to have stage III disease at the time of surgery, clinical trial data have shown the use of adjuvant checkpoint immunotherapy to prolong disease free survival.

5. it is more likely that the patient has stage II than stage III disease.

26

TREATMENT OF MICROSATELITE-HIGH MISMATCH REPAIR DEFICIENT METASTATIC

COLORECTAL CANCER

• more favorable natural history• less responsive to conventional

5-fluorouracil-based chemotherapy

27

PD-1 BLOCKADE FOR MISMATCH REPAIR (MMR)-DEFICIENT COLORECTAL CANCER (CRC)

• rationale− MMR deficient tumors demonstrate lymphocytic infiltration and

express immune checkpoint ligands− anecdotal “exceptional” responses have been observed when a

PD-1 inhibitor has been given to patients with MMR deficient CRC• phase II study in metastatic CRC (Le, et. al. N Engl J Med

2015;372:2509)− 11 patients with MMR deficient and 21 patients with MMR proficient

CRC were treated with pembrolizumab− update (ASCO 2016) – 28 patients with MMR deficiency and 25

patients with MMR proficiency

28

Slide 18

Presented By Dung Le at 2016 ASCO Annual Meeting

29

PEMBROLIZUMAB VERSUS CHEMOTHERAPY AS INITIAL TREATMENT FOR MICROSATELLITE-HIGH, MISMATCH REPAIR

DEFICIENT METASTATIC COLORECTAL CANCER

progression-free survivalrecurrence-free

# pts % events 12 months 24 monthspembrolizumab 183 54% 55% 48%

H.R. 0.060p=0.0002

conventional chemotherapy 184 73% 37% 19%

André T, et. al. N Engl J Med 2020;383:2207-2218

30

Progression-Free Survival


31

Duration of Response


32

B-RAF MUTATED METASTATIC COLORECTAL CANCER

• present in about 10% of patients• occurs more often in right sided tumors• seemingly the same V600E mutation as

in melanoma• associated with a poorer prognosis and

a shorter duration of response to chemotherapy

33


Van Cutsem, et. al. J Clin Oncol 2011;29:2011-2019

34


• in contrast to clinical experience in melanoma, the V600E B-RAF inhibitor vemurafenib is ineffective as a single agent in B-RAF mutated metastatic colorectal cancer

• laboratory models suggested synergy between vemurafenib and cetuximab in B-RAF mutated metastatic colorectal cancer, leading to a SWOG randomized phase II trial primary objective – progression-free survival

35

BEACON COLORECTAL CANCER STUDY:PHASE III TRIAL COMPARING DIFFERENT TREATMENTS AS SECOND LINE THERAPY IN

PATIENTS WITH METASTATIC B-RAF V610 MUTATED COLORECTAL CANCER

# ptsmedian overall

survival

confirmed objective response

rateencoraferib

(B-RAF inhibitor)+

binimetinib(MEK inhibitor)

+cetuximab

224 9.0 mos 26%

encorafenib+

cetuximab220 8.4 mos 22%

irinotecan (or FOLFIRI)+

cetuximab221 5.4 mos 2%

Kopetz S, et. al. N Engl J Med 2019;381:1632-1643

36Tabernero J, et. al. J Clin Oncol 2021;39:273-284

37

ADJUVANT THERAPY

38

STAGE II COLON CANCER

Benson AB 3rd, et. al. J Clin Oncol. 2004;22(16):3408-3419

• is adjuvant chemotherapy beneficial?• recent recommendations – “standard risk”

patients− NCCN – “adjuvant chemotherapy is not

recommended (JNCCN 2003;1 (suppl 3):S-9)− ASCO “the routine use of adjuvant

chemotherapy…is not recommended” (JCO 2004;22:3408)

39

PROBABILITY OF SURVIVAL FOR 648 T3N0M0PATIENTS PARTICIPATING IN INTERGROUP 0089

Le Voyer, TE et. al. J Clin Oncol 2003;21(15):2912-2919

40

VALUE OF TUMOR GENE EXPRESSION PROFILES IN STAGE II COLON CANCER

• provides unique PROGNOSTIC information independent of other factors

BUT

• has NOT yet been shown to offer any PREDICTIVEinformation so as to guide treatment decisions

Gray, et. al. J Clin Oncol 2011;29:4611-4619Kennedy, et. al. J Clin Oncol 2011;29:4620-4626O’Connell, et. al. J Clin Oncol 2010;28:3957-3946

Salazar, et. al. J Clin Oncol 2011;29:17-24Venook, et. al. J Clin Oncol 2013;31:1775-1781Yothers, et. al. J Clin Oncol 2013;31:4512-4519

41

ASSESSMENT OF MICROSATELLITE INSTABILITY (MSI) AS A PREDICTIVE BIOMARKER FOR 5-FU BASED ADJUVANT

CHEMOTHERAPY IN COLON CANCERDesign• DNA was extracted for microsatellite analysis from

tumor tissue from 1027/1952 patients with stages II or III colon cancer who had participated in one of five

randomized comparisons of 5-FU vs observation• MSI-H was found in 16.6% (165/1027) of all specimens

- stage II 19.2% (102/530)- stage III12.7% (63/497)

Sargent, et. al. J Clin Oncol 2010;28:3219Ribic, et. al. N Engl J Med 2003;349:247

42Sargent, et. al., J Clin Oncol 2010; 28: 3219-3226

p = 0.09 p = 0.98

p = 0.38p = 0.001

MSI-H MSI-H

MMSMMS

STAGE IIISTAGE II

43

ASSESSMENT OF MICROSATELLITE INSTABILITY (MSI) AS A PREDICTIVE BIOMARKER FOR 5-FU BASED ADJUVANT

CHEMOTHERAPY IN COLON CANCER

Interpretation• the value of adding irinotecan or oxaliplatin in the

treatment of MSI-H patients – particularly with stage III disease – is presently unknown

• testing for MSI status (either by molecular or immunohistochemical means) should be considered in all patients with stage II and – most likely - stage III disease

Sargent, et. al. J Clin Oncol 2010;28:3219Ribic, et. al. N Engl J Med 2003;349:247

44

ASSESSMENT OF TUMOR TISSUE FOR MISMATCH REPAIR/MICROSATELLITE STATUS

• techniques• mismatch repair

• immunohistochemical staining of tumor cell nuclei for MLH1, MSH2, MSH6, and PMS2 proteins

• methylation of the MLH1 promotor is the most common cause of sporadic MLH1 protein loss in colorectal adenocarcinoma

• inexpensive; available in standard hospital pathology departments

• microsatellite instability• polymerase chain reaction assay on DNA extracted from tumor

tissue• requires a molecular pathology laboratory

45

COLON CANCER

ACCENT* NSABP PETACC/SAKK+

Source # pts % MSI # pts % MSI # pts % MSI

all patients 1027 16.6% 1589 13.0% 1217 15.1%

stage II 530 19.2% 420 18.1% 398 21.4%

stage III 497 12.7% 1169 9.8% 829 11.9%

* Sargent DJ, et. al. J Clin Oncol 2010;28:3219-3226 Gavin PG, et. al. Clin Cancer Res 2012;18:6531-6541+ Roth AD, et. al. J Clin Oncol 2010;28:466-474

PROBABILITY OF MICROSATELLITE INSTABILITY BY SURGICAL STAGE

46

“MOSAIC” TRIALStratify

• T2 vs T3 vs T4

• N0 vs N1 vs N2

• bowel obstruction or perforation

• center

FOLFOX

5-FU/leucovorin

de Gramont A, et. al. J Clin Oncol. 2007;25(18S):4007

47André T, et. al. N Engl J Med 2004:350:2343-2351

INITIAL RESULTS – 38 MONTH MEDIAN F/U

48André T, et. al. J Clin Oncol 2015;33:4176-4187

OVERALL SURVIVAL: ALL PATIENTSMEDIAN F/U 9.5 YEARS

49

STAGE III – N2

André T, et. al. J Clin Oncol 2015;33:4176-4187

50

Probability of Overall Survival after 10 years

FOLFOX 5-FU/leucovorin difference

all patients 71.7% p=.043 67.1% 4.6%

stage II - all 78.4% p=.980 79.5% -1.1%

stage III- all 67.1% p=.016 59.0% 8.1%

- N1 71.4% p=.248 65.4% 6.0%

- N2 59.5% p=.013 46.6% 12.9%

MOSAIC STUDYOVERALL SURVIVAL DATA AFTER

A MEDIAN FOLLOW-UP OF 9.5 YEARS

André, et. al. J Clin Oncol 2015;33:4176-4187

51Salem ME, et. al. Ann Oncol 2020;31:480-486

ACCENT DATABASE:Pooled Analysis of 6501 Patients with Stage III Cancer Treated with Fluorouracil, Leucovorin, and

Oxaliplatin between 1996 - 2003 and 2004 - 2009

52Salem ME, et. al. Ann Oncol 2020;31:480-486

ACCENT DATABASE:Pooled Analysis of 6501 Patients with Stage III Cancer Treated with Fluorouracil, Leucovorin, and

Oxaliplatin between 1996 - 2003 and 2004 - 2009

53

ADJUVANT THERAPIES EXAMINED INSTAGE III DISEASE THAT DO NOT WORK

• irinotecan• 3 negative trials

• bevacizumab• NSABP C08• AVANT (? worse outcome with bevacizumab)

• cetuximab• NCCTG N0147

54

ARE THREE MONTHS OF ADJUVANT CHEMOTHERAPY EQUIVALENT TO SIX MONTHS OF THE SAME

CHEMOTHERAPY IN PATIENTS WITH STAGE III DISEASE?

• addressed by the IDEA (International Duration evaluation of Adjuvant Chemotherapy) collaboration− pooled data analysis of six independent clinical

trials involving 12,834 patients from 12 countries• objective – to evaluate the non-inferiority of three

months compared to six months of adjuvant oxaliplatin-based treatment with a goal of reducing neurotoxicity without diminishing anti-tumor efficacy

Grothey A, et. al. N Eng J Med 2018;378:1177-1188

55

OXALIPLATINIssues• peripheral neuropathy• hypersensitivity reactions

− increase in frequency after sixth exposure to drug− may be overcome by desensitization techniques

• hepatic sinusoidal injury (nodular regenerative hyperplasia)− can lead to portal hypertension splenomegaly

and varices splenic sequestration of platelets (thrombocytopenia)

56

STUDY SCHEMA

Stage III Colon

Cancer Patients R

3 months

6 months

Investigator’s choiceFOLFOX or CAPOX

Total planned accrual ≥ 10,500

1:1

FOLFOX: 5FU/LV + Oxaliplatin CAPOX: Capecitabine + Oxaliplatin

Grothey, et. al. N Engl J Med 2018;378:1177-1188

57

0 1 2 3 4 5 6

Years from Randomization

0

10

20

30

40

50

60

70

80

90

100

6 Months3 Months

Duration

0 1 2 3 4 5 6


0

10

20

30

40

50

60

70

80

90

100Pe

rcen

t With

out E

vent

6 Months3 Months

Duration

6424 5446 4464 3000 1609 826 3216410 5530 4477 3065 1679 873 334

PRIMARY DFS ANALYSIS (MITT)

Duration 3-yr DFS

3m 74.6 %

6m 75.5 %

3-yr DFS diff. = -0.9%, 95% CI, (-2.4 to 0.6%)

N PatientsAt risk

DFS HR = 1.0795% CI, 1.00 to 1.15


58

0 1 2 3 4 5 6


0

10

20

30

40

50

60

70

80

90

100

Perc

ent W

ithou

t Eve

nt

6 Months3 MonthsDuration

0 1 2 3 4 5 6


0

10

20

30

40

50

60

70

80

90

100

Perc

ent W

ithou

t Eve

nt


2634 2099 1640 1044 531 292 1072622 2151 1655 1094 586 301 110

0 1 2 3 4 5 6


0

10

20

30

40

50

60

70

80

90

100

Perc

ent W

ithou

t Eve

nt


0 1 2 3 4 5 6


0

10

20

30

40

50

60

70

80

90

100

Perc

ent W

ithou

t Eve

nt


3744 3313 2796 1934 1064 527 2113727 3336 2788 1949 1081 566 221

DFS COMPARISON BY RISK GROUPS

Duration 3-yr DFS

3m 83.1 %

6m 83.3 %

3-yr DFS diff. = -0.2% 95% CI, (-1.9 to 1.5%)

Duration 3-yr DFS

3m 62.7 %

6m 64.4 %

3-yr DFS diff. = -1.7% 95% CI, (-4.3 to 0.9%)

T1-3 N1 (58.7%) T4 or N2 (41.3%)

Interaction p-value = 0.11

N PatientsAt risk


59

INTERPRETATION OF THE IDEA COLLABORATION DATA

• there is consensus that high risk stage III patients (T4 and/or N2) should continue to receive six months of oxaliplatin-based adjuvant therapy

• for lower risk stage III patients (T1-3, N1)• subset analyses suggest non-inferiority for CAPOX but not

FOLFOX; should such patients receive three months of CAPOX?

• could one consider three months of FOLFOX followed by three months of FU/leucovorin?

• with the addition of oxaliplatin to FU/leucovorin in the MOSAIC trial not resulting in a statistically significant survival benefit in such patients, would six months of FU/leucovorin be sufficient?

60

RECTAL CANCER

61

ADJUVANT THERAPY FOR RECTAL CANCER

Baseline Principles• following complete surgical resection,

approximately 25% of patients experience a local recurrence

• the probability of local recurrence is reduced if preoperative or postoperative radiation therapy is administered; the effect of such treatment in overall survival appears marginal

62

SUMMARY RANDOMIZED TRIALS OF POSTOPERATIVE ADJUVANT THERAPY FOR RECTAL CANCER

source # patients

5 year overall survival

surgery radiation therapy

chemotherapy chemoradiation therapy

GITSG (1985) 227 44% 52% 50% 59%

NSABP (1988) 555 43% 41% 53% -

MRC (1996) 469 46% 52% - -

NSABP (2000) 694 - - 64% 66%

NCCTG (1991) 240 - 48% - 57%

GITSG (1992) 210 - - - 70%*

Intergroup (1994) 660 - - - 65%*

Intergroup (1997) 1695 - - - 64%

* four-year data

63

ADJUVANT THERAPY FOR RECTAL CANCER

Advantages of Preoperative Chemoradiation• preoperative “downstaging”• greater chance for curative sphincter-sparing

surgery• better chemotherapy distribution into the tumor

bed before anatomic disruption by surgery• less potential for toxicity to the small bowel

64

GERMAN RECTAL CANCER STUDY – ASTRO 2003Pre-op Post-op P

# patients 405 392

% local recurrence 7% 11% 0.02

% distant metastases 30% 34% 0.52

disease-free survival 59% 55% 0.23

overall survival 78% 73% 0.38

% sphincter preservation* 39% 19% 0.004

acute G3-4 toxicity 28.8% 31.7% NS

chronic anastomotic stenosis 2.7% 8.5% 0.001

post-op morbidity - - NS

pCR 8% N/A* measured for patients who were thought to require an APR at the time of enrollment into the study

Sauer, et. al. Int J Rad Oncol Biol Phys. 2009;57 (supple), 5124 (abstract #2)

66

TOTAL MESORECTAL EXCISION (TME) +/- PREOPERATIVE RADIATION THERAPY FOR RESECTABLE RECTAL CANCER

% recurrence

# pts local distant overall % survival

2500 cGy→TME 873 2.4% 14.8% 16.1% 82%

p=<0.001 p=0.87 p=0.09 p=0.84

TME 875 8.2% 16.8% 20.9% 81.8%

median f/u: 24.9 months

Kapiteijn, et. al. NEJM 2001:345;638

67

ONGOING ISSUES IN THE MULTIMODALITY MANAGEMENT OF RECTAL CANCER

• substitution of capecitabine for continuous infusional 5-FU− validated (NSABP RO-4)

• addition of oxaliplatin into preoperative chemoradiation regimens− refuted (NSABP RO-4 plus multiple European

studies)• the role of postoperative adjuvant chemotherapy

after preoperative chemoradiation treatment

68

RECTAL CANCERDURATION OF ADJUVANT THERAPY:

THE SAME SIX MONTHS WITH EITHER APPROACHPreoperative

chemo RT surgery adjuvant chemo(2 months) (4 months)

Postoperative

surgery chemo RT adjuvant chemo(2 months) (4 months)

69

ONGOING ISSUES IN THE MULTI MODALITY MANAGEMENT OF RECTAL CANCER

• is oxaliplatin required as part of post-operative/chemo RT adjuvant prognosis?

• is adjuvant therapy still mandated if chemo RT leads to a complete clinical or pathologic response?

• is surgery still mandated if chemo RT leads to a complete clinical response?

70

WHICH ONE OF THE FOLLOWING IS CORRECT IN REGARDS TO “TOTAL NEOADJUVANT THERAPY” (DELIVERY OF CHEMORADIATION AND CHEMOTHERAPY PRIOR TO SURGERY) IN THE TREATMENT OF RECTAL CANCER?1. preoperative FOLFOX followed by chemoradiation therapy is more effective in

prolonging 3-year disease-free survival than is preoperative chemoradiation therapy followed by FOLFOX

2. the addition of induction FOLFIRINOX prior to neoadjuvant radiation therapy (5040 cGy) + capecitabine has been shown to prolong overall survival when compared to similar preoperative radiation therapy/capecitabine alone

3. the use of preoperative short course/high fraction radiation therapy followed by 9 courses of preoperative FOLFOX has been shown to eliminate the need for postoperative (i.e. adjuvant) chemotherapy

4. preoperative short course/high fraction radiation therapy has been shown to be equivalent to neoadjuvant 5040 cGy radiation therapy plus capecitabine in reducing the local recurrence rate

5. none of the above

71

ONGOING ISSUES IN THE MULTIMODALITY MANAGEMENT OF RECTAL CANCER

• eliminating routine preoperative radiation therapy in patients who respond to neoadjuvant chemotherapy

• ongoing PROSPECT trial

72

TOTAL NEOADJUVANT THERAPY (“TNT”) FOR LOCALLY ADVANCED RECTAL CANCER

• definition – concentrating the timing of perioperative chemotherapy, radiation therapy, and chemoradiation therapy into the preoperative (“neo-adjuvant”) position

• goals− reduce the appearance of distant metastatic disease− increase the likelihood of pathologic complete

response− ultimately, improve overall survival

73

RAPIDO STUDYRectal Cancer And Preoperative Induction Therapy Followed by

Dedicated Operation

chemo RT surgery (TME)optional

chemotherapy

standard

5040 cGy RT+

capecitabine(5.5 weeks)

CAPOX x 8or

FOLFOX x 12(24 weeks)

newly diagnosed localized rectal cancer

- clinically high risk (T4N2); ECOG 0-1

radiation therapy chemotherapy surgery (TME)

experimental2500 cGy CAPOX x 6

orFOLFOX x 9

median f/u: 4.6 years

Bahadoer, RR, et. al. Lancet Oncology 2021;22:29-42

74Bahadoer RR, et. al. Lancet Oncology 2021;22:29-42

CUMULATIVE PROBABILITY OF DISEASE-RELATED TREATMENT FAILURE

75Bahadoer RR, et. al. Lancet Oncology 2021;22:29-42

OVERALL SURVIVAL

76

RAPIDO STUDYComments:• “loose” study design; in the standard arm, post-

operative (“adjuvant”) therapy optional− 47% treated, 41% not offered such treatment

• after a median follow-up time of 4.6 years:− difference in disease-related treatment failure at 3 years is

30.4% (“standard”) vs. 23.7% (“experimental”) (p=0.019) but no difference in overall survival

• is the radiation therapy an essential component to the “experimental” arm and is the adjuvant chemotherapy an essential component to the “standard” arm?

77

PRODIGE 23 TRIALStudy Design

chemo RT surgery (TME)adjuvant

chemotherapy

standard5040 cGy RT

+Capecitabine(5.0 weeks)

mFOLFOX (12 cycles)or

CAPOX (8 cycles)

stratify• cT3 vs cT4• cN0 vs cN4• extramural extension• tumor location

neoadjuvantchemotherapy

chemo RT surgery (TME) adjuvantchemotherapy

experimentalFOLFIRINOX x 6 50 cGy RT

+capecitabine

mFOLFOX6 (6 cycles)or

CAPOS (4 cycles)

median f/u: 46.5 months

Conroy T, et. al. Lancet Oncol 2021;22:702-715

78Conroy T, et. al. Lancet Oncol 2021;22:702-715

DISEASE-FREE SURVIVAL

79Conroy T, et. al. Lancet Oncol 2021;22:702-715

OVERALL SURVIVAL

80

PRODIGE 23 TRIALComments:• clever experimental design• overall survival outcome after three years is encouraging

in both arms; difference not (yet) statistically significant− pathologic CR increased from 13% (“standard”) to 28%

(“experimental”)• will long term toxicity from the more intensive treatment

negate these therapeutic differences?

82

Andrea Cercek, MDDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

Paul B. Romesser, MD, and Christopher H. Crane, MDDepartment of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

2021 Master Class Virtual Series AN UPDATE ON COLORECTAL ...

Documents

Transcript of 2021 Master Class Virtual Series AN UPDATE ON COLORECTAL ...