Landmark trials in Rectal cancer

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CHEMO AND RADIOTHERAPY
TRIALS IN RECTAL CANCER
Department of Surgical Oncology
Centre for Oncology
GRH,Royapettah

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Objectives
• Whether trimodality therapy improves survival
• If CRT should be given pre operatively or post operatively
• Precisely which patients should be irradiated
• Duration of adjuvant therapy
• When to operate

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EVOLUTION

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• 7.5 years consecutive series
• 115 pts
• At an average of 4·2 years
postoperatively, three pelvic
recurrences have developed but there
have been no staple-line recurrences in
patients who had "curative" surgery.

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Recommendations
• Tendency to "cone" the dissection plane towards the rectal wall
posteriorly and laterally has been condemned by Toddl
• Most rectal carcinomas can be treated without destruction of the
anal sphincters, provided that the mesorectum is completely
excised.

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• 1168 patients from 70 hospitals throughout Sweden who were randomly assigned to
treatment groups, 908 (78 percent; 454 in each group) were treated with curative intent
• one week of preoperative irradiation, followed by surgery within the next week
(radiotherapy-plus-surgery group), or to surgery with no additional radiotherapy
(surgery alone group)

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25 Gy delivered in 5 fractions for five days

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• At 5 years follow up, Local recurrence rate was 11% in preop RT group and
27% in surgery only group.
• Translated to both improved OS and cancer specific survival in all Duke’s
stages

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• 1805 pts
• SCRT followed by TME versus TME alone
• LRR at 2 years- 2.4% vs 8.2%
• But OS was 82% vs 81.8%

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• preoperative short-term
radiotherapy reduced 10-year local
recurrence by more than 50%
relative to surgery alone
• The effect of radiotherapy became
stronger as the distance from the
anal verge increased

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• Improved 10-year survival in patients with a negative circumferential
margin and TNM stage III
• For patients with a negative resection margin, the effect of radiotherapy
led to an improved cancer specific survival, which was nullified by an
increase in other causes of death, resulting in similar overall survival
rates

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• T3/T4-N+
• 50.4 Gy- 1.8Gy/# plus 5FU –
1000mg/sq.m as 120 hrs continuous
infusion on first and fifth week of RT
• Surgery after six weeks
• Post operatively four five day cycles of
5FU – 500mg/sq.m
• Post op CRT was similar with a 5Gy
boost

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• 421 patients were randomly assigned to receive preoperative chemoradiotherapy and
402 patients to receive postoperative chemoradiotherapy.
• The overall five-year survival rates were 76 percent and 74 percent, respectively
(P=0.80).
• The five-year cumulative incidence of local relapse was 6 percent for patients
assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-
treatment group (P=0.006).
• Grade 3 and 4 toxicity with radiotherapy in post op setting

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• arm 1, preop RT 45 Gy in 5 weeks
• arm 2, preop RT plus two 5-day CT courses
(fluorouracil 350 mg/m2 /d and leucovorin
20 mg/m2 /d) in the first and fifth week of
RT
• arm 3, preop RT plus four postoperative
CT courses
• arm 4, preop RT and CT plus
postoperative CT

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• 1011 patients were entered onto the trial
• 505 received preop RT (arms 1 and 3), and 506 received preop RT-CT (arms
2 and 4).
• Median interval to surgery was 5.4 weeks.

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• After preop RT-CT, tumors
were smaller
• Less advanced pT and pN
stages
• Had small numbers of
examined nodes
• Less frequent LVN invasions
• Mucinous tumors increased
after preop RT-CT

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• 80 centres in four countries.
• 1350 patients with operable adenocarcinoma of the rectum were randomly assigned
• Short-course preoperative radiotherapy (25 Gy in five fractions; n=674) or
• Initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions
with concurrent 5-fl uorouracil) restricted to patients with involvement of the
circumferential resection margin (n=676).
• The primary outcome measure was local recurrence

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• Median follow-up of surviving patients was 4 years.
• 99 patients had developed local recurrence (27 preoperative radiotherapy vs 72
selective postoperative chemoradiotherapy).
• Reduction of 61% in the relative risk of local recurrence for patients receiving
preoperative radiotherapy
• Relative improvement in disease-free survival of 24% for patients receiving
preoperative radiotherapy
• Overall survival did not differ between the groups

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• cT3–4 or any node-positive disease randomized to two groups
• A control group receiving standard fluorouracil-based combined modality
treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions
plus infusional fluorouracil (1000 mg/m² on days 1–5 and 29–33), followed
by surgery and four cycles of bolus fluorouracil (500 mg/m² on days 1–5
and 29);

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• Investigational group receiving preoperative radiotherapy of 50·4 Gy in 28
fractions plus infusional fluorouracil (250 mg/m² on days 1–14 and 22–35)
and oxaliplatin (50 mg/m² on days 1, 8, 22, and 29), followed by surgery and
eight cycles of oxaliplatin (100 mg/m² on days 1 and 15), leucovorin (400
mg/m² on days 1 and 15), and infusional fl uorouracil (2400 mg/m² on days
1–2 and 15–16).

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• Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and
adjuvant chemotherapy (at the doses and intensities used in this trial)
significantly improved disease-free survival of patients with clinically staged
cT3–4 or cN1–2 rectal cancer compared with former fluorouracil-based
combined modality regimen (based on CAO/ARO/AIO-94).

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• Clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in
25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily
fractions) were randomly assigned to one of the following chemotherapy regimens
• Continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m2 , 5 days per
week), with or without intravenous oxaliplatin (50 mg/m2 once per week for 5
weeks) or
• Oral capecitabine (825 mg/m2 twice per day, 5 days per week), with or without
oxaliplatin (50 mg/m2 once per week for 5 weeks)

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• Administering capecitabine with preoperative RT achieved similar rates of
pCR, sphincter-sparing surgery, and surgical downstaging compared with
CVI FU.
• Adding oxaliplatin did not improve surgical outcomes but added significant
toxicity

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In conclusion of three trials, STAR -01, NSABP – R04 and ACCORD 12
• No difference in pathological response, sphincter saving or surgical
downstaging
• More grade 3 and 4 adverse events

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Lyon R90-01 - Influence of the Interval Between Preoperative Radiation
Therapy and Surgery on Downstaging and on the Rate of Sphincter-Sparing
Surgery for Rectal Cancer

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• Population (n = 210) – Carcinoma rectum stage T2-3, NX, M0, were randomized before
radiotherapy
• Intervention (n = 99) – Short interval (SI) surgery (2 weeks)
• Comparator (n = 102) – Long interval (LI) surgery (6-8 weeks)
• Both arms received- total dose 39 Gy/ 3 Gy/fraction in 13 fractions deliveredover 17 days

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• Outcomes – Median FU -33 months
• long interval between preoperativeradiotherapyand surgery was associated with a
significantly better clinical tumor response (53.1% in the SI group v 71.7% in the LI
group, P = .007) and pathologicdownstaging (10.3% in the SI group v 26% in the LI
group, P = .005).
• No differences in morbidity, local relapse, and short-term survival between the two
groups.
• No difference in Sphincter sparing surgeries

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• The median follow-up was 17.2 years. The 5-, 10-, 15-and 17-year overall survival
rates were, respectively, 66.8%, 48.7%, 40.0%, and 34.0% for the SI group and,
respectively, 67.1%, 53.5%, 41.9%, and 34.0% for the LI group.
• There were no significant differences between groups in terms of survival or local
recurrences
• The radiation-induced sterilization rate of the preoperative cancer specimen was a
marker of good prognosis. The interval duration (the treatment being the same)
although it is modifying the sterilization rate has no impact on survival

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Stockholm III- Optimal fractionation of preoperative radiotherapy and
timing to surgery for rectal cancer ( non inferiority trial)
• Population: Resectable rectal cancer
• Intervention and Comparator:
• 3 arm randomization (n=840) (included grp 1 (n=129), grp 2 (n=128) and grp 3 (n=128))
• 2 arm randomization (n=455) (included grp 1 (n=228) & grp 2 (n=227))
• RT 5x5 Gy + surgery within 1 week (SRT)
• RT 5x5 Gy + surgery after 4-8 weeks (SRT- D)
• RT 25x2 Gy + surgery after 4-8 weeks (LRT-D)

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Stockholm III
• Outcomes: 5 year survival
• Median time to recurrence – grp 1 – 33.4 months, grp 2 – 19.3 months, grp 3 – 33.4 months.
• No OS or DFS benefit noted
• Postoperativecomplicationswas similar between all arms when the three-arm randomization was analyzed.
• However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative
complications was significantly lower after short-course radiotherapy with delay than after short-
course radiotherapy (53% vs 41%)
• Short-course radiotherapy with delay to surgery is a useful alternative to conventionalshort-course
radiotherapy with immediate surgery.

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Habr-Gamaet al. - Watch and Wait Approach Following Extended
Neoadjuvant Chemoradiation for Distal Rectal Cancer
• Population (n=72): T2-4, N0-2, M0 distal rectal cancer who completed Neoadjuvant
chemoradiotherapy (54 Gy and 5-fluorouracil/ leucovorin delivered in 6 cycles every 21
days). Patients were assessed for tumor response at 10 weeks from radiation completion
• Intervention: Patients with complete clinical response were not immediately operated on
and were monitored
• Comparator: Patients with incomplete clinical response were referred to immediate
surgery.

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Habr-Gamma et al.
• Outcomes: MedianFU- 56 months.
• Forty-seven (68%) patients had initial complete clinical response (i.e after 10 weeks). Of these, 8
developedlocal regrowth within the first 12 months of follow-up (17%).
• 39 (57%) sustained complete clinicalresponse (i.e after 12 months).
• An additional 4 patients (10%) developedlate local recurrences (>12 months of follow-up).
• Overall, 35 patients neverunderwent surgery (51%).

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The rectal cancer and preoperative induction therapy
followed by dedicated operation (RAPIDO) trail

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• It is a multicenter trial (54 centers)
• phase 3 randomized trail
• 920 patients
• Median follow up of 4.6yrs
• Standard vs experimental ( SCRT – Chemo – surgery )

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• Primary end point – disease related treatment failure
• At 3yrs - 30.4 % vs 23.7%
• P = 0.019
• Distant metastasis at 3 yrs 26.8% vs 20%
• Over all survival 88.8% vs 89.1%
• pCR is 14.3% vs 28.4%
• Ro resection rates are similar

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• Surgical complications are similar ( anastomotic
leaks more in experimental arm but not statistically
significant)
• Quality of life is similar

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PRODIGE 23 – A French trail
• Phase 3 RCT
• N= 461
• Standard vs experimental mFOLFIRINOX – CRT - surgery –
Adjuvant chemo
• Median follow up of 46months

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• Primary end point – 3yr
DFS
• 68.5 vs 75.7%
• P=0.019
• pCR – 11.7 vs 27.5%
• 3 yr Metastasis free survival
71.7 vs 78.8%
• 3 yr OS 87.8 vs 90.8%

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Chemotherapy without radiation
• OPRA trial – initiating treatment with chemoRT may improve colostomy
free survival
• FORWARC trial– neoadjuvant FOLFOX without RT had lower rates of
pCR
• PROSPECT trial – ongoing. Chemotherapy alone in stage II or III high
rectal cancer in patients with atleast 20% tumor regression following
neoadjuvant treatment

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Targeted agents
• EXPERT-C trial – additition of cetuximab to capecitabine based chemoRT.
Improvement in OS in KRAS exon2/3 wild type tumors
• SAKK41/07 trial – panitumumab in pre operative setting. pCR 53% vs 32%.
More grade 3 toxicity
• RaP/STAR -03 study – pCR not met

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cT1-2 N0
• pT1-2,N0 – no further treatment
• pT3,N0
• Observation – less than 2 mm invasion of mesorectum , well or moderately differentiated,
no LVSI, upper rectal
• FOLFOX/CAPEOX – margin neg proximal tumors
• Capecitabine +RT followed by FOLFOX
• pT4/N+- sandwich regimen – chemotherapy + concurrent chemoRT + addn
chemotherapy
• Total duration – 6 months

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• T3, N any with clear CRM and T1-2,N1-2
• chemoRT/ short course RT – transabdominal resection – adjuvant chemotherapy
• long course RT – restaging
• short course RT – within 1 week or > 6 to 8 weeks
Wait and watch
Total neoadjuvant therapy
FOLFOXIRI not recommended

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• cT3, N any + threatened CRM and T4, N any
chemoRT – restaging at 6 weeks
• bulky residue – 12 to 16 weeks chemo restaging and transabdominal
resection and addn chemotherapy
• clear CRM – surgery and adj chemo