Neoadjuvant Chemoradiotherapy for Rectal Cancer

1
Neoadjuvant Chemoradiotherapy for Rectal Cancer

• Jane S. Chawla, M.D.

2
Objectives

• Case
• Rectal Cancer Staging
• Indications for Neoadjuvant Chemoradiotherapy
• Neoadjuvant Radiotherapy
• Surgical Approaches
• Evidence to Support Neoadjuvant Approach
• Other neoadjuvant chemoradiotherapy regimens
  under investigation
• Conclusions

3
Case

• 50 y/o F with h/o rectal bleeding found to have a
  rectal mass with biopsy for moderately-different
  iated adenocarcinoma.
• CT ? No rectal lesion seen no evidence of
  metastatic disease
• TRUS ? Tumor 2.5 cm in diameter located 8 cm
  from anal verge scalloping of the peri-rectal
  fat one hyperechoic LN seen ? Staged as T3N1M0

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TNM Staging Treatment Strategies
T1-2/N0 ? Transanal Excision versus AR
T3-4/N0 or any T/N1-2 ? Neoadjuvant chemotherapy

• Definitive Indications
• T3-T4 tumors
• Relative Indications
• T1-T2 / N tumors (by TRUS / MRI)
• Distal rectal tumors likely to require APR
• Invasion of mesorectal fascia

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Staging workup

• Physical Exam
• Colonoscopy
• Rigid proctoscopy (measurement of distance from
  anal verge)
• CEA
• CT chest/abd/pelvis
• TRUS
• MRI

Recommended to assess depth Of tumor penetration
LN Status if available
Depth of invasion LN involvement help predict
prognosis
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Rectal Cancer Staging Meta-Analysis of US, CT
and MR
Meta-Analysis of 90 articles on rectal ca staging
Muscularis propria invasion 94 sensitivity for
US MR Specificity for US gt MR (p0.02)
Perirectal tissue invasion Sensitivity of US
(90) gt MR (82) gt CT (79) ? Understaging of T3
or Higher tumors with MR / CT Specificities
comparable 75-78
Adjacent organ invasion Sensitivities comparable
70-74 Specificities comparable 96-97
Lymph node involvement Sensitivities comparably
low 55-67 Specificities comparable 74-78
Bipat, S. Radiology, 2004.
US found to be best local staging
modality. Limitations Unable to depict LNs
outside range of transducer OR whether LNs are
within or outside mesorectal fascia Subset
analysis showed MR endorectal coil NOT superior
to US
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Rectal Cancer Staging MR

• Kwok et al ? Meta-analysis of US, CT MR found
• US most accurate for eval of wall penetration
• MR endorectal coil equivalent for eval of wall
  penetration superior for LN evaluation
• MERCURY Study ?MRI to assess extramural depth of
  tumor
• Tumor depths by MR histo-pathologic eval
  equivalent to within 0.5 mm
• LN evaluation not reported
• Radiologists require special training

MERCURY Study. Radiology, 2007.
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Surgical Approaches APR versus AR

• Abdominoperineal resection (APR)

• Anterior Resection of the Rectum (AR)

• Used for tumors of the lower 3rd of the rectum
• Necessary when margin-negative tumor resection
  will result in loss of anal sphincter function
• En bloc removal of the rectosigmoid colon,
  rectum, anus surrounding mesentery,
  mesorectum, and perianal soft tissue
• Colostomy required

• Used for tumors of the proximal 2/3 of the rectum
• Preserves the lower portion of the rectum the
  anus
• Allows for normal anal sphincter function
• Associated lymph nodes are removed
• Temporary colostomy may be necessary if adjuvant
  chemotherapy given

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Surgical Approaches Total mesorectal excision
(TME)

• En bloc removal of the entire mesorectum
  including associated vascular structures,
  lymphatic structures, fatty tissue, mesorectal
  fascia
• Sharp dissection
• Autonomic nerves spared
• In anal function preserved, then a coloanal
  anastomosis can be done

From UpToDate
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What is the Rate of Recurrence with Surgery Alone?

• Data from surgical studies ? local recurrence
  rates of 25-50 with T3-T4 or N disease after
  TME alone
• Dutch TME trial ? local failure (2-year) after
  TME was 15 in N patients
• Tumors located lower in the rectum have higher
  rates of local failure

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Neoadjuvant Radiotherapy

• Common regimens
• Swedish-Style, Short course 25 Gy in 5 fractions
  over 5 days, then immediate surgery
• Conventional 40-50 Gy in 20-25 fractions over
  4-5 weeks, then surgery in 3-6 weeks
• Regimens never compared directly
• Meta-analysis of 22 randomized trials ? RT
  surgery v. surgery alone
• OS marginally better with surgery RT v. surgery
  alone (62 v. 63 died, p0.06)
• ?risk of local recurrence with RT compared to
  surgery alone (46 ? for preop 37 ? for
  postop RT)
• Preoperative RT at doses 30 Gy ? risk of local
  recurrence death
• Fewer pts with preop RT died than those with
  surgery alone (45 versus 50, p0.0003)
• Impact of RT on sphincter preservation not clear

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Are there benefits to Neoadjuvant chemoradiation
in rectal cancer?

• Are rectal tumors downstaged with neoadjuvant
  CRT?
• Does neoadjuvant CRT ? rate of sphincter-sparing
  surgeries?
• Does neoadjuvant CRT ? OS or PFS?
• Does neoadjuvant CRT ? risk of local recurrence
  or distant recurrence?
• Is there a significant ? in toxicity with
  neoadjuvant CRT?
• How is patient compliance with neoadjuvant CRT?

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Major Randomized Trials Supporting Neoadjuvant
Chemoradiotherapy
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Preoperative Rt versus chemo-RT for resectable
t3-4 tumors
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FFCD 9203 Trial

• 762 pts with resectable T3-4 tumors, low to
  middle rectum (1993-2003)
• Randomized to preoperative RT versus CRT
• RT 45 Gy (25 fractions of 1.8 Gy over 5 wks)
• CRT Bolus 5-FU 350 mg/m²/d LV on the 1st 5th
  wks during RT
• Surgery AR or APR done 3-10 wks later TME
  recommended
• Adjuvant chemo (both arms) Bolus 5-FU/LV q4 wks
  x 4 cycles
• Staging TRUS done routinely

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FFCD 9203 Trial 1 2 Endpoints

• 1 End Point
• No significant difference in OS (5-yr) ? 67.9 RT
  v. 67.4 CRT (p0.684)
• 2 End Points
• No significant difference in PFS (5-yr) ? 55.5
  RT v. 59.4 CRT
• Significant difference in local recurrence rate
  (5-yr) ? 16.5 RT v. 8.1 CRT (p0.004)

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FFCD 9203 Trial More Secondary End Points
No statistical difference in rate of APR Between
RT group and CRT groups (41.7 42.3, p0.837)
Pathological complete sterilization rate 11.4
CRT and 3.6 RT, plt0.0001
Grade 3-4 Toxicities were RT (2.9) versus CRT
(14.9), plt0.0001
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Polish Trial

• 316 pts with resectable T3-4 rectal cancer, no
  sphincter involvement, tumor palpable on DRE
  (1999-2002)
• Randomized to RT versus CRT
• RT ? Preoperative RT (short-course) with 5 Gy/d x
  5 days
• CRT ? 50.4 Gy (given in 1.8 Gy per fx over 5.5
  weeks) bolus 5-FU 325 mg/m²/d LV x 5 days 1st
  and 5th wks of RT
• Surgery Within 7 days in RT group 4-6 wks in
  CRT group TME recommended for low-lying tumors
• Adjuvant chemo Optional consisted of bolus
  5-FU/LV x 4 months (in CRT group) or x 6 months
  (in RT group)
• Staging Freely movable tumors underwent TRUS or
  pelvic CT to r/u T1-2

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Polish Trial 1 2 Endpoints (4-year)

• ?rate of pCR in CRT group 16.1 CRT v. 0.7 RT
  (plt0.001)
• No difference in sphincter preservation rate - RT
  61.2 v. CRT 58 (p0.57)
• No difference in local recurrence - RT 10.6 v.
  CRT 15.6 (p0.210)
• No difference in distant mets - RT 31.4 v. CRT
  34.6 (p0.540)

Incidence of Local Recurrence
RT 10.6 CT-RT 15.6
(p0.210)
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Polish Trial 2 Endpoints (4-year)
Disease Free Survival
Overall Survival
RT 67.2 CT-RT 66.2
RT 58.4 CT-RT 55.6
(p0.960)
(p0.820)
No significant difference in OS or DFS at 4 years
between RT and CRT Groups
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EORTC 22921 Trial

• 1,011 pts with resectable T3 / T4M0 rectal cancer
  (1993-2003)
• Randomized to one of four arms using a 2 x 2
  factorial design
• Arm 1 preop RT (standard arm)
• Arm 2 preop CRT
• Arm 3 preop RT and postop CT
• Arm 4 preop CRT and postop CT
• Chemotherapy ?
• Bolus 5-FU 350 mg/m²/d IV LV x 5d during the
  1st and 5th wks of RT
• Arms 3 4 received adjuvant chemo x 4 cycles
• Radiotherapy ? 45 Gy (25 fractions of 1.8 Gy)
  over 5 weeks
• Surgery ? 3 to 10 wks later TME recommended
• Staging TRUS was optional (used in 64.8 of
  pts)

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EORTC 22921 Preoperative Chemotherapy Downstages
Tumors
Tumor size Reduction in CRT group
Lower disease Stage in CRT Group
2.5 fold ? in pT0 rate 5.3 v. 13.7
No change in Risk of nodal involvement
But ? in N stage ?in the of Retrieved LNs
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EORTC 22921 Overall Survival (5-year)
Preoperative RT v. CRT
Postoperative CT v. no Postoperative CT
Preop RT 65.8
Adjuvant CT 67.2
Preop CRT 64.8
No Adjuvant CT 63.2
No difference in OS between adjuvant CT no
adjuvant CT groups
No difference in OS between Preop RT Preop CRT
Groups
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EORTC 22921 Disease Free Survival (5-year)

• No difference in DFS between
• Adjuvant CT v. no adjuvant CT
• (p0.50)
• Preop RT v. Preop CRT (p0.13)

Adjuvant CT 58.2
No adjuvant CT 52.2
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EORTC 22921 ? Incidence of Local Recurrence in
Chemotherapy Groups
RT 17.1
CRT 8.7
RT Postop CT 9.6
CRT Postop CT 7.6
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EORTC 22921 Conclusions

• No significant difference in sphincter-sparing
  surgery ? 50.5 RT and 52.8 CRT
• Cumulative incidence of distant metastases did
  not differ significantly according to preop and
  postop treatment groups (p0.14, 0.62)
• Adjuvant CT did not affect PFS or OS, but
  survival curves diverged after 2 4 years

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Preoperative versus postoperative cRT
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The German CAA/ARO/AIO-94 Trial

• 823 pts with resectable T3/T4 or LN tumors lt16
  cm from anal verge (1995-2002)
• Randomized to preoperative or postoperative CRT
• Staging TRUS no pelvic MRI
• Preoperative CRT
• 50.4 Gy in 28 fractions of 1.8 Gy/d
• 5-FU 1000 mg/m²/d CIVI over 120 hours on wks 1
  5
• Surgery w/ TME done 6 weeks after CRT
• Adjuvant CT (1 month postop)? bolus 5-FU 500
  mg/m², 5 days/wk q4 wks x 4 cycles
• Postoperative CRT
• Identical to preop group except for a boost of
  5.4 Gy to tumor bed

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German Trial 1 and 2 End Points
Disease Free Survival (5-year)
Overall Survival (5-year)
Preop 76
Preop 68
Postop 74
Postop 65
No significant difference in OS or DFS between
Preop Postop Groups
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German Trial 2 Endpoints
Cumulative Incidence of Local Recurrence (5-year)
Cumulative Incidence of Distant Recurrence
(5-year)
Postop 13
Postop 38
Preop 36
Preop 6
Significant difference in incidence of local
recurrence between Preop Postop Groups
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German Trial Other 2 End Points

• ? pCR in preoperative CRT group (8 v. 0,
  plt0.001)
• No difference in sphincter-preserving surgeries
  between preop and postop groups as a whole
• Subset of pts thought to need an AP excision
  prior to randomization had ? rate of sphincter
  preservation with preop CRT (39 v. 19, plt0.004)
• Grade 3 or 4 acute toxicities (27 versus 40,
  p0.001)
• Rates of long-term toxic effects (14 versus 24,
  p0.01)

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Summary of Randomized Trials

• Are rectal tumors downstaged (pCR) with
  neoadjuvant CRT?
• FFCD 9203 Trial YES (11.4 CRT v. 3.6 RT
  plt0.0001)
• Polish Trial YES (16.1 CRT v. 0.7 RT
  plt0.001)
• EORTC 22921 Trial YES (13.7 CRT v. 5.3
  plt0.001)
• German Trial YES (8 Preop CRT v. 0 Postop
  CRT)
• Does neoadjuvant CRT ? rate of sphincter-sparing
  surgeries?
• FFCD 9203 Trial NO
• Polish Trial NO
• EORTC 22921 Trial NO
• German Trial NO (Preop vs Postop CRT)

All Studies Show ?pCR with CRT
No. But, in German Trial those Determined to
need AR prior To randomization had ? rates
of Sphincter-preservation with CRT Preoperatively.
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Summary of Randomized Trials

• Does neoadjuvant CRT ? OS or PFS?
• FFCD 9203 Trial NO - 67.4 / 59.4 (5-year)
• Polish Trial NO - 66.2 / 55.6 (4-year)
• EORTC 22921 Trial NO - 64.8 / 56.1 (5-year)
• German Trial NO - 76 / 68 (5-year)
• Does neoadjuvant CRT ?risk of local recurrence
  // distant recurrence?
• FFCD 9203 Trial YES (8.1 CRT v. 16.5 RT) //
  NO (36)
• Polish Trial NO (15.6 CRT v. 10.6 RT) // NO
  (34.6)
• EORTC 22921 Trial YES (13.7 CRT v. 5.3) //
  NO (34.4 all grps)
• German Trial YES (6 Preop CRT v. 13 Postop
  CRT) // NO (36 Pre)

NO. But better OS/PFS Seen in German Trial
YES, ?risk of local recurrence. NO ? risk of
distant recurrence
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Summary of Randomized Trials

• Is there an ? in grade 3-4 toxicity with
  neoadjuvant CRT?
• FFCD 9203 Trial YES (14.9 CRT v. 2.9
  plt0.0001)
• Polish Trial YES (18.2 CRT v. 3.2 RT
  plt0.001)
• EORTC 22921 Trial YES (Slight ? in toxicity
  CRTgtRT)
• German Trial NO (27 Preop v. 40 Postop
  p0.001)
• How is patient compliance with neoadjuvant CRT?
• FFCD 9203 Trial 93 Neoadj CT 78.1 Adjuvant
  CT
• Polish Trial Not reported
• EORTC 22921 Trial 82 Neoadj Adjuvant CT
  42.9
• German Trial 92 Preop CT 53 Postop CT

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Summary of Randomized Trials

• What is the rate of TME?
• FFCD 9203 Trial Not routine
• Polish Trial Recommended for low-lying tumors
  subtotal TME for mid-rectal tumors
• EORTC 22921 Trial About 25
• German Trial 100
• Was TRUS // MRI used?
• FFCD 9203 Trial YES // NO
• Polish Trial TRUS used if suspicion for T1-2
  tumor // NO
• EORTC 22921 Trial 64.8 //NO
• German Trial 100 // NO

• Standard Path review?
• FFCD 9203 Trial NO
• Polish Trial ?
• EORTC 22921 Trial YES
• German Trial YES
• Type of CT given
• FFCD 9203 Trial Bolus 5-FU
• Polish Trial Bolus 5-FU
• EORTC 22921 Trial Bolus 5-FU
• German Trial CIVI 5-FU

NCCTG trial (1994) ? ?OS with CIVI 5-FU compared
to bolus 5-FU Smalley et al (2006) no
difference OS but ? heme toxicity with bolus
5-FU
36
Capecitabine-based chemotherapy

• Phase I / II Studies evaluating
  capecitabine-based regimens for Neoadjuvant
  treatment of rectal cancer
• Phase II study (Kim et al) ? 94 pts with
  resectable, T3-4/N, distal two-thirds of the
  rectum
• XRT (50 Gy over 5 wk)s Capecitabine 1650
  mg/m²/day during XRT, followed by TME
• Adjuvant capecitabine (2500 mg/m(2)/day for 14
  days) x 4 cycles
• 98 had a complete resection downstaging rate
  76 by path 74 sphincter-sparing procedures
  grade 3 toxicities (3 diarrhea 1 neutropenia)
• Ongoing NSABP R-04 Trial ? CIVI 5-FU / RT v.
  Capecitabine / RT for resectable rectal cancer

37
Neoadjuvant Trials Capecitabine Oxaliplatin
RT
38
Neoadjuvant Trials Infusional 5-FU
Oxaliplatin RT
39
Neoadjuvant Trials Irinotecan-based regimens
40
Neoadjuvant regimens under investigation
Clinicaltrials.gov

• Avastin-containing chemo regimens
• Preop Cape Avastin RT
• Preop FOLFOX Bevacizumab without RT
• Cape/ox/bevacizumab ? Surgery ?
  FOLFOX/bevacizumab
• Short-course RT CT v. Conventional RT CT
• Short-course RT FOLFOX4 x 3c v. Conventional RT
  bolus 5-FU ox
• Regimens with Irinotecan v. Oxaliplatin
• Cape irino RT vs. Cape oxali RT
• Cetuximab-Containing regimens
• Cape/ox/cetux/50Gy ? TME ? FOLFOX4 Cetux
• PET to assess tumor response s/p neoadjuvant tx

41
Case revisited

• Our pt was enrolled in RTOG 0822 Trial
  Neoadjuvant Capecitabine 1500 mg bid 5d/wk
  weekly oxaliplatin x 5wks concurrently with RT
• She underwent LAR (TME) with temporary ostomy
• Path ? She had an R0 resection tumor was 1.5 cm
  in size no venous invasion 1/13 LNs ? pT3N1
• Pt is to undergo adjuvant chemotherapy with
  FOLFOX x 9 cycles

42
Conclusions

• Patients to consider for neoadjuvant
  chemoradiotherapy
• T3-4 and/or N disease
• Low-lying rectal lesions if considering
  sphincter-sparing procedures
• TRUS best for assessing tumor depth best imaging
  modality for assessing LN status controversial
  (TRUS v MR)
• TME is the preferred surgical procedure
• Neoadjuvant CRT compared to RT
• No improvement in OS or PFS
• Significant tumor downstaging ? local
  recurrence
• No ? in sphincter-sparing procedures

43
Conclusions

• Preoperative CRT compared to postoperative CRT
• No improvement in OS or PFS
• Significant tumor downstaging ? local
  recurrence
• ? improvement in sphincter-sparing procedures
• ? early and late toxicity
• Further study of other neoadjuvant regimens
  underway

44
NCCN Guidelines

• T3N0 or T1N1-2 disease
• Neoadjuvant chemo with CIVI 5-FU/LV RT
• (Alternatives bolus 5-FU/LV RT or Xeloda RT)
• Surgery 5-10 weeks s/p neoadjuvant treatment
• 6 months adjuvant chemo with 5-FU /- LV, FOLFOX,
  or Capecitabine
• Pts downstaged to pT1-2N0M0 can be observed w/o
  adj treatment
• T4 and/or locally unresectable disease
• Neoadjuvant chemo with CIVI 5-FU/LV RT (as
  above)
• Surgery if possible 5-10 weeks after neoadjuvant
  treatment
• Then adjuvant treatment as above
• Adjuvant chemo 5-FU /- LV or FOLFOX or Xeloda,
  then 5-FU/RT or Xeloda/RT, then 5-FU /- LV or
  Xeloda or FOLFOX

45
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