Neoadjuvant Therapy for Rectal Cancers

1
Neoadjuvant Therapy for Rectal Cancers

• Luis C. Rodriguez, M.D.
• 5-2-03

2
Rectal Anatomy
Left upper valve of Houston
Portion of Rectum
cm from anal verge
Right middle valve of Houston
upper 1/3 middle 1/3 lower 1/3
15
Peritoneum
10
Ampulla of Rectum
Left lower valve of Houston
6
Pelvic size/structures M vs. F
Anal verge
Cohen AM, et al. Cancer Principles Practice of
Oncology. 5th ed. 19971197.
3
Staging

• Biopsy, PE, DRE, rigid proctoscope, CXR, CT A/P,
  CEA
• EUS 82-93 accurate for depth of invasion, less
  for nodes
• T1 submucosa
• T2 muscularis propia
• T3 serosa and non-peritonealized peri-rectal
  tissue
• T4 other organs or visceral peritoneal surface
• N1 1-3 nodes
• N2 4 nodes
• Location, fixity, circumferential, size, grade,
  LVI, PNI
• Tumor spread circumferential and lateral into
  the mesorectum
• Stage I T1-2N0 Stage II T3-4N0 Stage III
  TxN

4
Surgery

• Radical surgery Anastomosis/margins
• APR permanent colostomy
• AR anastomosis
• Trans-anal excision
• One of the worst scenarios (other than
  recurrence) is to end up with a perineal
  colostomy
• -N. Petrelli

5
Local Recurrence

• Usually seen within 2 years, seldom cured
• Factors influencing local recurrence include
• TNM Stage
• Surgical experience/technique and completeness of
  resection (spillage)
• Use of adjuvant therapy
• Tumor differentiation and macroscopic appearance
  (circumferential, ulceration)
• LVI, NVI
• Stage 5 year, no adjuvant XRT
• T1 10
• T2 15-35
• T3 20-45
• T4 gt50
• N 40-65

McCall J, et al. Int J Colorectal Dis 1995 10.
126-132 Bokey EL, et al. BJS 1999
861164. Shirouzu et al., Am J. Surg 1993
165233
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Adjuvant Therapy

• Goal eradicate disease and improve survival
• Not a substitute for poor surgical techniques
• RT or chemotherapy can reduce local recurrence
• RT alone is not adequate for T3 or N tumors
• 5-FU based CRT reduces LR probably prolongs
  survival
• CIVI 5-FU better than bolus
• OTT 6 months for CRT
• Adjuvant CRT is more toxic than surgery alone
• higher average BM, incontinence, use of
  anti-diarrhea meds. Affected by RT fields and
  use of pouches

OConnell MJ, et al. NEJM 1994 331502. NIH
Concensus Conference JAMA 1990 2641444 CCCG.
Lancet 2001 358 1291 NCCN Guidelines 2003
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Neoadjuvant Therapy

• What are the goals?
• Reduce local recurrence and improve survival
• Facilitate surgery for otherwise unresectable or
  marginal lesions (downstage and/or downsize)
• Facilitate sphincter-sparing for low lying tumors
• Improve functional outcome QoL (less OTT)
• What are the advantages?
• Tissues better oxygenated, RT may work better
• Rapid treatment of sub-clinical disease (less
  seeding)
• Possibly less OTT
• Less Toxic not clear, probably trade-offs

8
Neoadjuvant Therapy

• What are the problems?
• Possible overtreatment of T1/2, N0 and M
  patients
• Loss of original pathologic staging, relying on
  clinical staging
• Longer term toxicity unclear, often not
  adequately reported or easy to sort out.
• Optimal modalities for each stage is evolving
• What are the problems with comparing studies over
  the past two decades?
• Preoperative staging inconsistent/inaccurate
• Small numbers of certain T stages
• Definition of curative surgery (technique)
• Anatomic location of tumors
• RT issues ( fields, total dose, fraction)
• Chemotherapy new agents
• Endpoints differ LR, survival, SP, toxicity,
  QoL/functional outcome
• Different follow up parameters

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Neoadjuvant RT

• Meta-analysis RTS vs. S for resectable cancer
• MEDLINE CANCERLIT 1970-1999, supplemented
• 14 RCTs (not including the Dutch trial)
• 5 year OS improved OR 0.84 (0.72-0.98) Stage
  II/III
• Cancer-related mortality reduces OR .71
• Local recurrence reduced OR 0.49 (CI 0.38-0.62)
• No change in distant metastasis
• Rarely needed RT dose reduction
• No excess post-op mortality, some increase
  complications
• Does not answer the question of RT dose,
  fraction, field, time till surgery

Cammá C, et al. JAMA 2000 2841008
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Neoadjuvant RT Short Course

• Swedish Rectal Cancer Trial
• 1987-1990
• 1147 eligible patients with resectable tumors
  (29 stage I)
• Surgery not standardized, within 7 days
• Tumors distal to the promontory point
• Surgery vs. RT (5Gy x 5) ? Surgery (imbalance in
  Stage I and III)
• In-hospital mortality 4 vs. 3, higher for lt4
  field RT
• 5 yr OS 54 vs. 48
• Local Recurrence 11 vs. 27
• Recurrence was the same for type of surgery
  ARAPR
• Hard to know about downstaging effect
• Increased post-op fistulas, pelvic/fem fx,
  altered SP fnx with RT

NEJM 1997 336980 and 3361539. Swedish Rectal
Cancer Trial. Initial results B J Surg 1993
801333.
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Neoadjuvant RT Short Course

• Dutch Colorectal Cancer Study Group
• 1997-1999
• 1805 eligible patients with resectable tumors
  (28 Stage I)
• Non-fixed tumors within lt15 cm of the anal verge
• Surgery standardized, performed within 10 days
• TME vs. RT (5 Gy x5) TME
• No adjuvant Rx unless margins or tumor
  spillage
• 57 with macroscopically incomplete resection
  and 95 with mets
• LR at 2 years for patients with macroscopically
  CR
• 8.2 with TME alone
• 2.4 with combined treatment (p lt 0.001), HR
  3.42
• Overall survival and development of distant
  metastases not different
• More blood loss and perineal complications in RT
  patients
• No significant downstaging after SCRT if surgery
  within 10 days (less node)

Kapiteijn E, et al. NEJM 2001 345638
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Neoadjuvant RT Medium Course

• Italy
• Prospective single institution study
• 59 patients with resectable tumors, Stage II or
  III
• Within 8 cm of the anal verge, uT2/3, N0-1
• 45 Gy in 3 weeks (1.5 Gy fx bid)? EUS ? Surgery
  2-3 wks
• Post RT US agreed with path in 72
• Downstaged 25 by US, increase SSS by 50
  compared to controls
• pCR 8.5, rare cells seen in 69
• 2 year LR 12, (2 LR alone)
• 2 year DFS 77
• 2 year DFS 86 for pT0-1
• 2 year DFS 73 for pT2-3

• Bozzetti F, et al. Cancer 1999 86398

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Neoadjuvant CRT Long course

• MD Anderson
• 117 patients 1991-1995, single surgeon
• Locally advanced by exam, CT, EUS (26 stage I)
• Mean 5cm from anal verge (1-13 cm), 60
  circumferential
• 45 Gy (25 fx) 5FU 300mg/m2/d ? S after 6 wks
  ?Mayo x4-6 cycles
• 62 downstaged, 45 with gt1 T-stage level
  improvement
• 27 pCR 32
• 40 of patients with tumor lt 6 cm from AV avoided
  colostomy
• Tumors gt 5cm in size less likely to be downstaged
• Patients with downstaging more likely to have SP
• Less nodes involved in downstaged patients

Janjan et al. Int J Rad Onc Bio Phys 1999 441027
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Neoadjuvant CRT Long course

• Stanford
• 32 patients, Resectable, 1999-2001
• 19 uT3NO, 12 uT3N1, 1 uT2N1
• 50.4 Gy in 25 frx 5-FU 200mg/m2/d weekly
  CPT-11 50mg/m2 x 4
• Surgery 4-6 weeks post CRT (4-11 wks)
• No grade 4 toxicity, 25 grade 3
  diarrhea/mucositis/rectal sores
• 25 required chemotherapy dose reduction
• 100 uninvolved margins, 23 (71) downstaged,
  some change in surgery
• 37 pCR, rare cells in 34
• Of 13 uN, 11 had sterile nodes

Mehta et al. Int J Rad Onc Biol Phys 2003 55132
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Neoadjuvant CRT Long course

• French
• 40 operable patients
• T3/4 or T2N1 or T2 circumferential, PD, lt 5cm
  from the anus
• EUS, proctoscope, etc
• 3 field RT to 45 Gy in 25 fx boost to 50 Gy
• Oxaliplatin 130 mg/m2 day 1 and 39
• CIVI 5FU 350 mg/m2/d LV 100 mg/m2/d over 30 min
  d1-5 29-33
• 39 patients without treatment modifications
• Evaluation at 4 wks 75 with 50 reduction in
  tumor, 5 CR
• 100 gross resection, 38 with clear margins, SS
  65
• 15 pCR, 30 few cells

Gerard et al. 2003 211119
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Downstaging Timing of Surgery

• Studies with longer intervals b/w RT and S
  demonstrate significant downstaging, as high as
  50 with high dose RT
• Allow 4-12 weeks if downstaging/downsizing is the
  goal especially if in conjunction with SSS.
• French R09-01
• 201 patients T2/3, Nx
• RT 39 Gy in 13 frx
• Randomized surgery at 2 wks vs. 6-8 wks
• cRR 53 vs. 71
• pDS 10 vs. 26 (p.005)
• pCR 7 vs. 14 (ns)
• trend toward increased SSS

• Francois et al. JCO 1999 172396 Marijnen C, et
  al.. JCO 2001 191976. Gibbs et al. Dis Col
  Rectum March 2003
• Chen E, et al. Int J Rad Oncol Biol Phys 1994
  30169. Ngan SY, et al. Int J of Rad Onc 2001
  50883

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Sphincter Preservation
Preoperative RT and sphincter-preserving resection
Kachnic and Willett. Current Opinion in Onc 2001
13300
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(No Transcript)
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Neoadjuvant vs. Adjuvant RT

• Uppsala trial
• N471 5Gy x 5 vs. 2 Gy x 30
• 5y LR 13 vs. 22 (p.02)
• SB complications 5 vs. 11
• No difference in OS
• Colorectal Cancer Collaborative Group
  Meta-analysis
• 14 pre-op, 8 post-op trials (mostly without
  chemo) assessed effect of RT by BED
• 5y isolated LR 5y any R
• Pre-op 12.5 vs. 22.5 (plt.00001)
  46 vs. 53 (plt.00001)
• Post-op 15.3 vs. 22.9 (p.0002) 50 vs. 54
  (ns)
• 5y OS 45 vs. 42 favor RT
• 10y OS 27 vs. 25 favor RT
• Less rectal cancer specific death with pre-op
• Increased risk of non-rectal cancer death with RT
  (1 in 21)

• Frykholm G et al. Dis Colon Rectum 1993 36
  564-572 Lancet 2001 3581291
• Grann et. al. Dis Col Rectum 1997 40515 Gibbs
  et al. Dis Colon Rec. March 2003 p389 ASCO
  200120123a

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Neoadjuvant RT vs. CRT

• EORTC 22921
• Ongoing accrual
• Low dose bolus chemotherapy with RT.
• SCRT? S ? observation
• RT x5wks FU/LV weeks 15? S ? observation
• SCRT? S ? FU/LV x 4 months
• RT x 5 wks FU/LV wks 15? S ? FU/LV x 4 months

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Neoadjuvant vs. Adjuvant CRT

• NSABP R-03 and INT 1047
• Prospective Randomized Trials
• Resectable patients
• Closed because of low accrual

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Neoadjuvant vs. Adjuvant CRT

• German CAO/ARO/AIO-94
• uT3/4 or uN
• S vs. ?55.4 Gy ? 4 cycles adjuvant
• RT (2 x 25) CIVI wk 14 ? S ? 4 cycles adjuvant
• Surgery TME
• Completed accrual

Sauer et al. Int J Rad Onc Bio Phy 2000 48119
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NSABP R-04
Operable Stage II (N0 defined as lt 0.5 cm) or III
(N1 or 2 defined as gt 0.5 cm) Clinically staged
by endoluminal ultrasound and CT scan or MRI
Randomize
RT CIVI FU /- EPO
RT Cap /- EPO
lt 8 wks
lt 8 wks
Surgery
Intergroup E 3201
Adjuvant FU based therapy
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E 3201 Intergroup Rectal Adjuvant
R E G I S T E R
Group I Pre-op CRT
CPR-11/LV/infFU Oxal/LV/infFU LV-FU
Surgery
5FU/RT
MD Choice
NSABP R04
R E G I S T E R
CPT-11/LV/FU?FU/RT?CPT-11/LV/FU Oxal/LV/FU?FU/RT?
Oxal/LV/5FU LV/FU?FU/RT?LV/FU
Group II Post-op CRT
Surgery
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Studies Ongoing at Wash U

• Pharmacogenomics Selective pre-operative CRT
• 5-FU or 5-FU CPT-11 with RT depending on TS
• Pre-op weekly Ox CIVI 5-FU and RT Phase I/II
• Tumor within 12 cm of anal verge, fixed, T4 or
  uT3
• 50 Gy with surgery 4-6 weeks later
• Pre-RT PET with copper-60 labeled ATSM to assess
  tissue hypoxia and correlate with response

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Conclusions

• Goals of neoadjuvant therapy are varied
• Has advantages over adjuvant therapy
• All non-metastatic patients are candidates for
  pre-op RT or CRT
• Patient selection by detailed pre-op staging very
  important
• RT total dose/fraction/fields are not uniformly
  agreed upon
• Chemotherapy selection changing
• Optimal timing of surgery is not clear
• Neoadjuvant adjuvant therapy needed in many
  cases
• Potential to select the right therapy for each
  patient with tissue-based prognostic factors and
  pharmacogenomics