Neoadjuvant Therapy for Rectal Cancer by mikesanye

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									Neoadjuvant Therapy for Rectal

      Luis C. Rodriguez, M.D.
                          Rectal Anatomy
 Portion                                   Left upper valve of Houston
              cm from
             anal verge
                                                               Right middle valve of Houston

upper 1/3         15

middle 1/3        10             Ampulla
                                   of                                      Left lower valve
                                 Rectum                                      of Houston

lower 1/3          6
                                                                      Pelvic size/structures: M vs. F

                                                                        Anal verge

                                 Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1197.
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+
• Radical surgery:
    – APR: permanent
    – AR: anastomosis
• Trans-anal excision

“ One of the worst scenarios (other
   than recurrence) is to end up with a
   perineal colostomy”
                   -N. Petrelli
                                          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                         >50%
                                       N+                         40-65%

McCall J, et al. Int J Colorectal Dis 1995 10. 126-132
Bokey EL, et al. BJS 1999; 86:1164.
Shirouzu et al., Am J. Surg 1993; 165:233
                                  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
O’Connell MJ, et al. NEJM 1994; 331:502.   NIH Concensus Conference JAMA 1990 264:1444
CCCG. Lancet 2001 358: 1291                NCCN Guidelines 2003
             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
                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
                                      Neoadjuvant RT
 Meta-analysis: RT+S 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

Cammá C, et al. JAMA 2000; 284:1008
               Neoadjuvant RT: Short Course
                                         Swedish Rectal Cancer Trial
   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 <4 field RT
   5 yr OS 54% vs. 48%
   Local Recurrence: 11% vs. 27%
   Recurrence was the same for type of surgery AR=APR
   Hard to know about downstaging effect
   Increased post-op fistulas, pelvic/fem fx, altered SP fnx with RT
NEJM 1997; 336:980 and 336:1539.
Swedish Rectal Cancer Trial. Initial results B J Surg 1993; 80:1333.
                  Neoadjuvant RT: Short Course
                                     Dutch Colorectal Cancer Study Group
      1805 eligible patients with resectable tumors (28% Stage I)
      Non-fixed tumors within <15 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 < 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; 345:638
     Neoadjuvant RT: Medium Course
 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; 86:398
    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 >1 T-stage level improvement
 27% pCR 32
 40% of patients with tumor < 6 cm from AV avoided colostomy
 Tumors > 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; 44:1027
   Neoadjuvant CRT: Long course
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; 55:132
  Neoadjuvant CRT: Long course
40 operable patients
T3/4 or T2N1+ or T2 circumferential, PD, < 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; 21:1119
        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; 17:2396                   Marijnen C, et al.. JCO 2001; 19:1976.                 Gibbs et al. Dis Col Rectum March 2003
Chen E, et al. Int J Rad Oncol Biol Phys 1994; 30:169.                   Ngan SY, et al. Int J of Rad Onc 2001; 50:883
                          Sphincter Preservation
         Preoperative RT and sphincter-preserving resection

Kachnic and Willett. Current Opinion in Onc 2001; 13:300

       "Locally advanced“
                                                               "Locally Advanced“ resectable
      Probably unresectable                                                                                                T1,2, N0
                                                                 Mobile, non-circumferential
  Fixed/tethered, circumferential                                                                                        Lower rectum
                                                                          T3 or N+
      near obstructing or T4

                                                                                                                                         local excision
                                        Preoperative RT +/- chemo                                Surgery
Preoperative long course RT +/- chemo               Or                               Pre-op Rx +/- chemo to facilitate
                                                                                                                                        endocavitary RT
                                           Post-op RT + chemo                               sphincter sparing
                                                                                                                                           with EBRT

                                                            Short course vs. long course RT + chemo

                                                                      Post op RT + chemo
           Neoadjuvant vs. Adjuvant RT
                                                              Uppsala trial
   N=471: 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% (p<.00001)                   46% vs. 53% (p<.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; 358:1291
Grann et. al. Dis Col Rectum 1997; 40:515         Gibbs et al. Dis Colon Rec. March 2003; p389   ASCO 2001;20:123a
       Neoadjuvant RT vs. CRT
                    EORTC 22921
Ongoing accrual
Low dose bolus chemotherapy with RT.
SCRT→ S → observation
RT x5wks + FU/LV weeks 1&5→ S → observation
SCRT→ S → FU/LV x 4 months
RT x 5 wks + FU/LV wks 1&5→ S → FU/LV x 4 months
 Neoadjuvant vs. Adjuvant CRT
        NSABP R-03 and INT 1047
Prospective Randomized Trials
Resectable patients
Closed because of low accrual
               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 1&4 → S → 4 cycles adjuvant
    • Surgery TME
    • Completed accrual

Sauer et al. Int J Rad Onc Bio Phy 2000; 48:119
                         NSABP R-04
Operable Stage II (N0 defined as < 0.5 cm) or III (N1 or 2 defined as > 0.5 cm)
Clinically staged by endoluminal ultrasound and CT scan or MRI


RT + Cap                                                      RT + CIVI FU
+/- EPO                                                       +/- EPO

        < 8 wks                                            < 8 wks

                        Intergroup E 3201

            Adjuvant FU based therapy
       E 3201: Intergroup Rectal Adjuvant
Group I                                          CPR-11/LV/infFU
                G                     Surgery
Pre-op CRT              5FU/RT                   Oxal/LV/infFU
                S                                LV-FU
  MD                                            NSABP R04
 Choice                 R
                        E        CPT-11/LV/FU→FU/RT→CPT-11/LV/FU
                        I        Oxal/LV/FU→FU/RT→Oxal/LV/5FU
Group II                S
              Surgery            LV/FU→FU/RT→LV/FU
Post-op CRT             T
    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
•   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

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