Rectal Carcinoma

1
Rectal Carcinoma

• Dr. Ralph Wong
• Medical Oncologist
• Cancer Care Manitoba
• Winnipeg, MB

2
Learning Objectives

• As a result of reading the following case study,
  physicians will be able to
• Discuss some controversies surrounding the
  peri-operative management of rectal carcinoma
• Review the data surrounding pre-operative vs.
  post-operative therapy of rectal carcinoma
• Discuss current management strategies in
  treatment protocols

3
Ms. K.L.

• 55 year male presents with three month history of
  rectal bleeding. No weight loss.
• Previously healthy.
• Physical exam normal. Rectal exam normal.

4
Ms. K.L.

• Labs
• WBC 4.5
• Hgb 100 microcytic, hypochromic
• Plt - normal
• LFTs normal
• Lytes,urea, creatinine normal
• Lower GI endoscopy
• ulcerating mass 10 cm from anal verge.
• Biopsy
• adenocarcinoma.

5
Practice Point

• In your practice, what other tests and
  investigations need to be done?
• CEA
• CT Chest/Abdo/Pelvis or CXR CT Abdo/Pelvis
• Endoscopic Ultrasound

6
Carcinoembryonic Antigen (CEA)

• Carcinoembryonic antigen (CEA) has been shown to
  have some prognostic value.
• If the CEA is elevated pre-operatively, this has
  been shown to correlate with a poor prognosis in
  node negative cancers.
• In addition an elevated white cell count greater
  than 10,000 or a elevated lactate dehydrogenase
  (LDH) have also been correlated with decreased
  survival.

7
Computed Tomography

• CT cannot distinguish the various layers within
  the wall of the gastrointestinal tract.
• Lymphadenopathy is usually defined as greater
  than 1 cm
• there is a poor correlation between lymph node
  size and content
• lymphadenopathy may be either secondary to an
  inflammatory reaction or malignant involvement.
• CT cannot accurately delineate the depth of
  rectal wall invasion (T stage) or the presence of
  metastatic lymph nodes (N stage).

8
Computed Tomography

• CT can assess tumour invasion beyond the rectal
  wall and distant metastatic disease.
• It has a sensitivity and specificity of 53 to
  100 and 27 to 67 respectively for the detection
  of extramural invasion of rectal cancer
• It has a 25 to 67 sensitivity with 53 to 85
  specificity for lymph node metastases

9
Magnetic Resonance Imaging

• Conventional MRI has a similar sensitivity and
  specificity as CT.
• Several MRI techniques can be used to increase
  the accuracy of this technique, i.e. endorectal
  coils.
• The overall accuracy of a conventional MRI has
  been reported to be 66 for tumour extension and
  72 for lymph node involvement.
• Determination of the T stage is more accurate
  using the endorectal coil.

10
Endoscopic Ultrasound

• In most comparative studies EUS has been shown to
  more accurate than digital examination or CT for
  local staging of rectal cancer.
• Numerous studies have found EUS is not only more
  accurate in evaluating for perirectal fat
  invasion but also for lymph node involvement and
  for depth of wall invasion.
• A meta analysis of 90 studies showed that for
  muscularis propria invasion, ultrasound and MR
  Imaging had similar sensitivities (94) while the
  specificity for ultrasound (86) was
  significantly higher than for MR Imaging (69).
• For perirectal tissue invasion the sensitivity of
  endoscopic ultrasound (90) was significantly
  higher than that of CT (79) and MR Imaging
  (82). Specificities were comparable.
• For adjacent organ invasion and lymph node
  involvement the sensitivities and specificities
  for all three modalities were comparable.

11
Endoscopic Ultrasound

• Endorectal ultrasound has the ability to
  determine the depth of tumour invasion within the
  bowel wall with an accuracy reported between 75
  and 94 when compared with the final pathologic
  stage.
• It is particularly accurate in excluding full
  thickness penetration of the rectal wall by
  tumour.

12
Ms. K.L.

• Evaluation by endoscopic ultrasound shows
• probable T3 lesion
• three 2 cm mesorectal lymph nodes.
• Evaluation by CT scan does not show evidence of
  metastatic disease.
• This patient is referred by the local surgeon for
  discussion of therapy.

13
Practice Point

• Given the findings, what is the most appropriate
  treatment recommendations?
• Pre-operative therapies
• Short course RT
• Long course chemoradiotherapy
• Post-operative chemoradiotherapy

14
Rectal Carcinoma

• There is a significant risk of loco-regional
  failure as the only or primary site of recurrence
  in patients with curatively resected rectal
  cancer
• Historically local recurrence rates have been as
  high as 30 with the main prognostic determinant
  being stage.
• Loco-regional failure is associated with
  significant morbidity.
• Most occur within 2 to 3 years and successful
  salvage is rare

15
Post-operative Therapy

• Until recently post-operative therapy has been
  the preferred management in North America.
• Two prospective randomized North American trials
  (The Gastrointestinal Tumour Study Group Protocol
  7175/North Central Cancer Treatment Group
  Protocol 79-47-51) demonstrated both an increase
  in local control, disease-free survival and
  overall survival when post-operative radiation
  was administered concurrently with chemotherapy
  after surgical resection
• Associated with significant grade 3 to 4
  toxicity.
• The advantage of this approach is that it allows
  for accurate determination of tumour stage and
  therefore patients with early stage (T1 T2, N0)
  or undetected metastatic disease may be spared
  adjuvant therapy.
• Radiotherapy given in these protocols appears to
  decrease local recurrence but not significantly
  improve survival. The 5-FU based chemotherapy
  has been demonstrated by the NSABP trials R-01
  and R-02 to be the component that improves
  survival.

16
Post-operative Therapy

• NSABP R-01 randomly assigned patients with high
  risk rectal cancers to observation, radiation
  therapy alone or chemotherapy alone after
  surgical resection.
• Adjuvant pelvic radiation resulted in improved
  local control whereas chemotherapy increased
  disease free and overall survival.
• Benefits with chemotherapy were restricted to
  male patients.
• The NSABP R-02 trial addressed the question of
  whether the addition of radiotherapy to
  chemotherapy would enhance the survival advantage
  in R-01
• Patients randomly assigned to receive radiation
  and chemotherapy had a significantly reduced
  loco-regional relapse rate compared to patients
  receiving chemotherapy alone
• No benefit was seen in disease free survival with
  the addition of radiotherapy.

17
How to deliver 5-FU

• The optimal 5-FU based delivery system for
  post-operative chemo/radiation therapy is also
  being looked at in a randomized study.
• The intergroup 86-47-51 trial suggested a 10
  survival advantage with the use of continuous
  infusion (CIVI) 5-FU throughout the course of
  radiotherapy compared to Bolus 5-FU
• The intergroup 0144 study compared continuous
  5-FU administered throughout the entire adjuvant
  chemotherapy course compared with Bolus 5-FU.
• Although the relapse free survival and overall
  survival rates were similar, the toxicity was
  significantly less in the continuous infusion
  5-FU arm.
• Despite the requirement for a indwelling
  catheter, CIVI 5-FU concurrent with radiotherapy
  has become the preferred method of delivering
  chemoradiotherapy in North America.

18
Practice Point

• The current acceptable post-operative combined
  modality therapy (CMT) for patients with stage II
  or III rectal cancer includes 4 cycles of Bolus
  5-FU with or without leucovorin and continuous
  infusion or Bolus 5-FU during 45 to 50 Gy of
  pelvic radiation.

19
Pre-operative Therapy

• Pre-operative treatment has now gaining
  acceptance as the standard adjuvant rectal cancer
  therapy.
• Potential advantages of this approach includes
• decreased tumour seeding
• enhanced radiosensitivity secondary to increased
  cell oxygenization
• visibility of the tumour volume for radiation
  planning
• improved sphincter presentation
• decreased likelihood of acute and delayed
  radiation injury to the small bowel.
• The primary disadvantage of this therapy is the
  potential for over treating patients with stage I
  or IV disease.
• This risk has been significantly decreased with
  the onset of EUS as part of the staging modality.

20
Swedish Rectal Trial

• The Swedish Rectal Cancer Trial
• Randomized 1,110 patients with clinically
  stagedT1-T3 rectal cancer to surgery alone versus
  pre-operative radiation (25 Gy in 5 fractions).
• After 5 years of follow-up the patients receiving
  radiotherapy halved the rate of local recurrence
  (11 versus 27)
• 10 absolute improvement in overall survival (58
  versus 48).

Swedish Rectal Trial Group, N Engl J Med
1997336 980-7
21
Dutch Rectal Trial

• Dutch colorectal cancer group trial failed to
  confirm any overall survival benefit using a
  similar fractionation scheme.
• They have confirmed that radiotherapy
  significantly decreases the risk of local
  recurrence.

Kapiteijn, E., et al., N Engl J Med, Vol. 345,
No. 9
22
North America

• In North America concurrent chemotherapy with
  long course radiotherapy (45 to 50.4 Gy) has been
  favoured by oncologists.
• The reported pathological complete response rates
  vary from 20 to 26 compared to 6 to 12 with
  radiotherapy alone.
• Using this pre-operative CMT approach
  approximately 60 to 80 of patients with distal
  rectal cancers can achieve sphincter sparing
  resection as an alternative to abdominal perineal
  resection (APR).
• This CMT strategy is being compared to
  pre-operative radiation alone in a number of
  on-going randomized trials.
• Preliminary information suggests that the use of
  pre-operative CMT increases pathological complete
  response but is balanced out by an increased
  grade 3 4 acute toxicity.

23
Pre-operative vs. Post-operative Radiation

• Three randomized trials have compared
  pre-operative versus post-operative adjuvant CMT
  for clinical resectable rectal cancers.
• The two North American trials (Intergroup 0147
  and NSABP R-03) were both closed due to lack of
  accrual.
• Preliminary results of the NSABP R-03 showed a
  trend to prolong the overall and disease free
  survival in favour of the pre-operative arm.
• These results will be difficult to interpret due
  to the premature closure of this trial.

24
Pre-operative vs. Post-operative Radiation

• In the CAO/ARO/AIO-94 study, 799 patients with
  clinical stage T3 or T4 or node positive disease
  were randomized to receive either pre-operative
  or post-operative long course CMT.
• In the pre-operative arm surgery was performed 6
  weeks after the completion of CMT.
• One month after surgery 4 cycles of Bolus 5
  fluorouracil were given. The endpoint was
  overall survival.
• With a median follow-up of 4 years the overall 5
  year survival rate was 76 versus 74
  respectively (P0.80).
• The 5 year cumulative incidence of local relapse
  was 6 for patients assigned to the pre-operative
  CMT and 13 for the post-operative treatment arm
  (P.006).
• Less grade 3/4 toxic events occurred in the
  pre-operative treatment group (20 versus 40
  P.001).
• There was also less rates of long term toxic
  effects (14 versus 24 P.01).
• The authors concluded that pre-operative
  chemoradiation improved local control and was
  associated with reduced toxicity but did not
  improve overall survival.
• On the basis of this trial, pre-operative
  chemoradiotherapy has now increasingly become the
  modality of choice in treatment of operative
  rectal cancer.

25
Therapy Choices

• Pre-operative therapy followed by total
  meso-rectal excision (TME) is currently becoming
  the widely accepted standard of care for the
  loco-regional management of rectal carcinoma.

26
Ms. K.L.

• The patient was referred to both medical and
  radiation oncology.
• She underwent long course pre-operative
  chemo/radiotherapy consisting of 5040 cGy
  delivered in fractions of 180 cGy per day, 5 days
  per week and 5-FU given CIVI throughout the
  course of radiotherapy.
• She developed grade 3 diarrhea and grade 1 nausea
  and vomiting.

27
Practice Point

• Is there further role for staging?
• The accuracy of EUS after neo-adjuvant therapy is
  decreased.
• Radiation therapy or CMT downstages tumours
  pathologically.
• Up to 20 of patients treated with pre-operative
  CMT have no evidence of residual tumour in their
  final pathology.
• The CAO/ARO/AIO-94 trial showed a complete
  response rate of 8.
• Pools of mucin, fibrosis and inflammation replace
  the tumour at pathologic analysis and these are
  indistinguishable from carcinoma under EUS.
• The evaluation of rectal tumours with EUS after
  radiation is inaccurate and unreliable and not
  recommended.
• This also is true for CT and MRI.

28
Ms. K.L.

• Patient subsequently underwent a low anterior
  resection.
• The final pathologic stage was a T2 N1(2 out of
  10 lymph nodes) M0 stage III rectal carcinoma.

29
Practice Point

• Is there a role for further therapy?
• Currently the subject of an NIH/NCI trial which
  is designed to determine whether the timing of
  surgery is significant.
• 6 arms with successively more chemotherapy being
  given pre-operatively

30
Post-operative Therapy

• The current standard of care in the adjuvant
  chemotherapy of rectal cancer is 5-fluorouracil
  with or without leucovorin.
• No trials documenting significant benefit but
  inference is made from the trials in stage III
  colon cancer

31
Post-operative Therapy

• In colon cancer a number of other
  chemotherapeutic drugs have been shown to
  efficacious in adjuvant therapy.
• Both oxaliplatin and capecitabine have shown to
  be superior to Bolus 5-FU based therapy in the
  treatment of stage III colon cancers.
• Capecitabine in particular is attractive because
  it can be given orally and obliviate the need for
  central lines.
• Phase I/II trials have shown that capecitabine in
  combination with radiation can be given with
  acceptable toxicity.
• Overall down staging occurs in approximately 70
  to 84 and pathological complete response is
  between 10 and 31 of patients.
• Both irinotecan and oxaliplatin have also been
  evaluated with radiotherapy in Phase I and Phase
  II trials.
• Acceptable toxicity and encouraging response
  rates have been seen with both drugs.
• However there have been no Phase III studies at
  this time. The routine use of capecitabine,
  oxaliplatin or irinotecan in the treatment of
  curative rectal cancer cannot be recommended
  outside the context of a clinical trial.

32
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