Adjuvant Chemotherapy

1
Adjuvant Chemotherapy

• Dr. Charles Butts
• Medical Oncologist
• Cross Cancer Institute
• Edmonton AB

2
Learning Objectives

• As a result of reading the following case study,
  physicians will be able to
• Discuss some controversies in immediate
  management of early stage colorectal carcinoma
• Review the treatments of adjuvant colon cancer
• Discuss future directions in treatment protocols

3
Mr. D.J.

• 50 year old male presented with rectal bleeding
  and was found to have lesion in sigmoid colon.
• Colonoscopy confirmed obstructing lesion in
  sigmoid and patient was referred for surgical
  resection.
• Initial attempt at laparoscopic resection was
  converted to open resection because of bleeding
  complications.
• Patient recovered from surgery well and was
  discharged within 1 week of surgery.

4
Mr. D.J.

• Pathology from the surgical specimen showed T3N2
  low-grade carcinoma
• 8/12 peri-colic nodes involved.
• Patient is referred for adjuvant therapy.

5
Mr. D.J.

• He has no significant past medical history nor
  drug allergies, and is on no medications.
• His only complaint is of bilateral thigh numbness
  and paresthesiae since the time of surgery.

6
Mr. D.J.

• Physical exam is negative aside from
• well healed incision
• objective decreased sensation in distribution of
  the lateral cutaneous nerve to thigh bilaterally.
  
• BSA is 2.63 m2.

7
Mr. D.J.

• CT scan of chest, abdomen and pelvis showed no
  abnormality
• Post-operative CEA is in normal range

8
Practice Point

• What is the role for the increasing use of
  laparoscopic cancer surgery?
• The Clinical Outcomes in Surgical Therapy Study
  Group (COST) (NEJM 20043502050-9).
• Randomized trial done in 48 centers in U.S. and
  Canada.
• 872 patients with resectable colon cancer were
  randomized to open or laparoscopicly assisted
  colectomy.
• The primary end-point was time to tumor
  recurrence.
• Secondary end-points included DFS,OS,
  complication rates, variables related to recovery
  , and QoL.

9
Results

• 21 of patients originally planned for
  laparoscopic procedure were converted to open
  colectomy at the time of surgery due to
  complications.
• OR times were also significantly longer with the
  laparoscopic approach (150 versus 95 minutes) but
  the extent of resection, resection margins, and
  numbers of nodes recovered were similar.
• There was no significant differences in
• the rate of recurrence
• overall survival
• recurrence in the surgical wound.
• The duration of hospitalization was shorter in
  the laparoscopic group, the difference amounted
  to 1 day (6 days versus 5 days).

10
Results

• Laparoscopic cancer surgery
• This important trial has put to rest many of the
  initial concerns regarding the role of
  laparoscopic colectomy, particularly the concern
  regarding wound recurrence.
• The increasing number of surgeons trained in
  these techniques and patient demand will
  certainly result in increased use in the future.

11
Practice Point

• What is the baseline risk for this patient for
  recurrence?
• One of the most important responsibilities of
  the medical oncologist in assessing a patient for
  adjuvant therapy is an assessment of the risk of
  relapse and the benefit of adjuvant therapy and
  conveying that information in a way that the
  patient can understand CB
• While the risk of relapse after surgical
  resection of node positive is generally quoted as
  50, clearly patients with N2 disease have a much
  higher risk.
• Gill et al (JCO 200422 1797-1806) presented
  pooled data from 7 randomized trials of 5-FU
  based chemotherapy versus surgery alone in
  patients with stage II and III colorectal cancer.
  
• This data is very useful in estimating baseline
  risk and potential benefit from adjuvant
  chemotherapy (5-FU based).
• The predicted 5 year DFS with surgery alone for a
  patient such as this (T3, gt 5 nodes , low grade)
  is 24 (19-31) and age-specific 5 year OS of
  35 (29-42).
• This data has been used to derive a model
  estimate for survival that can be accessed at
  www.mayoclinics.com/calcs.

12
Practice Point

• What adjuvant therapy would you recommend?
• FUFA (Mayo)
• FUFA (Roswell Park)
• Capecitabine
• FOLFOX4
• Other?

13
Treatment

• 5FU-based adjuvant regimens have long been the
  standard of care in colorectal cancer.
• Multiple randomized trials have shown consistent
  improvements in DFS and OS, particularly in
  patients with stage III (node positive) disease.
• Estimates of survival benefit of adjuvant therapy
  in subsets of patients has been refined in the
  previously cited article by Gill et al.

14
Mr. D.J.

• In the patient described in this case
• Estimated improvement in 5 year DFS is 24
  (19-31) for surgery alone to 43 (37-49) for
  5-FU chemotherapy.
• Actual 5 year DFS for similar patients in the
  pooled data was 26 surgery alone to 48 with the
  addition of adjuvant therapy.
• The 5 year OS estimate improves from 35
  (29-42) to 51 (45-57).
• While 5FU - based adjuvant therapy offers
  significant improvements in survival, randomized
  trials comparing 5-FU to capecitabine (X-ACT),
  FOLFOX (MOSAIC), and FLOX (NSABP CO-7) have lead
  to a change in the standard of care.

15
X-ACT

• The X-ACT trial (NEJM 20053522696-2704)
• Compared standard MAYO 5-FU/ Leucovorin to
  Capecitabine (1250 mg/m2 BID Day 1-14 q 3 weeks)
  in 1987 patients with stage III colorectal
  cancer.

Twelves, C. et al. N Eng J Med 20053522696-2704.
16
X-ACT Trial

• A total of 1987 patients from 164 centers were
  randomized between 11/98 and 11/01.
• The arms were well balanced for prognostic
  factors.
• Median follow-up was 3.8 years.

Twelves, C. et al. N Eng J Med 20053522696-2704.
17
Relapse-Free Survival (ITT)
Twelves, C. et al. N Eng J Med 20053522696-2704.
18
Disease-Free Survival (ITT)
3-year Capecitabine (n1 004) 64.2 5-FU/LV
(n983) 60.6
1.0 0.8 0.6 0.4
HR 0.87 (95 CI 0.751.00)p0.0528
Estimated probability
0 1 2 3 4 5 6
Years
Twelves, C. et al. N Eng J Med 20053522696-2704.
19
Trend to improved overall survival (ITT)
3-year Capecitabine (n1 004) 81.3 5-FU/LV
(n983) 77.6
1.0 0.8 0.6 0.4
Estimated probability
HR 0.84 (95 CI 0.691.01)p0.0706
0 1 2 3 4 5 6
Years
Twelves, C. et al. N Eng J Med 20053522696-2704.
20
X-ACT

• This trial had significant Canadian contribution
  (Drs. Alfred Wong and Jean Maroun were both
  co-authors)
• Results demonstrated that oral Capecitabine is
  better tolerated and at least equivalent to
  intravenous bolus 5-FU given on the Mayo clinic
  schedule.
• Despite the increased drug acquistion costs for
  Capecitabine, cost analysis suggests a slight
  cost saving overall.
• Oral route is generally favored by patients,
  results in significantly less clinic visits, and
  frees up considerable chair time in the
  chemotherapy unit.

Twelves, C. et al. N Eng J Med 20053522696-2704.
21
Mosaic Trial

• Adjuvant colon cancer
• 2246 patients divided equally between arms
• 40 Stage II
• 60 Stage III
• FOLFOX 4 vs. LVFU2 (de Gramont)
• 12 cycles planned
• Endpoint 3 yr DFS 79 vs. 73

Andre, T. et al, NEJM, 350 (23)
2343-2351 DeGramont et al., Proc ASCO 2005
22
Mosaic
p lt 0.001
(gt400 pts)
Andre, T. et al, NEJM, 350 (23)
2343-2351 DeGramont et al., Proc ASCO 2005
23
Mosaic Trial
Andre, T. et al, NEJM, 350 (23)
2343-2351 DeGramont et al., Proc ASCO 2005
24
Ongoing Follow-up
Overall
Stage III
25
Neuropathy

• 3.4 of patients had persistent neuropathy at 4
  years
• 2.7 grade 3
• 0.7 grade 4

Andre, T. et al, NEJM, 350 (23)
2343-2351 DeGramont et al., Proc ASCO 2005
26
NSABP CO7

• Between February 2000 and November 2002, 2,407
  patients with stage II (28.6) or III carcinoma
  of the colon were randomized.
• Arm A - FULV (5-FU, 500 mg/m2 iv bolus weekly x
  6 LV, 500 mg/m2 iv weekly x 6, each 8 week cycle
  x 3)
• Arm B - FLOX (same FULV regimen with oxaliplatin
  85 mg/m2 iv administered on weeks 1, 3, and 5 of
  each 8 week cycle x 3

Wolmark, N., et al, Proc ASCO 2005
27
NSABP CO 7

• Characteristics were monotonously well
  distributed
• Grade 3 neuropathy was noted to be 8 at end of
  therapy but decreased to 0.5 at 12 months post
• Cumulative dose of Oxaliplatin
• FOLFOX4 1020 mg/m2
• FLOX 765 mg/m2

Wolmark, N., et al, Proc ASCO 2005
28
NSABP CO 7
The global test of interaction between the
treatment and tumour stage was not significant
with a p value of 0.70
Wolmark, N., et al, Proc ASCO 2005
29
Oxaliplatin Benefit
The addition of Oxaliplatin to weekly bolus FU
infers a statistically significant 3y DFS in
patients with Stage II and III Colon Carcinoma
Wolmark, N., et al, Proc ASCO 2005
30
Practice Point

• Given this data, what should be offered to the
  patient in the case above?
• At the time this patient presented for
  evaluation, the updated data from the MOSAIC
  trial and the CO-7 trials were not available.
• The GI tumor group opinion was that the lack of
  survival advantage seen with FOLFOX, the toxicity
  and lack of coverage for oxaliplatin in the
  adjuvant setting did not justify its use outside
  of a clinical trial setting. He was therefore
  started on Capecitabine adjuvant therapy.
• With the new data available, a strong case would
  be made to offer FOLFOX to this patient. The N2
  nature of his primary and the subset analysis
  from the MOSAIC trial showing the greatest
  absolute difference in DFS in this group would
  support this recommendation.

31
Future Direction

• Further improvements in outcomes in the adjuvant
  setting will only come with well designed
  randomized trials.
• Recent reports from adjuvant trials of
  irinotecan/5-FU combination therapy have been
  negative and have relegated these regimens to the
  metastatic setting only.
• The standard arm for most controlled trials is
  the FOLFOX regimen.
• The current generation of trials explores the
  addition of the monoclonal antibodies Bevacizumab
  or Cetuximab to FOLFOX.

32
Future Direction

• The AVANT trial is a 3 arm randomized trial
  comparing FOLFOX as the reference standard to
  FOLFOX plus Bevacizumab or XELOX plus
  Bevacizumab.
• The primary end point is 3 year DFS (OS is a
  secondary end point) and the study is designed to
  detect a difference of 6 (72.2-77.8).
• Our patient was initially considered for this
  trial. He was deemed to be ineligible based on
  his baseline neuropathy, even though this was
  felt to be transitory and reversible.

33
Summary

• There now exist a number of options for adjuvant
  therapy after resection of stage III colorectal
  cancer.
• A thorough discussion of the baseline risk of
  recurrence, the expected benefits from adjuvant
  therapy, and the toxicity of this therapy is
  essential.
• Increasing evidence supports an incremental
  improvement in DFS from oxaliplatin based
  combination chemotherapy, which may be greatest
  in those at highest risk (N2).
• Further improvements may come from trials
  currently being conducted which explore the
  addition of monoclonal antibodies (Bevacizumab
  and Cetuximab) to oxaliplatin combinations .
• Such benefits, if realized are likely to be
  incremental, and will need to be weighed against
  the additional toxicity and cost of such regimens.