Adjuvant Chemotherapy by T3MNMo


									Adjuvant Chemotherapy

   Dr. Charles Butts
       Medical Oncologist
      Cross Cancer Institute
          Edmonton AB
                  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
                                  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.
                                    Mr. D.J.
• Pathology from the surgical specimen showed T3N2 low-grade

• 8/12 peri-colic nodes involved.

• Patient is referred for adjuvant therapy.
                         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.
                           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.
                           Mr. D.J.
• CT scan of chest, abdomen and pelvis showed no

• Post-operative CEA is in normal range
                              Practice Point
• What is the role for the increasing use of laparoscopic cancer

       • The Clinical Outcomes in Surgical Therapy Study Group (COST)
         (NEJM 2004;350:2050-9).

       • 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.
• 21% of patients originally planned for laparoscopic procedure were
  converted to open colectomy at the time of surgery due to

• 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).
• 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.
                                               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 2004;22: 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, > 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
                            Practice Point
• What adjuvant therapy would you recommend?

      •   FUFA (Mayo)
      •   FUFA (Roswell Park)
      •   Capecitabine
      •   FOLFOX4
      •   Other?
• 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.
                                     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%-

• 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.

• The X-ACT trial (NEJM 2005;352:2696-

• 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 2005;352:2696-2704.
                   X-ACT Trial

• A total of 1987 patients from 164 centers
  were randomized between 11/98 and

• The arms were well balanced for
  prognostic factors.

• Median follow-up was 3.8 years.
                              Twelves, C. et al. N Eng J Med 2005;352:2696-2704.
                                  Relapse-Free Survival (ITT)
                        1.0                                                   3-year
                                            Capecitabine (n=1004)             65.5%
                                            5-FU/LV (n=983)                   61.9%
Estimated probability

                        0.8                     HR = 0.86 (95% CI: 0.74–0.99)


                              0    1    2     3        4                5                 6

                                                        Twelves, C. et al. N Eng J Med 2005;352:2696-2704.
                                  Disease-Free Survival (ITT)
                        1.0                                                   3-year
                                            Capecitabine (n=1004)             64.2%
                                            5-FU/LV (n=983)                   60.6%
Estimated probability

                        0.8                     HR = 0.87 (95% CI: 0.75–1.00)


                              0    1    2     3        4                5                 6

                                                        Twelves, C. et al. N Eng J Med 2005;352:2696-2704.
                                  Trend to improved overall survival (ITT)
                        1.0                                                         3-year
                                                 Capecitabine (n=1004)              81.3%
                                                 5-FU/LV (n=983)                    77.6%
Estimated probability


                                                        HR = 0.84 (95% CI: 0.69–1.01)

                              0       1     2     3           4               5                 6

                                                              Twelves, C. et al. N Eng J Med 2005;352:2696-2704.
• 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 2005;352:2696-2704.
                          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

                                 FOLFOX4   LVFU2      Abs Δ

            DFS                   76.4%    69.8%     6.6% *           p < 0.001

             OS                   84.9%    82.8%      2.1%

           Stage II               85.1%    81.3%      3.8%

          Stage III               69.7%    61.0%     8.7% *

↑Risk Stage II Risk Reduction                         5.4%

Stage IIIA (N1) Risk Reduction                        7.2%

Stage IIIB (N2) Risk Reduction                       11.5%
          (>400 pts)
                                                   Andre, T. et al, NEJM, 350; (23) 2343-2351
                                                         DeGramont et al., Proc ASCO 2005
                               Mosaic Trial
                                        FOLFOX4                 LV5FU2
                                        (n= 1123)              (n= 1123)

    Median Follow-up (months)             56.2                      56.2

         Total # events (%)             279 (24.8)             345 (30.7)

Patients alive without recurrence (%)   844 (75.2)             778 (69.3)

 Patients alive with recurrence (%)      83 (7.4)              134 (11.9)

       Deaths all causes (%)            196 (17.5)             211 (18.8)
                                                    Andre, T. et al, NEJM, 350; (23) 2343-2351
                                                          DeGramont et al., Proc ASCO 2005
                                              Ongoing Follow-up
                                              FOLFOX4        LV5FU2
           Update      Median F/U                                          Δ
                                                OS             OS

          April 2003     37.9 m                78.2%         72.9%        5.3%

          June 2004      48.6 m                75.9%         69.1%        6.8%

          July 2005      56.2 m                76.4%         69.8%        6.6%

                                                                        FOLFOX4   LV5FU2
                                               Update      Median F/U                       Δ
                                                                          OS        OS

                                              April 2003     37.9 m      84.0%    81.9%    2.1%
                                  Stage III

                                              June 2004      48.6 m      79.2%    76.6%    2.6%

                                              July 2005      56.2 m      80.2%    77.0%    3.2%
• 3.4% of patients had persistent neuropathy at 4
               • 2.7% grade 3

               • 0.7% grade 4

  Grade              I                 II                             III                             IV                        V
                                                         mild objective weakness
                                                                                             objective weakness
 Neuropathy-                subjective weakness but      interfering with function,
                   normal                                                                 interfering with activities        paralysis
      motor                   no objective findings       but not interfering with
                                                                                                of daily living
                                                          activities of daily living
                               loss of deep tendon       objective sensory loss or
                                                                                              sensory loss or
                            reflexes or paresthesia         paresthesia (including                                      permanent sensory
 Neuropathy-                                                                              paresthesia interfering
                   normal    (including tingling) but     tingling), interfering with                                   loss that interferes
     sensory                                                                               with activities of daily
                                not interfering with    function, but not interfering                                      with function
                                      function          with activities of daily living

                                                                                                      Andre, T. et al, NEJM, 350; (23) 2343-2351
                                                                                                            DeGramont et al., Proc ASCO 2005
                     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
                           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
                         NSABP CO 7

                            FLOX                     FULV

DFS (mos)                                           71.6%
                          p < 0.004

    HR                      0.79
 [95% CI]               [0.67 – 0.93]

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
                      Oxaliplatin Benefit

             3y DFS             Δ              HR               p value

 CO7          76.5%           4/9%             0.79               0.004

Mosaic        77.9%           5.1%             0.77               0.001

   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
                                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
                         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

• The current generation of trials explores the addition of the
  monoclonal antibodies Bevacizumab or Cetuximab to
                        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.
•   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.

To top