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 carcinoma • 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 abnormality • Post-operative CEA is in normal range Practice Point • What is the role for the increasing use of laparoscopic cancer surgery? • 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. 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). 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. 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 www.mayoclinics.com/calcs. Practice Point • What adjuvant therapy would you recommend? • FUFA (Mayo) • FUFA (Roswell Park) • Capecitabine • FOLFOX4 • Other? 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. 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. X-ACT • The X-ACT trial (NEJM 2005;352:2696- 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 2005;352:2696-2704. 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 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) p=0.0407 0.6 0.4 0 1 2 3 4 5 6 Years 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) p=0.0528 0.6 0.4 0 1 2 3 4 5 6 Years 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 0.8 0.6 HR = 0.84 (95% CI: 0.69–1.01) p=0.0706 0.4 0 1 2 3 4 5 6 Years Twelves, C. et al. N Eng J Med 2005;352:2696-2704. 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 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 Mosaic 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% Overall 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% Neuropathy • 3.4% of patients had persistent neuropathy at 4 years • 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 living 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 76.5% 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 recommendation. 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. 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. 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.
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